Sense (molecular biology)

Sense, when applied in a molecular biology context, is a general concept used to compare the polarity of nucleic acid molecules, such as DNA or RNA, to other nucleic acid molecules. Depending on the context within molecular biology, sense may have slightly different meanings.

DNA sense

Molecular biologists call a DNA single strand or sequence sense (or positive sense) if an RNA version of the same sequence is translated or translatable into protein, and they call its complement antisense (or negative sense). Sometimes the phrase coding strand is encountered; however, protein coding and non-coding RNA's can be transcribed similarly from both strands, in some cases being transcribed in both directions from a common promoter region, or being transcribed from within introns, on both strands.

Antisense DNA

Schematic showing how antisense DNA strands can interfere with protein translation.

Antisense molecules interact with complementary strands of nucleic acids, modifying expression of genes.

Some regions within a double strand of DNA code for genes, which are usually instructions specifying the order of amino acids in a protein along with regulatory sequences, splicing sites, noncoding introns and other complicating details. For a cell to use this information, one strand of the DNA serves as a template for the synthesis of a complementary strand of RNA. The template DNA strand is called the transcribed strand with antisense sequence and the mRNA transcript is said to be sense sequence (the complement of antisense). Because the DNA is double-stranded, the strand complementary to the antisense sequence is called non-transcribed strand and has the same sense sequence as the mRNA transcript (though T bases in DNA are substituted with U bases in RNA).

DNA strand 1: sense strand

DNA strand 2: antisense strand (copied to)→ RNA strand (sense)

Many forms of antisense have been developed and can be broadly categorized into enzyme-dependent antisense or steric blocking antisense.

Enzyme-dependent antisense includes forms dependent on RNase H activity to degrade target mRNA, including single-stranded DNA, RNA, and phosphorothioate antisense. The R1 plasmid hok/sok system is an example of mRNA antisense regulation process, through enzymatic degradation of the resulting RNA duplex. Double stranded RNA acts as enzyme-dependent antisense through the RNAi/siRNA pathway, involving target mRNA recognition through sense-antisense strand pairing followed by target mRNA degradation by the RNA-induced silencing complex (RISC).

Steric blocking antisense (RNase-H independent antisense) interferes with gene expression or other mRNA-dependent cellular processes by binding to a target sequence of mRNA and getting in the way of other processes. Steric blocking antisense includes 2'-O alkyl (usually in chimeras with RNase-H dependent antisense), peptide nucleic acid (PNA), locked nucleic acid (LNA) and Morpholino antisense.

Antisense nucleic acid molecules have been used experimentally to bind to mRNA and prevent expression of specific genes. Antisense therapies are also in development; in the USA, the Food and Drug Administration (FDA) has approved a phosphorothioate antisense oligo, fomivirsen (Vitravene), for human therapeutic use.

Cells can produce antisense RNA molecules naturally, which interact with complementary mRNA molecules and inhibit their expression.

Ambisense

A single-stranded genome which contains both positive-sense and negative-sense is said to be ambisense. Bunya viruses have 3 single-stranded RNA (ssRNA) fragments containing both positive-sense and negative-sense sections; arenaviruses are also ssRNA viruses with an ambisense genome, as they have 2 fragments which are mainly negative-sense except for part of the 5' ends of the large and small segments of their genome.

Antisense mRNA

Antisense mRNA is an mRNA transcript that is complementary to endogenous mRNA. In other words, it is a non-coding strand complementary to the coding sequence of mRNA; this is similar to negative-sense viral RNA. Introducing a transgene coding for antisense mRNA is a technique used to block expression of a gene of interest. Radioactively-labelled antisense mRNA can be used to show the level of transcription of genes in various cell types. Some alternative antisense structural types are being experimentally applied as antisense therapy, with at least one antisense therapy approved for use in humans.

RNA sense

In virology, the genome of a RNA virus can be said to be either positive-sense, also known as a "plus-strand", or negative-sense, also known as a "minus-strand". In most cases, the terms sense and strand are used interchangeably, making such terms as positive-strand equivalent to positive-sense, and plus-strand equivalent to plus-sense. Whether a virus is positive-sense or negative-sense can be used as a basis for classifiying viruses.

Positive-sense

Positive-sense (5' to 3') viral RNA signifies that a particular viral RNA sequence may be directly translated into the desired viral proteins. Therefore, in positive-sense RNA viruses, the viral RNA genome can be considered viral mRNA, and can be immediately translated by the host cell. Unlike negative-sense RNA, positive-sense RNA is of the same sense as mRNA. Some viruses (e.g. Coronaviridae) have positive-sense genomes which can act as mRNA and be used directly to synthesise proteins without the help of a complementary RNA intermediate. Because of this, these viruses do not need to have an RNA transcriptase packaged into the virion.

Negative-sense

Negative-sense (3' to 5') viral RNA is complementary to the viral mRNA and thus must be converted to positive-sense RNA by an RNA polymerase prior to translation. Negative-sense RNA (like DNA) has a nucleotide sequence complementary to the mRNA that it encodes. Like DNA, this RNA cannot be translated into protein directly. Instead, it must first be transcribed into a positive-sense RNA which acts as an mRNA. Some viruses (Influenza, for example) have negative-sense genomes and so must carry an RNA polymerase inside the virion.

Base pair

In molecular biology, two nucleotides on opposite complementary DNA or RNA strands that are connected via hydrogen bonds are called a base pair (often abbreviated bp). In the canonical Watson-Crick base pairing, adenine (A) forms a base pair with thymine (T), as does guanine (G) with cytosine (C) in DNA. In RNA, thymine is replaced by uracil (U). Non-Watson-Crick base pairing with alternate hydrogen bonding patterns also occur, especially in RNA; common such patterns are Hoogsteen base pairs. Pairing is also the mechanism by which codons on messenger RNA molecules are recognized by anticodons on transfer RNA during protein translation. Some DNA- or RNA-binding enzymes can recognize specific base pairing patterns that identify particular regulatory regions of genes.

The size of an individual gene or an organism's entire genome is often measured in base pairs because DNA is usually double-stranded. Hence, the number of total base pairs is equal to the number of nucleotides in one of the strands (with the exception of non-coding single-stranded regions of telomeres). The haploid human genome (23 chromosomes) is estimated to be about 3 billion base pairs long and to contain 20,000-25,000 distinct genes.

A kilobase (kb) is a unit of measurement in molecular biology equal to 1000 base pairs of DNA or RNA.

Examples

The following DNA sequences illustrate pair double-stranded patterns. By convention, the top strand is written from the 5' end to the 3' end; thus the bottom strand is written 3' to 5'.

A base-paired DNA sequence:

ATCGAT
TAGCTA

The corresponding RNA sequence, in which uracil is substituted for thymine:

AUCGAU

Length measurements

The following abbreviations are commonly used to describe the length of a DNA/RNA molecule:

• bp = base pair(s)—one bp corresponds to circa 3.4 Å of length along the strand
• kb (= kbp) = kilo base pairs = 1,000 bp
• Mb = mega base pairs = 1,000,000 bp
• Gb = giga base pairs = 1,000,000,000 bp

In case of single stranded DNA/RNA we talk about nucleotides, abbreviated nt (or knt, Mnt, Gnt), rather than base pairs, as they are not paired. For distinction between units of computer storage and bases kbp, Mbp, Gbp etc may be used for disambiguation.

The Centimorgan is also often used to imply distance along a chromosome, but the number of base-pairs it corresponds to varies widely. In the Human genome, it is about 1 million base pairs.

Hydrogen bonding and stability

A GC base pair demonstrating three intermolecular hydrogen bonds

An AT base pair demonstrating two intermolecular hydrogen bonds

Hydrogen bonding is the chemical mechanism that underlies the base-pairing rules described above. Appropriate geometrical correspondence of hydrogen bond donors and acceptors allows only the "right" pairs to form stably. DNA with high GC-content is more stable than DNA with low GC-content, but contrary to popular believe, the hydrogen bonds do not stabilize the DNA significantly and stabilization is mainly due to stacking interactions.

The larger nucleobases, adenine and guanine, are members of a class of doubly-ringed chemical structures called purines; the smaller nucleobases, cytosine and thymine (and uracil), are members of a class of singly-ringed chemical structures called pyrimidines. Purines are only complementary with pyrimidines: pyrimidine-pyrimidine pairings are energetically unfavorable because the molecules are too far apart for hydrogen bonding to be established; purine-purine pairings are energetically unfavorable because the molecules are too close, leading to electrostatic repulsion. The only other possible pairings are GT and AC; these pairings are mismatches because the pattern of hydrogen donors and acceptors do not correspond. (It should be noted that the GU pairing, with two hydrogen bonds, does occur fairly often in RNA but rarely in DNA.)

Paired DNA and RNA molecules are comparatively stable at room temperature but the two nucleotide strands will separate above a melting point that is determined by the length of the molecules, the extent of mispairing (if any), and the GC content. Higher GC content results in higher melting temperatures; it is therefore unsurprising that the genomes of extremophile organisms such as Thermus thermophilus are particularly GC-rich. Conversely, regions of a genome that need to separate frequently - for example, the promoter regions for often-transcribed genes - are comparatively GC-poor (for example, see TATA box). GC content and melting temperature must also be taken into account when designing primers for PCR reactions.

Base stacking

Base stacking interactions between the pi orbitals of the bases' aromatic rings also contribute to stability, and again GC stacking interactions with adjacent bases tend to be more favorable. (Note, though, that a GC stacking interaction with the next base pair is geometrically different from a CG interaction.) Base stacking effects are especially important in the secondary structure of RNA; for example, RNA stem-loop structures are stabilized by base stacking in the loop region.

Base analogs and intercalators

Chemical analogs of nucleotides can take the place of proper nucleotides and establish non-canonical base-pairing, leading to errors (mostly point mutations) in DNA replication and DNA transcription. One common mutagenic base analog is 5-bromouracil, which resembles thymine but can base-pair to guanine in its enol form.

Other chemicals, known as DNA intercalators, fit into the gap between adjacent bases on a single strand and induce frameshift mutations by "masquerading" as a base, causing the DNA replication machinery to skip or insert additional nucleotides at the intercalated site. Most intercalators are large polyaromatic compounds and are known or suspected carcinogens. Examples include ethidium bromide and acridine.

DNA

The structure of part of a DNA double helix

Deoxyribonucleic acid (DNA) is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms and some viruses. The main role of DNA molecules is the long-term storage of information. DNA is often compared to a set of blueprints or a recipe, or a code, since it contains the instructions needed to construct other components of cells, such as proteins and RNA molecules. The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in regulating the use of this genetic information.

Chemically, DNA consists of two long polymers of simple units called nucleotides, with backbones made of sugars and phosphate groups joined by ester bonds. These two strands run in opposite directions to each other and are therefore anti-parallel. Attached to each sugar is one of four types of molecules called bases. It is the sequence of these four bases along the backbone that encodes information. This information is read using the genetic code, which specifies the sequence of the amino acids within proteins. The code is read by copying stretches of DNA into the related nucleic acid RNA, in a process called transcription.

Within cells, DNA is organized into structures called chromosomes. These chromosomes are duplicated before cells divide, in a process called DNA replication. Eukaryotic organisms (animals, plants, fungi, and protists) store their DNA inside the cell nucleus, while in prokaryotes (bacteria and archae) it is found in the cell's cytoplasm. Within the chromosomes, chromatin proteins such as histones compact and organize DNA. These compact structures guide the interactions between DNA and other proteins, helping control which parts of the DNA are transcribed.

Properties

The chemical structure of DNA. Hydrogen bonds are shown as dotted lines.

DNA is a long polymer made from repeating units called nucleotides. The DNA chain is 22 to 26 Ångströms wide (2.2 to 2.6 nanometres), and one nucleotide unit is 3.3 Å (0.33 nm) long. Although each individual repeating unit is very small, DNA polymers can be enormous molecules containing millions of nucleotides. For instance, the largest human chromosome, chromosome number 1, is approximately 220 million base pairs long.

In living organisms, DNA does not usually exist as a single molecule, but instead as a tightly-associated pair of molecules. These two long strands entwine like vines, in the shape of a double helix. The nucleotide repeats contain both the segment of the backbone of the molecule, which holds the chain together, and a base, which interacts with the other DNA strand in the helix. In general, a base linked to a sugar is called a nucleoside and a base linked to a sugar and one or more phosphate groups is called a nucleotide. If multiple nucleotides are linked together, as in DNA, this polymer is called a polynucleotide.

The backbone of the DNA strand is made from alternating phosphate and sugar residues. The sugar in DNA is 2-deoxyribose, which is a pentose (five-carbon) sugar. The sugars are joined together by phosphate groups that form phosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings. These asymmetric bonds mean a strand of DNA has a direction. In a double helix the direction of the nucleotides in one strand is opposite to their direction in the other strand. This arrangement of DNA strands is called antiparallel. The asymmetric ends of DNA strands are referred to as the 5′ (five prime) and 3′ (three prime) ends, with the 5' end being that with a terminal phosphate group and the 3' end that with a terminal hydroxyl group. One of the major differences between DNA and RNA is the sugar, with 2-deoxyribose being replaced by the alternative pentose sugar ribose in RNA.

The DNA double helix is stabilized by hydrogen bonds between the bases attached to the two strands. The four bases found in DNA are adenine (abbreviated A), cytosine (C), guanine (G) and thymine (T). These four bases are attached to the sugar/phosphate to form the complete nucleotide, as shown for adenosine monophosphate.

These bases are classified into two types; adenine and guanine are fused five- and six-membered heterocyclic compounds called purines, while cytosine and thymine are six-membered rings called pyrimidines. A fifth pyrimidine base, called uracil (U), usually takes the place of thymine in RNA and differs from thymine by lacking a methyl group on its ring. Uracil is not usually found in DNA, occurring only as a breakdown product of cytosine.

Grooves

Animation of the structure of a section of DNA. The bases lie horizontally between the two spiraling strands. Large version

The double helix is a right-handed spiral. As the DNA strands wind around each other, they leave gaps between each set of phosphate backbones, revealing the sides of the bases inside (see animation). There are two of these grooves twisting around the surface of the double helix: one groove, the major groove, is 22 Å wide and the other, the minor groove, is 12 Å wide. The narrowness of the minor groove means that the edges of the bases are more accessible in the major groove. As a result, proteins like transcription factors that can bind to specific sequences in double-stranded DNA usually make contacts to the sides of the bases exposed in the major groove.

Base pairing

Each type of base on one strand forms a bond with just one type of base on the other strand. This is called complementary base pairing. Here, purines form hydrogen bonds to pyrimidines, with A bonding only to T, and C bonding only to G. This arrangement of two nucleotides binding together across the double helix is called a base pair. As hydrogen bonds are not covalent, they can be broken and rejoined relatively easily. The two strands of DNA in a double helix can therefore be pulled apart like a zipper, either by a mechanical force or high temperature. As a result of this complementarity, all the information in the double-stranded sequence of a DNA helix is duplicated on each strand, which is vital in DNA replication. Indeed, this reversible and specific interaction between complementary base pairs is critical for all the functions of DNA in living organisms.

Top, a GC base pair with three hydrogen bonds. Bottom, an AT base pair with two hydrogen bonds. Non-covalent hydrogen bonds between the pairs are shown as dashed lines.

The two types of base pairs form different numbers of hydrogen bonds, AT forming two hydrogen bonds, and GC forming three hydrogen bonds (see figures, left). DNA with high GC-content is more stable than DNA with low GC-content, but contrary to popular belief, this is not due to the extra hydrogen bond of a GC basepair but rather the contribution of stacking interactions (hydrogen bonding merely provides specificity of the pairing, not stability). As a result, it is both the percentage of GC base pairs and the overall length of a DNA double helix that determine the strength of the association between the two strands of DNA. Long DNA helices with a high GC content have stronger-interacting strands, while short helices with high AT content have weaker-interacting strands. In biology, parts of the DNA double helix that need to separate easily, such as the TATAAT Pribnow box in some promoters, tend to have a high AT content, making the strands easier to pull apart. In the laboratory, the strength of this interaction can be measured by finding the temperature required to break the hydrogen bonds, their melting temperature (also called Tm value). When all the base pairs in a DNA double helix melt, the strands separate and exist in solution as two entirely independent molecules. These single-stranded DNA molecules have no single common shape, but some conformations are more stable than others.

Sense and antisense

A DNA sequence is called "sense" if its sequence is the same as that of a messenger RNA copy that is translated into protein. The sequence on the opposite strand is called the "antisense" sequence. Both sense and antisense sequences can exist on different parts of the same strand of DNA (i.e. both strands contain both sense and antisense sequences). In both prokaryotes and eukaryotes, antisense RNA sequences are produced, but the functions of these RNAs are not entirely clear. One proposal is that antisense RNAs are involved in regulating gene expression through RNA-RNA base pairing.

A few DNA sequences in prokaryotes and eukaryotes, and more in plasmids and viruses, blur the distinction between sense and antisense strands by having overlapping genes. In these cases, some DNA sequences do double duty, encoding one protein when read along one strand, and a second protein when read in the opposite direction along the other strand. In bacteria, this overlap may be involved in the regulation of gene transcription, while in viruses, overlapping genes increase the amount of information that can be encoded within the small viral genome.

Supercoiling

DNA can be twisted like a rope in a process called DNA supercoiling. With DNA in its "relaxed" state, a strand usually circles the axis of the double helix once every 10.4 base pairs, but if the DNA is twisted the strands become more tightly or more loosely wound. If the DNA is twisted in the direction of the helix, this is positive supercoiling, and the bases are held more tightly together. If they are twisted in the opposite direction, this is negative supercoiling, and the bases come apart more easily. In nature, most DNA has slight negative supercoiling that is introduced by enzymes called topoisomerases. These enzymes are also needed to relieve the twisting stresses introduced into DNA strands during processes such as transcription and DNA replication.

From left to right, the structures of A, B and Z DNA

Alternative structures

DNA exists in many possible conformations. However, only A-DNA, B-DNA, and Z-DNA have been observed in organisms. Which conformation DNA adopts depends on the sequence of the DNA, the amount and direction of supercoiling, chemical modifications of the bases and also solution conditions, such as the concentration of metal ions and polyamines. Of these three conformations, the "B" form described above is most common under the conditions found in cells. The two alternative double-helical forms of DNA differ in their geometry and dimensions.

The A form is a wider right-handed spiral, with a shallow, wide minor groove and a narrower, deeper major groove. The A form occurs under non-physiological conditions in dehydrated samples of DNA, while in the cell it may be produced in hybrid pairings of DNA and RNA strands, as well as in enzyme-DNA complexes. Segments of DNA where the bases have been chemically-modified by methylation may undergo a larger change in conformation and adopt the Z form. Here, the strands turn about the helical axis in a left-handed spiral, the opposite of the more common B form. These unusual structures can be recognized by specific Z-DNA binding proteins and may be involved in the regulation of transcription.

Structure of a DNA quadruplex formed by telomere repeats. The conformation of the DNA backbone diverges significantly from the typical helical structure

Quadruplex structures

At the ends of the linear chromosomes are specialized regions of DNA called telomeres. The main function of these regions is to allow the cell to replicate chromosome ends using the enzyme telomerase, as the enzymes that normally replicate DNA cannot copy the extreme 3′ ends of chromosomes. These specialized chromosome caps also help protect the DNA ends, and stop the DNA repair systems in the cell from treating them as damage to be corrected. In human cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simple TTAGGG sequence.

These guanine-rich sequences may stabilize chromosome ends by forming structures of stacked sets of four-base units, rather than the usual base pairs found in other DNA molecules. Here, four guanine bases form a flat plate and these flat four-base units then stack on top of each other, to form a stable G-quadruplex structure. These structures are stabilized by hydrogen bonding between the edges of the bases and chelation of a metal ion in the centre of each four-base unit. Other structures can also be formed, with the central set of four bases coming from either a single strand folded around the bases, or several different parallel strands, each contributing one base to the central structure.

In addition to these stacked structures, telomeres also form large loop structures called telomere loops, or T-loops. Here, the single-stranded DNA curls around in a long circle stabilized by telomere-binding proteins. At the very end of the T-loop, the single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA and base pairing to one of the two strands. This triple-stranded structure is called a displacement loop or D-loop.

Chemical modifications

cytosine	5-methylcytosine	thymine

Structure of cytosine with and without the 5-methyl group. After deamination the 5-methylcytosine has the same structure as thymine

Base modifications

The expression of genes is influenced by how the DNA is packaged in chromosomes, in a structure called chromatin. Base modifications can be involved in packaging, with regions of that have low or no gene expression usually containing high levels of methylation of cytosine bases. For example, cytosine methylation, produces 5-methylcytosine, which is important for X-chromosome inactivation. The average level of methylation varies between organisms - the worm Caenorhabditis elegans lacks cytosine methylation, while vertebrates have higher levels, with up to 1% of their DNA containing 5-methylcytosine. Despite the importance of 5-methylcytosine, it can deaminate to leave a thymine base, methylated cytosines are therefore particularly prone to mutations. Other base modifications include adenine methylation in bacteria and the glycosylation of uracil to produce the "J-base" in kinetoplastids.

Damage

Benzopyrene, the major mutagen in tobacco smoke, in an adduct to DNA

DNA can be damaged by many different sorts of mutagens, which change the DNA sequence. Mutagens include oxidizing agents, alkylating agents and also high-energy electromagnetic radiation such as ultraviolet light and X-rays. The type of DNA damage produced depends on the type of mutagen. For example, UV light can damage DNA by producing thymine dimers, which are cross-links between pyrimidine bases. On the other hand, oxidants such as free radicals or hydrogen peroxide produce multiple forms of damage, including base modifications, particularly of guanosine, and double-strand breaks. In each human cell, about 500 bases suffer oxidative damage per day. Of these oxidative lesions, the most dangerous are double-strand breaks, as these are difficult to repair and can produce point mutations, insertions and deletions from the DNA sequence, as well as chromosomal translocations.

Many mutagens fit into the space between two adjacent base pairs, this is called intercalating. Most intercalators are aromatic and planar molecules, and include Ethidium bromide, daunomycin, and doxorubicin. In order for an intercalator to fit between base pairs, the bases must separate, distorting the DNA strands by unwinding of the double helix. This inhibits both transcription and DNA replication, causing toxicity and mutations. As a result, DNA intercalators are often carcinogens, and benzopyrene diol epoxide, acridines, aflatoxin and ethidium bromide are well-known examples. Nevertheless, due to their ability to inhibit DNA transcription and replication, these toxins are also used in chemotherapy to inhibit rapidly-growing cancer cells.

Biological functions

DNA usually occurs as linear chromosomes in eukaryotes, and circular chromosomes in prokaryotes. The set of chromosomes in a cell makes up its genome; the human genome has approximately 3 billion base pairs of DNA arranged into 46 chromosomes. The information carried by DNA is held in the sequence of pieces of DNA called genes. Transmission of genetic information in genes is achieved via complementary base pairing. For example, in transcription, when a cell uses the information in a gene, the DNA sequence is copied into a complementary RNA sequence through the attraction between the DNA and the correct RNA nucleotides. Usually, this RNA copy is then used to make a matching protein sequence in a process called translation which depends on the same interaction between RNA nucleotides. Alternatively, a cell may simply copy its genetic information in a process called DNA replication. The details of these functions are covered in other articles; here we focus on the interactions between DNA and other molecules that mediate the function of the genome.

Genes and genomes

Genomic DNA is located in the cell nucleus of eukaryotes, as well as small amounts in mitochondria and chloroplasts. In prokaryotes, the DNA is held within an irregularly shaped body in the cytoplasm called the nucleoid. The genetic information in a genome is held within genes, and the complete set of this information in an organism is called its genotype. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, as well as regulatory sequences such as promoters and enhancers, which control the transcription of the open reading frame.

In many species, only a small fraction of the total sequence of the genome encodes protein. For example, only about 1.5% of the human genome consists of protein-coding exons, with over 50% of human DNA consisting of non-coding repetitive sequences. The reasons for the presence of so much non-coding DNA in eukaryotic genomes and the extraordinary differences in genome size, or C-value, among species represent a long-standing puzzle known as the "C-value enigma." However, DNA sequences that do not code protein may still encode functional non-coding RNA molecules, which are involved in the regulation of gene expression.

T7 RNA polymerase (blue) producing a mRNA (green) from a DNA template (orange).

Some non-coding DNA sequences play structural roles in chromosomes. Telomeres and centromeres typically contain few genes, but are important for the function and stability of chromosomes. An abundant form of non-coding DNA in humans are pseudogenes, which are copies of genes that have been disabled by mutation. These sequences are usually just molecular fossils, although they can occasionally serve as raw genetic material for the creation of new genes through the process of gene duplication and divergence.

Transcription and translation

A gene is a sequence of DNA that contains genetic information and can influence the phenotype of an organism. Within a gene, the sequence of bases along a DNA strand defines a messenger RNA sequence, which then defines one or more protein sequences. The relationship between the nucleotide sequences of genes and the amino-acid sequences of proteins is determined by the rules of translation, known collectively as the genetic code. The genetic code consists of three-letter 'words' called codons formed from a sequence of three nucleotides (e.g. ACT, CAG, TTT).

In transcription, the codons of a gene are copied into messenger RNA by RNA polymerase. This RNA copy is then decoded by a ribosome that reads the RNA sequence by base-pairing the messenger RNA to transfer RNA, which carries amino acids. Since there are 4 bases in 3-letter combinations, there are 64 possible codons (43 combinations). These encode the twenty standard amino acids, giving most amino acids more than one possible codon. There are also three 'stop' or 'nonsense' codons signifying the end of the coding region; these are the TAA, TGA and TAG codons.

DNA replication. The double helix is unwound by a helicase and topoisomerase. Next, one DNA polymerase produces the leading strand copy. Another DNA polymerase binds to the lagging strand. This enzyme makes discontinuous segments (called Okazaki fragments) before DNA ligase joins them together.

Replication

Cell division is essential for an organism to grow, but when a cell divides it must replicate the DNA in its genome so that the two daughter cells have the same genetic information as their parent. The double-stranded structure of DNA provides a simple mechanism for DNA replication. Here, the two strands are separated and then each strand's complementary DNA sequence is recreated by an enzyme called DNA polymerase. This enzyme makes the complementary strand by finding the correct base through complementary base pairing, and bonding it onto the original strand. As DNA polymerases can only extend a DNA strand in a 5′ to 3′ direction, different mechanisms are used to copy the antiparallel strands of the double helix. In this way, the base on the old strand dictates which base appears on the new strand, and the cell ends up with a perfect copy of its DNA.

Interactions with proteins

All the functions of DNA depend on interactions with proteins. These protein interactions can be non-specific, or the protein can bind specifically to a single DNA sequence. Enzymes can also bind to DNA and of these, the polymerases that copy the DNA base sequence in transcription and DNA replication are particularly important.

DNA-binding proteins

Interaction of DNA with histones (shown in white, top). These proteins' basic amino acids (below left, blue) bind to the acidic phosphate groups on DNA (below right, red).

Structural proteins that bind DNA are well-understood examples of non-specific DNA-protein interactions. Within chromosomes, DNA is held in complexes with structural proteins. These proteins organize the DNA into a compact structure called chromatin. In eukaryotes this structure involves DNA binding to a complex of small basic proteins called histones, while in prokaryotes multiple types of proteins are involved. The histones form a disk-shaped complex called a nucleosome, which contains two complete turns of double-stranded DNA wrapped around its surface. These non-specific interactions are formed through basic residues in the histones making ionic bonds to the acidic sugar-phosphate backbone of the DNA, and are therefore largely independent of the base sequence. Chemical modifications of these basic amino acid residues include methylation, phosphorylation and acetylation. These chemical changes alter the strength of the interaction between the DNA and the histones, making the DNA more or less accessible to transcription factors and changing the rate of transcription. Other non-specific DNA-binding proteins in chromatin include the high-mobility group proteins, which bind to bent or distorted DNA. These proteins are important in bending arrays of nucleosomes and arranging them into the larger structures that make up chromosomes.

A distinct group of DNA-binding proteins are the DNA-binding proteins that specifically bind single-stranded DNA. In humans, replication protein A is the best-understood member of this family and is used in processes where the double helix is separated, including DNA replication, recombination and DNA repair. These binding proteins seem to stabilize single-stranded DNA and protect it from forming stem-loops or being degraded by nucleases.

The lambda repressor helix-turn-helix transcription factor bound to its DNA target

In contrast, other proteins have evolved to bind particular DNA sequences. The most intensively-studied of these are the various transcription factors, which are proteins that regulate transcription. Each transcription factor binds to one particular set of DNA sequences and activates or inhibits the transcription of genes that have these sequences close to their promoters. The transcription factors do this in two ways. Firstly, they can bind the RNA polymerase responsible for transcription, either directly or through other mediator proteins; this locates the polymerase at the promoter and allows it to begin transcription. Alternatively, transcription factors can bind enzymes that modify the histones at the promoter; this will change the accessibility of the DNA template to the polymerase.

As these DNA targets can occur throughout an organism's genome, changes in the activity of one type of transcription factor can affect thousands of genes. Consequently, these proteins are often the targets of the signal transduction processes that control responses to environmental changes or cellular differentiation and development. The specificity of these transcription factors' interactions with DNA come from the proteins making multiple contacts to the edges of the DNA bases, allowing them to "read" the DNA sequence. Most of these base-interactions are made in the major groove, where the bases are most accessible.

The restriction enzyme EcoRV (green) in a complex with its substrate DNA

DNA-modifying enzymes

Nucleases and ligases

Nucleases are enzymes that cut DNA strands by catalyzing the hydrolysis of the phosphodiester bonds. Nucleases that hydrolyse nucleotides from the ends of DNA strands are called exonucleases, while endonucleases cut within strands. The most frequently-used nucleases in molecular biology are the restriction endonucleases, which cut DNA at specific sequences. For instance, the EcoRV enzyme shown to the left recognizes the 6-base sequence 5′-GAT|ATC-3′ and makes a cut at the vertical line. In nature, these enzymes protect bacteria against phage infection by digesting the phage DNA when it enters the bacterial cell, acting as part of the restriction modification system. In technology, these sequence-specific nucleases are used in molecular cloning and DNA fingerprinting.

Enzymes called DNA ligases can rejoin cut or broken DNA strands. Ligases are particularly important in lagging strand DNA replication, as they join together the short segments of DNA produced at the replication fork into a complete copy of the DNA template. They are also used in DNA repair and genetic recombination.

Topoisomerases and helicases

Topoisomerases are enzymes with both nuclease and ligase activity. These proteins change the amount of supercoiling in DNA. Some of these enzyme work by cutting the DNA helix and allowing one section to rotate, thereby reducing its level of supercoiling; the enzyme then seals the DNA break. Other types of these enzymes are capable of cutting one DNA helix and then passing a second strand of DNA through this break, before rejoining the helix. Topoisomerases are required for many processes involving DNA, such as DNA replication and transcription.

Helicases are proteins that are a type of molecular motor. They use the chemical energy in nucleoside triphosphates, predominantly ATP, to break hydrogen bonds between bases and unwind the DNA double helix into single strands. These enzymes are essential for most processes where enzymes need to access the DNA bases.

Polymerases

Polymerases are enzymes that synthesize polynucleotide chains from nucleoside triphosphates. The sequence of their products are copies of existing polynucleotide chains - which are called templates. These enzymes function by adding nucleotides onto the 3′ hydroxyl group of the previous nucleotide in a DNA strand. Consequently, all polymerases work in a 5′ to 3′ direction. In the active site of these enzymes, the incoming nucleoside triphosphate base-pairs to the template: this allows polymerases to accurately synthesize the complementary strand of their template. Polymerases are classified according to the type of template that they use.

In DNA replication, a DNA-dependent DNA polymerase makes a DNA copy of a DNA sequence. Accuracy is vital in this process, so many of these polymerases have a proofreading activity. Here, the polymerase recognizes the occasional mistakes in the synthesis reaction by the lack of base pairing between the mismatched nucleotides. If a mismatch is detected, a 3′ to 5′ exonuclease activity is activated and the incorrect base removed. In most organisms DNA polymerases function in a large complex called the replisome that contains multiple accessory subunits, such as the DNA clamp or helicases.

RNA-dependent DNA polymerases are a specialized class of polymerases that copy the sequence of an RNA strand into DNA. They include reverse transcriptase, which is a viral enzyme involved in the infection of cells by retroviruses, and telomerase, which is required for the replication of telomeres. Telomerase is an unusual polymerase because it contains its own RNA template as part of its structure.

Transcription is carried out by a DNA-dependent RNA polymerase that copies the sequence of a DNA strand into RNA. To begin transcribing a gene, the RNA polymerase binds to a sequence of DNA called a promoter and separates the DNA strands. It then copies the gene sequence into a messenger RNA transcript until it reaches a region of DNA called the terminator, where it halts and detaches from the DNA. As with human DNA-dependent DNA polymerases, RNA polymerase II, the enzyme that transcribes most of the genes in the human genome, operates as part of a large protein complex with multiple regulatory and accessory subunits.

Genetic recombination

Structure of the Holliday junction intermediate in genetic recombination. The four separate DNA strands are coloured red, blue, green and yellow.

Recombination involves the breakage and rejoining of two chromosomes (M and F) to produce two re-arranged chromosomes (C1 and C2).

A DNA helix usually does not interact with other segments of DNA, and in human cells the different chromosomes even occupy separate areas in the nucleus called "chromosome territories". This physical separation of different chromosomes is important for the ability of DNA to function as a stable repository for information, as one of the few times chromosomes interact is during chromosomal crossover when they recombine. Chromosomal crossover is when two DNA helices break, swap a section and then rejoin.

Recombination allows chromosomes to exchange genetic information and produces new combinations of genes, which increases the efficiency of natural selection and can be important in the rapid evolution of new proteins. Genetic recombination can also be involved in DNA repair, particularly in the cell's response to double-strand breaks.

The most common form of chromosomal crossover is homologous recombination, where the two chromosomes involved share very similar sequences. Non-homologous recombination can be damaging to cells, as it can produce chromosomal translocations and genetic abnormalities. The recombination reaction is catalyzed by enzymes known as recombinases, such as RAD51. The first step in recombination is a double-stranded break either caused by an endonuclease or damage to the DNA. A series of steps catalyzed in part by the recombinase then leads to joining of the two helices by at least one Holliday junction, in which a segment of a single strand in each helix is annealed to the complementary strand in the other helix. The Holliday junction is a tetrahedral junction structure that can be moved along the pair of chromosomes, swapping one strand for another. The recombination reaction is then halted by cleavage of the junction and re-ligation of the released DNA.

Evolution

DNA contains the genetic information that allows all modern living things to function, grow and reproduce. However, it is unclear how long in the 4-billion-year history of life DNA has performed this function, as it has been proposed that the earliest forms of life may have used RNA as their genetic material. RNA may have acted as the central part of early cell metabolism as it can both transmit genetic information and carry out catalysis as part of ribozymes. This ancient RNA world where nucleic acid would have been used for both catalysis and genetics may have influenced the evolution of the current genetic code based on four nucleotide bases. This would occur since the number of unique bases in such an organism is a trade-off between a small number of bases increasing replication accuracy and a large number of bases increasing the catalytic efficiency of ribozymes.

Unfortunately, there is no direct evidence of ancient genetic systems, as recovery of DNA from most fossils is impossible. This is because DNA will survive in the environment for less than one million years and slowly degrades into short fragments in solution. Claims for older DNA have been made, most notably a report of the isolation of a viable bacterium from a salt crystal 250-million years old, but these claims are controversial.

Uses in technology

Genetic engineering

Methods have been developed to purify DNA from organisms, such as phenol-chloroform extraction and manipulate it in the laboratory, such as restriction digests and the polymerase chain reaction. Modern biology and biochemistry make intensive use of these techniques in recombinant DNA technology. Recombinant DNA is a man-made DNA sequence that has been assembled from other DNA sequences. They can be transformed into organisms in the form of plasmids or in the appropriate format, by using a viral vector. The genetically modified organisms produced can be used to produce products such as recombinant proteins, used in medical research, or be grown in agriculture.

Forensics

Forensic scientists can use DNA in blood, semen, skin, saliva or hair found at a crime scene to identify a matching DNA of an individual, such as a perpetrator. This process is called genetic fingerprinting, or more accurately, DNA profiling. In DNA profiling, the lengths of variable sections of repetitive DNA, such as short tandem repeats and minisatellites, are compared between people. This method is usually an extremely reliable technique for identifying a matching DNA. However, identification can be complicated if the scene is contaminated with DNA from several people. DNA profiling was developed in 1984 by British geneticist Sir Alec Jeffreys, and first used in forensic science to convict Colin Pitchfork in the 1988 Enderby murders case.

People convicted of certain types of crimes may be required to provide a sample of DNA for a database. This has helped investigators solve old cases where only a DNA sample was obtained from the scene. DNA profiling can also be used to identify victims of mass casualty incidents. On the other hand, many convicted people have been released from prison on the basis of DNA techniques, which were not available when a crime had originally been committed.

Bioinformatics

Bioinformatics involves the manipulation, searching, and data mining of DNA sequence data. The development of techniques to store and search DNA sequences have led to widely-applied advances in computer science, especially string searching algorithms, machine learning and database theory. String searching or matching algorithms, which find an occurrence of a sequence of letters inside a larger sequence of letters, were developed to search for specific sequences of nucleotides. In other applications such as text editors, even simple algorithms for this problem usually suffice, but DNA sequences cause these algorithms to exhibit near-worst-case behaviour due to their small number of distinct characters. The related problem of sequence alignment aims to identify homologous sequences and locate the specific mutations that make them distinct. These techniques, especially multiple sequence alignment, are used in studying phylogenetic relationships and protein function. Data sets representing entire genomes' worth of DNA sequences, such as those produced by the Human Genome Project, are difficult to use without annotations, which label the locations of genes and regulatory elements on each chromosome. Regions of DNA sequence that have the characteristic patterns associated with protein- or RNA-coding genes can be identified by gene finding algorithms, which allow researchers to predict the presence of particular gene products in an organism even before they have been isolated experimentally.

DNA nanotechnology

The DNA structure at left (schematic shown) will self-assemble into the structure visualized by atomic force microscopy at right. DNA nanotechnology is the field which seeks to design nanoscale structures using the molecular recognition properties of DNA molecules. Image from Strong, 2004.

DNA nanotechnology uses the unique molecular recognition properties of DNA and other nucleic acids to create self-assembling branched DNA complexes with useful properties. DNA is thus used as a structural material rather than as a carrier of biological information. This has led to the creation of two-dimensional periodic lattices (both tile-based as well as using the "DNA origami" method) as well as three-dimensional structures in the shapes of polyhedra. Nanomechanical devices and algorithmic self-assembly have also been demonstrated, and these DNA structures have been used to template the arrangement of other molecules such as gold nanoparticles and streptavidin proteins.

History and anthropology

Because DNA collects mutations over time, which are then inherited, it contains historical information and by comparing DNA sequences, geneticists can infer the evolutionary history of organisms, their phylogeny. This field of phylogenetics is a powerful tool in evolutionary biology. If DNA sequences within a species are compared, population geneticists can learn the history of particular populations. This can be used in studies ranging from ecological genetics to anthropology; for example, DNA evidence is being used to try to identify the Ten Lost Tribes of Israel.

DNA has also been used to look at modern family relationships, such as establishing family relationships between the descendants of Sally Hemings and Thomas Jefferson. This usage is closely related to the use of DNA in criminal investigations detailed above. Indeed, some criminal investigations have been solved when DNA from crime scenes has matched relatives of the guilty individual.

History of DNA research

James Watson

Francis Crick

Rosalind Franklin

DNA was first isolated by the Swiss physician Friedrich Miescher who, in 1869, discovered a microscopic substance in the pus of discarded surgical bandages. As it resided in the nuclei of cells, he called it "nuclein". In 1919 this discovery was followed by Phoebus Levene's identification of the base, sugar and phosphate nucleotide unit. Levene suggested that DNA consisted of a string of nucleotide units linked together through the phosphate groups. However, Levene thought the chain was short and the bases repeated in a fixed order. In 1937 William Astbury produced the first X-ray diffraction patterns that showed that DNA had a regular structure.

In 1928, Frederick Griffith discovered that traits of the "smooth" form of the Pneumococcus could be transferred to the "rough" form of the same bacteria by mixing killed "smooth" bacteria with the live "rough" form. This system provided the first clear suggestion that DNA carried genetic information, when Oswald Avery, along with coworkers Colin MacLeod and Maclyn McCarty, identified DNA as the transforming principle in 1943. DNA's role in heredity was confirmed in 1952, when Alfred Hershey and Martha Chase in the Hershey-Chase experiment showed that DNA is the genetic material of the T2 phage.

In 1953, based on X-ray diffraction images taken by Rosalind Franklin and the information that the bases were paired, James D. Watson and Francis Crick suggested what is now accepted as the first accurate model of DNA structure in the journal Nature. Experimental evidence for Watson and Crick's model were published in a series of five articles in the same issue of Nature. Of these, Franklin and Raymond Gosling's paper was the first publication of X-ray diffraction data that supported the Watson and Crick model, this issue also contained an article on DNA structure by Maurice Wilkins and his colleagues. In 1962, after Franklin's death, Watson, Crick, and Wilkins jointly received the Nobel Prize in Physiology or Medicine. However, debate continues on who should receive credit for the discovery.

In an influential presentation in 1957, Crick laid out the "Central Dogma" of molecular biology, which foretold the relationship between DNA, RNA, and proteins, and articulated the "adaptor hypothesis". Final confirmation of the replication mechanism that was implied by the double-helical structure followed in 1958 through the Meselson-Stahl experiment. Further work by Crick and coworkers showed that the genetic code was based on non-overlapping triplets of bases, called codons, allowing Har Gobind Khorana, Robert W. Holley and Marshall Warren Nirenberg to decipher the genetic code. These findings represent the birth of molecular biology.

Cat eye syndrome

Cat Eye Syndrome is a very rare malformation involving Chromosome 22. The short arm (p) and a small section of the long arm (q) are present three (trisomic) or four times (tetrasomic) instead of the usual two times. The additional chromosome 22 usually arises spontaneously (de novo), though it has been reported to have been passed down in families, and some reports show the parents as mosaic for the marker chromosome but who show no phenotypic (outer) symptoms of the syndrome.

The chromosomal area included in the Cat Eye Syndrome "critical region" is 22pter-->q11.

Partial trisomy of chromosome 22 resulting from an interstitial duplication of 22q11.2 in a child with typical cat eye syndrome

History

The first association of the common abnormalities common to CES was established over 100 years ago (1898) by Haab, and first described in association with a small marker chromosome in 1965 by Schachenmann.

A first report of a familial trisomy 22 pter-->q11happened in 1972 by Bühler et al. Early reports of Cat Eye Syndrome discuss the possibility of chromosome 13 involvement. Now, CES is considered to be present with the chromosome 22 trisomy findings.

Genetics

22q11.2 is a very unstable region of chromosome 22, which is involved in other syndromes, such as 22q11 deletion (a microdeletion of that area of the chromosome) and supernumerary der(22) syndrome, also known as trisomy 22 or partial trisomy 11/22.

Presentation

The most common association of symptoms include coloboma of the iris, renal abnormalities, and imperforate anus. Life expectancy is not significantly reduced in those patients who do not present with life threatening abnormalities.

The term "Cat Eye" syndrome was coined due to the particular appearance of the vertical colobomas in the eyes of some patients. However, over 1/2 of the CES patients in the literature do not display this trait.

Characteristics

• Anal atresia (abnormal obstruction of the anus)
• Unilateral or bilateral iris coloboma (absence of tissue from the colored part of the eyes)
• Palpebral fissures (downward slanting openings between the upper and lower eyelids)
• Preauricular pits/tags (small depressions/growths of skin on the outer ears)
• Cardiac defects
• Kidney problems (missing, extra, or underdeveloped kidneys)
• Short stature
• Scoliosis/Skeletal problems
• Mental retardation -- although most are borderline normal to mildly retarded, and a few even have normal intelligence, CES patients occasionally exhibit moderate to severe retardation.
• Micrognathia (smaller jaw)
Hernias
Cleft palate
• Rarer malformations can affect almost any organ

Small supernumerary marker chromosome

Humans typically have 22 pairs of autosomal chromosomes in our cells, and a pair of sex chromosomes. About 2.7 million individuals have an extra, 47th autosomal chromosome called a small supernumerary marker chromosome (sSMC). These small supernumerary marker chromosomes can originate from any of the 24 different human chromosomes. About 70% of the cases with sSMC are de novo (new mutations), 30% are inherited within a family.

About 30% of the carriers of a sSMC are clinically abnormal. The main problem in connection with a sSMC appears when the diagnosis of the presence of a sSMC is made prenatally. Until recently there was no possibility to make clear predictions about the outcome of the pregnancy. However, research is being carried out into the link between the presence of a sSMC in individuals and any consequent symptoms.

Triple X syndrome

Triple X syndrome is a form of chromosomal variation characterized by the presence of an extra X chromosome in each cell of a human female. The condition is also known as triplo-X, trisomy X, XXX syndrome, and 47,XXX aneuploidy. Triple X results during division of a parent's reproductive cells and occurs about once in every 1,000 births. Unlike most other chromosomal conditions (such as fragile X), there is usually no distinguishable difference to the naked eye between women with triple X and the rest of the female population.

Cause

Triple X syndrome is not inherited, but usually occurs as an event during the formation of reproductive cells (ovum and sperm). An error in cell division called nondisjunction can result in reproductive cells with additional chromosomes. For example, an oocyte or sperm cell may gain an extra copy of the X chromosome as a result of the nondisjunction. If one of these cells contributes to the genetic makeup of a child, the child will have an extra X chromosome in each of her cells. In some cases, trisomy X occurs during cell division in early embryonic development.

Some females with triple X syndrome have an extra X chromosome in only some of their cells. These cases are called 46,XX/47,XXX mosaics.

Symptoms

Due to inactivation and formation of a Barr body in all female cells, only one X chromosome is active at any time in a female cell. Thus, triple X syndrome most often causes no unusual physical features or medical problems. Females with the condition may have menstrual irregularities, and, although rarely exhibiting severe mental impairments, have an increased risk of learning disabilities, delayed speech, and language skills.

In Triple X, XYY and Klinefelter's syndrome, a lanky/youthful appearance with increased facial beauty has been described, or in some instances varying degrees of androgeny, but these cases usually reflect traits present in near relatives. An individual producing a child with the above abnormalities has higher than average risk to produce more. Most commonly, there is no observable difference in triple X, other than being taller than average. The additional X chromosome can come from either the maternal or paternal side. The condition is verified only by karyotype testing.

Most women with triple X have normal sexual development accompanied with prolonged physical/emotional youth and are able to conceive children. Some experience an early onset of menstruation. Triple X women are rarely diagnosed, apart from pre-natal testing methods, such as amniocentesis and blood tests for medical reasons later in life. Most medical professionals do not regard the condition a disability. However, such status can be sought by parents for early intervention treatment if mild delays are present.

Incidence

Triple X syndrome occurs in around 1 in 1,000 girls. On average, five to ten girls with triple X syndrome are born in the United States each day.

First case

The first published report of a woman with a 47,XXX karyotype was by Patricia A. Jacobs, et al. at Western General Hospital in Edinburgh, Scotland, in 1959. It was found in a 35-year-old, 5 ft. 9 in. (176 cm) tall, 128 lb. (58.2 kg) woman who had premature ovarian failure at age 19; her mother was age 41 and her father was 40 at the time of her conception.

Klinefelter's syndrome

Klinefelter's syndrome, 47,XXY or XXY syndrome is a condition caused by a chromosome aneuploidy. Affected individuals have at least two X chromosomes and at least one Y chromosome.

The principal effects are development of small testicles and reduced fertility. A variety of other physical and behavioral differences and problems are common, though severity varies and many boys and men with the condition have few detectable symptoms. Named after Dr. Harry Klinefelter, an endocrinologist at Massachusetts General Hospital, Boston, Massachusetts, who first described it in 1942, it is the second most common disease involving the presence of an extra chromosome. The condition exists in roughly 1 out of every 500 males. Because of the extra chromosome, individuals with the condition are usually referred to as "XXY Males", or "47, XXY Males".

Klinefelter's syndrome
47,XXY

Signs and symptoms

Affected males are almost always effectively Infertile although advanced reproductive assistance is sometimes possible. Some degree of language learning impairment may be present, and neuropsychological testing often reveals deficits in executive functions. In adults, possible characteristics vary widely and include little to no signs of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue). Gynecomastia is present to some extent in about a third of affected individuals, a slightly higher percentage than in the XY population, but only about 10% of XXY males' gynecomastia is noticeable enough to require surgery.

The term "hypogonadism" in XXY symptoms is often misinterpreted to mean "small testicles" or "small penis". In fact, it means decreased testicular hormone/endocrine function. Because of this hypogonadism, patients will often have a low serum testosterone level but high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. Despite this misunderstanding of the term, however, it is true that XXY men often also have "microorchidism" (i.e. small testicles).

The more severe end of the spectrum of symptom expression is also associated with an increased risk of germ cell tumors, breast cancer, and osteoporosis, risks shared to varying degrees with females. Additionally, medical literature shows some individual case studies of Klinefelter's syndrome coexisting with other disorders, such as pulmonary disease, varicose veins, diabetes mellitus, and rheumatoid arthritis, but possible correlations between Klinefelter's and these other conditions are not well characterized or understood.

In contrast to these potentially increased risks, it is currently thought that rare X-linked recessive conditions occur even less frequently in XXY males than in normal XY males, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions.

There are many variances within the XXY population, just as in the most common 46,XY population. While it is possible to characterise 47,XXY males with certain body types, that in itself should not be the method of identification as to whether or not someone has 47,XXY. The only reliable method of identification is karyotype testing.

Diagnosis

A karyotype is used to confirm the diagnosis. In this procedure, a small blood sample is drawn. White blood cells are then separated from the sample, mixed with tissue culture medium, incubated, and checked for chromosomal abnormalities, such as an extra X chromosome.

Cause

The extra X chromosome is retained because of a nondisjunction event during meiosis (sex cell division). The XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in about 1 in 500 live male births.

In mammals with more than one X chromosome, the genes on all but one X chromosome are not expressed; this is known as X inactivation. This happens in XXY males as well as normal XX females. A few genes located in the pseudoautosomal regions, however, have corresponding genes on the Y chromosome and are capable of being expressed. These triploid genes in XXY males may be responsible for symptoms associated with Klinefelter's syndrome.

The first published report of a man with a 47,XXY karyotype was by Patricia A. Jacobs and Dr. J.A. Strong at Western General Hospital in Edinburgh, Scotland in 1959. This karyotype was found in a 24-year-old man who had signs of Klinefelter's syndrome. Dr. Jacobs described her discovery of this first reported human or mammalian chromosome aneuploidy in her 1981 William Allan Memorial Award address.

Treatment

The genetic variation is irreversible, but its symptoms can be altered or treated in a number of ways, including the use of Testosterone treatment.

Inadequately treated hypogonadism in Klinefelter syndrome increases recognized psychosocial morbidity. At least one study indicates that planned and timed support should be provided for young men with Klinefelter syndrome, to ameliorate current poor psychosocial outcomes.

Variations

The 48, XXYY (male) syndrome occurs 1 in 17,000 births and has traditionally been considered to be a variation of Klinefelter's syndrome. XXYY tetrasomy is no longer generally considered a variation of KS, although it has not yet been assigned an ICD-10 code.

Males with Klinefelter syndrome may have a mosaic 47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Mosaicism 47,XXY/46,XX with clinical features suggestive of Klinefelter syndrome is very rare. Thus far, only about 10 cases have been described in literature.

Jacobsen syndrome

Jacobsen Syndrome, also known as 11q deletion, is a rare congenital disorder resulting from deletion of a terminal region of chromosome 11 that includes band 11q24.1. It can cause mild mental retardation, a distinctive facial appearance, and a variety of physical problems including heart defects and a bleeding disorder. The syndrome was first identified by Danish physician Petra Jacobsen in 1973, and is believed to occur in approximately 1 out of every 100,000 births.

Physical characteristics

• Closely-set eyes caused by trigonocephaly
• Folding of the skin near the eye (epicanthus)
• Short, upturned nose (anteverted nostrils)
• Thin lips that curve inward
• Displaced receding chin (retrognathia)
• Low-set, misshapen ears
• Permanent upward curvature of the pinkie and ring fingers (bilateral camptodactyly)
Hammer toes

In addition, patients tend to be shorter than average and have poor psychomotor skills.

Outlook

Patients with this disorder can often live relatively normal lives within the limitations of their disability, although this varies from person to person, and congenital heart disease that does not manifest itself until adulthood is common. There is a greater incidence of various forms of cancer among Jacobsen patients. The vast majority of patients have a bleeding disorder called Paris-Trousseau Syndrome, which causes reduced blood platelet counts and an impairment of platelets' normal blood clotting function. Platelet counts increase during childhood and can eventually reach normal levels, but many patients still have poor clotting due to abnormalities in platelet function. Unless their platelet function has been tested and shown to be normal, Jacobsen patients should be assumed to have a bleeding disorder.

The majority of Jacobsen syndrome cases are not familial in nature, resulting from a spontaneous mutation occurring in a single parental gamete. However, some instances of familial disease resulting from local chromosome fragility or an unbalanced translocation have been described.

Isodicentric 15

Isodicentric 15, or idic(15), is a chromosome abnormality in which a child is born with extra genetic material from chromosome 15. People with idic(15) are typically born with 47 chromosomes in their body cells, instead of the normal 46. The extra chromosome is made up a piece of chromosome 15 that has been duplicated end-to-end like a mirror image. It is the presence of this extra genetic material that is thought to account for the symptoms seen in some people with idic(15). Individuals with idic(15) have a total of four copies of this chromosome 15 region instead of the normal two copies (1 copy each on the maternal and paternal chromosomes.

The extra chromosome is usually found in mosaic state, i.e. some of the cells carry the marker chromosome. However, mostly because of the marker's instability and tendency to be lost during cell division (mitosis), some cells are completely normal with 46 chromosomes. Occasionally, cells may have more than one idic(15), resulting in 48 or 49 chromosomes in all or some of their cells. The same clinical picture could be expected in individuals that have the extra chromosome 15 material as an interstitial duplication; not as a marker chromosome; thus having 46 chromosomes.

Signs and symptoms

Iindividuals with idic(15) have delays in language development and motor skills such as walking or sitting up. Other traits may include low muscle tone (hypotonia), seizures, short stature, and mental retardation. Distinctive facial features associated with idic(15) may include epicanthal folds (skin folds at the inner corners of the eyes), a flattened nasal bridge, button nose, and a high arched palate (roof of the mouth). Some individuals with idic(15) also have features of autism, such as problems with communication, social interactions, and repetitive and stereotyped behaviors (e.g., lining up toys, playing with a toy in the same manner over and over again, hand flapping, rocking back and forth).

Epidemiology

About half of all marker chromosomes are idic(15) but idic (15) in itself is one of the rare chromosome abnormalities. It is estimated that 1 out of 8000 babies are affected. This number includes the children with a large IDIC (15) marker as well as children with a small marker (without negative phenomena). There are organizations for families with idic(15) children that offer extensive information and support.

Genetics

Generally, idic(15) is not inherited; it is said to appear de novo; in one member of the family, by chance. In most cases, the abnormal chromosome is generated in the mother's germ cells; oocytes. This finding is due to ascertainment bias; i.e. cases with maternally derived idic(15) usually have clinical findings and attract attention but those with paternally derived idic(15) usually do not. Thus, established cases are usually patients with maternally inherited idic (15).

People with idic(15) have extra genetic material that has developed from chromosome 15. The material usually exists as a little extra chromosome 15; which is called marker chromosome or extra structurally abnormal chromosome (ESAC). The marker usually exists as an isodicentric chromosome; i.e. 2 copies of a specific part of the long arm of chromosome 15 (most commonly, 15q11-q13) that is mirrored and doubled, with 2 centromeres and 2 satellites. The smallest markers appear to be harmless and they may go undetected. However, if they are large enough to contain a number of important genes, they may result in "idic(15) syndrome" which is characterized by mental retardation, autism and other neurological symptoms. One of the regions responsible for the symptoms of idic(15)syndrome is the critical PWS/AS-region named after the Prader-Willi and/or Angelman syndromes.

idic(15) is also referred to as partial tetrasomy 15q or inverted duplication 15 (inv dup 15).

Diagnosis/Testing

The extra chromosome in people with idic(15) can be easily detected through chromosome analysis (karyotyping). Additional tests are usually required. FISH (Fluorescent in situ hybridization) is used to confirm the diagnosis by distinguishing idic(15) from other supernumerary marker chromosomes. Array CGH could be used to determine the gene content and dosage so that clinical picture could be foreseen. Interstitial duplications of chromosome 15 can be more difficult to detect on a routine chromosome analysis but are clearly identifiable using a 15q FISH study. Families should always discuss the results of chromosome and FISH studies with a genetic counselor or other genetics professionals to ensure accurate interpretation.

Isodicentric chromosome 15 and autism

For more than 12 years, scientists have noticed that some individuals with autism also have idic(15). In fact, idic(15) is the most frequently identified chromosome problem in individuals with autism. (A chromosome anomaly involves extra or missing chromosomal material, not changes within the genes such as Fragile X syndrome). It is suggested that the co-occurrence of autism and idic(15) is not by chance. There may be a gene or genes in the 15q11-q13 region that is/are related to the development of autism in some individuals.

Genetic research studies of individuals without chromosome anomalies also support this idea that an autism-related gene may be present in 15q11-q13. Specifically, research studies found that certain DNA markers from the 15q11-q13 region were found more often in individuals with autism than in individuals without autism. Although these DNA markers are too small to be genes, they suggest that researchers may be getting close to finding an autism gene in this region.

Prognosis/Management

At the present time, there is no specific treatment that can undo any chromosomal abnormality, nor the genetic pattern seen in people with idic(15). The extra chromosomal material in those affected was present at or shortly after conception, and its effects on brain development began taking place long before the child was born. Therapies are available to help address many of the symptoms associated with idic(15). Physical, occupational, and speech therapies along with special education techniques can stimulate children with idic(15) to develop to their full potential.

In terms of medical management of the symptoms associated with dup15q syndrome, families should be aware that individuals with chromosome 15 duplications may tolerate medications differently and may be more sensitive to side effects for some classes of medications, such at the serotonin reuptake inhibitor type medications (SSRI). Thus, these should be used with caution and any new medication should be instituted in a controlled setting, with slow titration of levels and with a clear endpoint as to what the expected outcome for treatment is.

Genetic Counseling

In general, idic(15) occurs de novo but the parents must be karyotyped to make sure it is not inherited, mostly because this will affect the course of genetic counseling given to the family. If the abnormality is found prenatally and one of the parents harbour the marker, the child has a chance of being normal. Further tests should however be done to prove the marker has not been rearranged while being inherited. This information is also necessary for counseling of future pregnancies. Each family is unique and should therefore be handled individually.

Patau syndrome

Patau syndrome, also known as trisomy 13, is a chromosomal abnormality, a syndrome in which a patient has an additional chromosome 13 due to a non-disjunction of chromosomes during meiosis. Some are caused by Robertsonian translocations. The extra chromosome 13 disrupts the normal course of development, causing the characteristic features of Patau syndrome. Like all non-disjunction diseases (Down syndrome, Edwards syndrome, etc.), the risk of disease in the offspring increases with maternal age at pregnancy, with about 31 years being the average. Patau syndrome affects approximately 1 in 12,000 live births.

Patau syndrome
Chromosome 13

Causes

Most cases of Patau's syndrome result from trisomy 13, which means each cell in the body has three copies of chromosome 13 instead of the usual two copies. A small percentage of cases occur when only some of the body's cells have an extra copy, resulting in a mixed population of cells with a differing number of chromosomes; such cases are called mosaic Patau.

Patau syndrome can also occur when part of chromosome 13 becomes attached to another chromosome (translocated) before or at conception. Affected people have two copies of chromosome 13, plus extra material from chromosome 13 attached to another chromosome. With a translocation, the person has a partial trisomy for chromosome 13 and often the physical signs of the syndrome differ from the typical Patau syndrome.

Most cases of Patau syndrome are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called non-disjunction can result in reproductive cells with an abnormal number of chromosomes. For example, an egg or sperm cell may gain an extra copy of the chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra chromosome 13 in each of the body's cells. Mosaic Patau syndrome is also not inherited. It occurs as a random error during cell division early in fetal development.

Patau syndrome due to a translocation can be inherited. An unaffected person can carry a rearrangement of genetic material between chromosome 13 and another chromosome. This rearrangement is called a balanced translocation because there is no extra material from chromosome 13. Although they do not have signs of Patau syndrome, people who carry this type of balanced translocation are at an increased risk of having children with the condition.

Manifestations and physical findings

Of those embryos that do survive to gestation and subsequent birth, common anomalies include:

• mental & motor challenged
• polydactyly (extra digits)
microcephaly
• low-set ears
• holoprosencephaly (failure of the forebrain to divide properly).
• heart defects
• structural eye defects, including microphthalmia, Peters anomaly, cataract, iris and/or fundus (coloboma), retinal dysplasia or retinal detachment, sensory nystagmus, cortical visual loss, and optic nerve hypoplasia
• cleft palate or hare lip
• meningomyelocele (a spinal defect)
• omphalocele (abdominal defect)
• abnormal genitalia
• abnormal palm pattern
• overlapping of fingers over thumb.
• cutis aplasia (missing portion of the skin/hair)
• prominent heel

Recurrence risk

Unless one of the parents is a carrier of a translocation the chances of a couple having another trisomy 13 affected child is less than 1% (less than that of Down Syndrome).

History

Trisomy 13 was first observed by Erasmus Bartholin in 1657, but the chromosomal nature of the disease was ascertained by Dr. Klaus Patau in 1960. The disease is named in his honor. Patau syndrome was also described in Pacific island tribes. These reports were thought to have been caused by radiation from atomic bomb tests. The tribes were temporarily moved before and during the test by an x amount of distance. They were then put back where they had been taken; all of this occurred before it was known how long, or even if, radiation still lingered on after a nuclear explosion.

Edwards syndrome

Trisomy 18
Chromosome 18

Trisomy 18 or Edwards Syndrome is a genetic disorder caused by the presence of all or part of an extra 18th chromosome. It is named after John H. Edwards, who first described the syndrome in 1960. It is the most common autosomal trisomy, after Down Syndrome, that carries to term.

Trisomy 18 is caused by the presence of three — as opposed to two — copies of chromosome 18 in a fetus or infant's cells. The incidence of the syndrome is estimated as one in 3,000 live births. The incidence increases as the mother's age increases. The syndrome has a very low rate of survival, resulting from heart abnormalities, kidney malformations, and other internal organ disorders.

Prognosis

The survival rate of Edwards Syndrome is very low. About 95% die in utero. Of liveborn infants, only 50% live to 2 months, and only 5–10% will survive their first year of life. Major causes of death include apnea and heart abnormalities. It is impossible to predict the exact prognosis of an Edwards Syndrome child during pregnancy or the neonatal period. Because major medical interventions are routinely withheld from these children, it is difficult to determine what the survival rate or prognosis would be with aggressive medical treatment. The median life span is five to fifteen days. One percent of children born with this syndrome live to age ten, typically in cases of the less severe mosaic Edwards syndrome.

Incidence/prevalence

The rate of occurrence for Edwards Syndrome is approximately one in 3,000 (for conception) and approximately one in 6,000 (for live births), as 50% of those diagnosed prenatally with the condition will not survive the prenatal period. Although women in their 20s and 30s may conceive Edwards Syndrome babies, there is an increased risk of conceiving a child with Edwards Syndrome as a woman's age increases, with the average age for this disorder being 32½.

Genetics

Edwards syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 18th chromosome, either in whole (trisomy 18) or part (such as due to translocations). The additional chromosome usually occurs before conception. The effects of the extra copy vary greatly among people, depending on the extent of the extra copy, genetic history, and chance. Edwards syndrome occurs in all human populations, but is more prevalent in females.

A healthy egg or sperm cell contains individual chromosomes — one to contribute to each of the 23 pairs of chromosomes needed to form a normal cell with typical human karyotype of 46 chromosomes. Numerical errors arise at either of the two meiotic divisions and cause the failure of segregation of a chromosome into the daughter cells (non-disjunction). This results in an extra chromosome making the haploid number 24 rather than 23. Fertilization of these eggs or sperm that contain an extra chromosome results in trisomy, or three copies of a chromosome rather than two.

Trisomy 18 (47,XX,+18) is caused by a meiotic nondisjunction event. With nondisjunction, a gamete (i.e., a sperm or egg cell) is produced with an extra copy of chromosome 18; the gamete thus has 24 chromosomes. When combined with a normal gamete from the other parent, the embryo now has 47 chromosomes, with three copies of chromosome 18.

A small percentage of cases occur when only some of the body's cells have an extra copy of chromosome 18, resulting in a mixed population of cells with a differing number of chromosomes. Such cases are sometimes called mosaic Edwards syndrome. Very rarely, a piece of chromosome 18 becomes attached to another chromosome (translocated) before or after conception. Affected people have two copies of chromosome 18, plus extra material from chromosome 18 attached to another chromosome. With a translocation, the person has a partial trisomy for chromosome 18 and the abnormalities are often less than for the typical Edwards syndrome.

Features and characteristics

Infants born with Edwards syndrome may have some or all of the following characteristics: kidney malformations, structural heart defects at birth (i.e., ventricular septal defect, atrial septal defect, patent ductus arteriosus), intestines protruding outside the body (omphalocele) esophageal atresia, mental retardation, developmental delays, growth deficiency, feeding difficulties, breathing difficulties, and arthrogryposis (a muscle disorder that causes multiple joint contractures at birth).

Some physical malformations associated with Edwards syndrome include: a small head (microcephaly) accompanied by a prominent back portion of the head (occiput), low-set, malformed ears, abnormally small jaw (micrognathia), cleft lip/cleft palate, upturned nose, narrow eyelid folds (palpebral fissures), widely-spaced eyes (ocular hypertelorism), drooping of the upper eyelids (ptosis), a short breast bone, clenched hands, underdeveloped thumbs and or nails, absent radius, webbing of the second and third toes, clubfoot or Rocker bottom feet, and undescended testicles in males.

In utero, the most common characteristic is cardiac anomalies, followed by central nervous system anomalies such as head shape abnormalities. The most common head shape anomaly is the presence of choroid plexus cysts, which is a pocket of fluid on the brain that is not problematic in itself but may be a marker for Trisomy 18. Sometimes excess amniotic fluid or polyhydramnios is exhibited.

Cri du chat

Cri du chat syndrome (French for cry or call of the cat referring to the specific mew-like cry of affected children), also known as cri-du-chat syndrome, chromosome 5p deletion syndrome, 5p minus syndrome or Lejeune’s syndrome, is a rare genetic disorder due to a missing portion of chromosome 5. It was first described by Jérôme Lejeune in 1963. The condition affects an estimated 1 in 20,000 to 50,000 live births. The disorder is found in people of all ethnic backgrounds and is more common in females by a 4:3 ratio.

Cri du chat or Cri-du -chat
Facial features of a patient with Cri du Chat syndrome at age of 8 months (A), 2 years (B), 4 years (C) and 9 years 6/12 (D)

Signs and symptoms

The syndrome gets its name from the characteristic cry of infants born with the disorder. The infant sounds just like a meowing kitten, due to problems with the larynx and nervous system. This cry identifies the syndrome. About 1/3 of children lose the cry by age 2. Other symptoms of cri du chat syndrome may include:

• feeding problems because of difficulty swallowing and sucking,
• low birth weight and poor growth,
• severe cognitive, speech, and motor delays,
• behavioral problems such as hyperactivity, aggression, tantrums, and repetitive movements,
• unusual facial features which may change over time.
• excessive dribbling.
• constipation.

In addition, common findings include hypotonia, microcephaly, growth retardation, a round face with full cheeks, hypertelorism, epicanthal folds, down-slanting palpebral fissures, strabismus, flat nasal bridge, down-turned mouth, micrognathia, low-set ears, short fingers, single palmar creases, and cardiac defects (eg, ventricular septal defect [VSD], atrial septal defect [ASD], patent ductus arteriosus [PDA], tetralogy of Fallot). The Cri du chat affected people are fertile and can reproduce.

Less frequently encountered findings include cleft lip and palate, preauricular tags and fistulas, thymic dysplasia, gut malrotation, megacolon, inguinal hernia, dislocated hips, cryptorchidism, hypospadias, rare renal malformations (eg, horseshoe kidneys, renal ectopia or agenesis, hydronephrosis), clinodactyly of the fifth fingers, talipes equinovarus, pes planus, syndactyly of the second and third fingers and toes, oligosyndactyly, and hyperextensible joints.

Late childhood and adolescence findings include severe mental retardation, microcephaly, coarsening of facial features, prominent supraorbital ridges, deep-set eyes, hypoplastic nasal bridge, severe malocclusion, and scoliosis.

Affected females reach puberty, develop secondary sex characteristics, and menstruate at the usual time. The genital tract is usually normal in females except for a report of a bicornuate uterus.

In males, testes are often small, but spermatogenesis is thought to be normal.

Dermatoglyphics: Transverse flexion creases, distal axial triradius, increased whorls and arches on digits, single line on the palm of the hand (simian crease).

Genetics

Cri du chat syndrome is due to a partial deletion of the short arm of chromosome number 5. Approximately 80% of cases results from a sporadic de novo deletion, while about 10-15% are due to unequal segregation of a parental balanced translocation where the 5p monosomy is often accompanied by a trisomic portion of the genome. The phenotypes in these individuals may be more severe than in those with isolated monosomy of 5p because of this additional trisomic portion of the genome. Most cases involve terminal deletions with 30-60% loss of 5p material. Fewer than 10% of cases have other rare cytogenetic aberrations (eg, interstitial deletions, mosaicisms, rings and de novo translocations). The deleted chromosome 5 is paternal in origin in about 80% of the cases.

Loss of a small region in band 5p15.2 (cri du chat critical region) correlates with all the clinical features of the syndrome with the exception of the catlike cry, which maps to band 5p15.3 (catlike critical region). The results suggest that 2 noncontiguous critical regions contain genes involved in this condition's etiology. Two genes, Semaphorine F (SEMA5A) and [delta catenin] (CTNND2), which have been mapped to the critical regions are potentially involved in cerebral development and its deletion may be associated in CdCS patients. Also the deletion of the telomerase reverse transcriptase (hTERT) gene localized in 5p15.33 should contribute to the phenotypic changes in CdCS.

Although the size of the deletion varies, a deletion at region 5p15.3 is responsible for the unique cry and deletion at the critical region of 5p15.2 for the other features. The deletion is of paternal origin in about 80 % of cases in which the syndrome is de novo.

Diagnosis

Diagnosis is based on the distinctive cry and accompanying physical problems. Genetic counseling and genetic testing may be offered to families with individuals who have cri du chat syndrome.

Polyploidy

Polyploidy occurs in cells and organisms when there are more than two homologous sets of chromosomes.

Known paleopolyploidy in eukaryotes

Polyploidy is a state different from most organisms which are normally diploid meaning they have only two sets of chromosomes - one set inherited from each parent; polyploidy may occur due to abnormal cell division. It is most commonly found in plants. Haploidy may also occur as a normal stage in an organism's life. A haploid has only one set of chromosomes.

Polyploidy occurs in some animals, such as goldfish, salmon, and salamanders, but is especially common among ferns and flowering plants (see Hibiscus Rosa-Sinensis), including both wild and cultivated species. Wheat, for example, after millennia of hybridization and modification by humans, has strains that are diploid (two sets of chromosomes), tetraploid (four sets of chromosomes) with the common name of durum or macaroni wheat, and hexaploid (six sets of chromosomes) with the common name of bread wheat. Many agriculturally important plants of the genus Brassica are also tetraploids; their relationship is described by the Triangle of U.

The occurrence of polyploidy is a mechanism of speciation and is known to have resulted in new species of the plant Salsify (also known as "goatsbeard").

Speciation via polyploidy: A diploid cell undergoes failed meiosis, producing diploid gametes, which self-fertilize to produce a tetraploid zygote.

Polyploidy can be induced in cell culture by some chemicals: the best known is colchicine, which can result in chromosome doubling, though its use may have other less obvious consequences as well.

Polyploidy types

Polyploid types are labelled according to the number of chromosome sets in the nucleus:

• triploid (three sets; 3x), for example the phylum Tardigrada
• tetraploid (four sets; 4x), for example Salmonidae fish
• pentaploid (five sets; 5x)
• hexaploid (six sets; 6x), for example wheat, kiwifruit
• oktoploid (eight sets; 8x), for example Acipenser (genus of sturgeon fish)
• dekaploid (ten sets; 10x), for example certain strawberries
• dodecaploid (twelve sets; 12x), for example the plant Celosia argentea

Polyploidy in animals

Examples in animals are more common in the 'lower' forms such as flatworms, leeches, and brine shrimp. Polyploid animals are often sterile, so they often reproduce by parthenogenesis. Polyploid salamanders and lizards are also quite common and parthenogenetic. While mammalian liver cells are polyploid, rare instances of polyploid mammals are known, but most often result in prenatal death.

One of the only known exceptions to this 'rule' is an octodontid rodent of Argentina's harsh desert regions, known as the Red Viscacha-Rat (Tympanoctomys barrerae). This rodent is not a rat, but kin to guinea pigs and chinchillas. Its "new" diploid [2n] number is 102 and so its cells are roughly twice normal size. Its closest living relation is Octomys mimax, the Andean Viscacha-Rat of the same family, whose 2n=56. It is surmised that an Octomys-like ancestor produced tetraploid (i.e., 4n=112) offspring that were, by virtue of their doubled chromosomes, reproductively isolated from their parents; but that these likely survived the ordinarily catastrophic effects of polyploidy in mammals by shedding (via translocation or some similar mechanism) the "extra" set of sex chromosomes gained at this doubling.

However, induced polyploid dairy livestock have been experimented with, particularly in developing agricultural economies. Experiments have produced diploid, triploid, tetraploid, hexaploid and octaploid individuals. The latter two ployploid beef livestock types are marked by much enhanced muscular development (which was the main reason for their development, as a food protein source), as well as requiring a veterinary caesarian to be performed for delivery, negating the advantages gained. However, the protein and fat content of polyploid cow's milk are much enhanced.

Ovine and Caprine Polyploids have on occasion been attempted in the history of Agricultural research, but generally experimental results are discouraging, as polycephaly and polydactyly often occur. This suggests that the genomes of sheep and goats is resistant to genetic damage, both genomes are being actively studied to understand why this is so. Environmental and evolutionary stresses are thought to have been pressures that favoured the development of these characteristics.

Polyploidy in humans (Aneuploidy)

True polyploidy rarely occurs in humans, although it occurs in some tissues (especially in the liver). Polyploidy refers to a numerical change in a whole set of chromosomes. Organisms in which a particular chromosome, or chromosome segment, is under- or overrepresented are said to be aneuploid (from the Greek words meaning "not," "good," and "fold"). Therefore the distinction between aneuploidy and polyploidy is that aneuploidy refers to a numerical change in part of the chromosome, whereas polyploidy refers to a numerical change in the whole set of chromosomes.

Polyploidy occurs in humans in the form of triploidy (69,XXX) and tetraploidy (92,XXXX), not to be confused with 47,XXX or 48, XXXX aneuploidy. Triploidy, usually due to polyspermy, occurs in about 2-3% of all human pregnancies and ~15% of miscarriages. The vast majority of triploid conceptions end as miscarriage and those that do survive to term typically die shortly after birth. In some cases survival past birth may occur longer if there is mixoploidy with both a diploid and a triploid cell population present.

Triploidy may be the result of either digyny (the extra haploid set is from the mother) or diandry (the extra haploid set is from the father). Diandry is almost always caused by the fertilization of an egg by two sperm (dispermy). Digyny is most commonly caused by either failure of one meiotic division during oogenesis leading to a diploid oocyte or failure to extrude one polar body from the oocyte. Diandry appears to predominate among early miscarriages while digyny predominates among triploidy that survives into the fetal period. However, among early miscarriages, digyny is also more common in those cases <8.5>

Complete tetraploidy is more rarely diagnosed than triploidy, but is observed in 1-2% of early miscarriages. However, some tetraploid cells are commonly found in chromosome analysis at prenatal diagnosis and these are generally considered 'harmless'. It is not clear whether these tetraploid cells simply tend to arise during in vitro cell culture or whether they are also present in placental cells in vivo. There are, at any rate, very few clinical reports of fetuses/infants diagnosed with tetraploidy mosaicism.

Mixoploidy is quite commonly observed in human preimplantation embryos and includes haploid/diploid as well as diploid/tetraploid mixed cell populations. It is unknown whether these embryos fail to implant and are therefore rarely detected in ongoing pregnancies or if there is simply a selective process favoring the diploid cells.

Polyploidy in plants

Polyploidy is pervasive in plants and some estimates suggest that 30-80% of living plant species are polyploid, and many lineages show evidence of ancient polyploidy (paleopolyploidy) in their genomes. Huge explosions in angiosperm species diversity appear to have coincided with the timing of ancient genome duplications shared by many species. Polyploid plants can arise spontaneously in nature by several mechanisms, including meiotic or mitotic failures, and fusion of unreduced (2n) gametes. Both autopolyploids (eg. potato) and allopolyploids (eg. canola, wheat, cotton) can be found among both wild and domesticated plant species. Most polyploids display heterosis relative to their parental species, and may display novel variation or morphologies that may contribute to the processes of speciation and eco-niche exploitation. The mechanisms leading to novel variation in newly formed allopolyploids may include gene dosage effects (resulting from more numerous copies of genome content), the reunion of divergent gene regulatory hierarchies, chromosomal rearrangements, and epigenetic remodeling, all of which affect gene content and/or expression levels. Many of these rapid changes may contribute to reproductive isolation and speciation.

There are few naturally occurring polyploid conifers. One example is the giant tree Sequoia sempervirens or Coast Redwood which is a hexaploid (6x) with 66 chromosomes (2n=6x=66), although the origin is unclear.

Polyploid crops

Polyploid plants tend to be larger and better at flourishing in early succession habitats such as farm fields. In the breeding of crops, the tallest and best thriving plants are selected for. Thus, many crops (and agricultural weeds) may have unintentionally been bred to a higher level of ploidy.

The induction of polyploidy is a common technique to overcome the sterility of a hybrid species during plant breeding. For example, Triticale is the hybrid of wheat (Triticum turgidum) and rye (Secale cereale). It combines sought-after characteristics of the parents, but the initial hybrids are sterile. After polyploidization, the hybrid becomes fertile and can thus be further propagated to become triticale.

In some situations polyploid crops are preferred because they are sterile. For example many seedless fruit varieties are seedless as a result of polyploidy. Such crops are propagated using asexual techniques such as grafting.

Polyploidy in crop plants is most commonly induced by treating seeds with the chemical colchicine.

Examples of Polyploid Crops

• Triploid crops: banana, apple, ginger, watermelon, citrus
• Tetraploid crops: durum or macaroni wheat, maize, cotton, potato, cabbage, leek, tobacco, peanut, kinnow, Pelargonium
• Hexaploid crops: chrysanthemum, bread wheat, triticale, oat, kiwifruit
• Octaploid crops: strawberry, dahlia, pansies, sugar cane

Some crops are found in a variety of ploidy. Apples, tulips and lilies are commonly found as both diploid and as triploid. Daylilies (Hemerocallis) cultivars are available as either diploid or tetraploid. Kinnows can be tetraploid, diploid, or triploid.

Terminology

Autopolyploidy

Autopolyploids are polyploids with multiple chromosome sets derived from a single species. Autopolyploids can arise from a spontaneous, naturally occurring genome doubling (for example, the potato). Others might form following fusion of 2n gametes (unreduced gametes). Bananas and apples can be found as triploid autopolyploids. Autopolyploid plants typically display polysomic inheritance, and are therefore often infertile and propagated clonally

Allopolyploidy

Allopolyploids are polyploids with chromosomes derived from different species. Triticale is an example of an allopolyploid, having six chromosome sets, four from wheat (Triticum turgidum) and two from rye (Secale cereale). Amphidiploid is another word for an allopolyploid. Some of the best examples of allopolyploids come from the Brassicas, and the Triangle of U describes the relationships among the three common diploid Brassicas (B. oleracea, B. rapa, and B. nigra) and three allotetraploids (B. napus, B. juncea, and B. carinata) derived from hybridization among the diploids.

Homoeologous

The term is used to describe the relationship of similar chromosomes or parts of chromosomes brought together following inter-species hybridization and allopolyploidization, and whose relationship was completely homologous in an ancestral species. In allopolyploids, the homologous chromosomes within each parental sub-genome should pair faithfully during meiosis, leading to disomic inheritance; however in some allopolyploids, the homoeologous chromosomes of the parental genomes may be nearly as similar to one another as the homologous chromosomes, leading to tetrasomic inheritance (four chromosomes pairing at meiosis), intergenomic recombination, and reduced fertility.

Homoeologous chromosomes - An example

Duram wheat is the result of the inter-species hybridization of two diploid grass species Triticum urartu and Aegilops speltoides. Both the diploid ancestors had two sets of 7 chromosomes. Geneticists give these chromosomes numbers from one to seven. These sets of chromosomes pair together during meiosis such that two chromsome number ones pair up together as do 2 chromosome number twos etc. The chromosome number ones in Triticum urartu and the chromosome numbers ones in Aegilops speltoides are similar in terms of size and genes contained on them. As are the chromosome number twos etc. The Duram wheat contains two chromosome number ones dervied from Triticum urartu and two chromosome number ones derived from Aegilops speltoides. The chromosome number one derived from the Triticum urartu parent is homoeologous to the chromosome number one derived from the Aegilops speltoides parent. In contrast the two chromosome number ones derived from the Triticum urartu parent are homologous chromosomes. During meiosis in the duram wheat the homologous chromosomes pair up with each other while the homoeologous chromosomes do not.

Homologous

The term is used to describe the relationship of similar chromosomes that pair at mitosis and meiosis. In a diploid, one homolog is derived from the male parent (pollen or sperm) and one is derived from the female parent (egg). During meiosis and gametogenesis, homologous chromosomes pair and exchange genetic material by recombination, leading to the production of sperm/pollen or eggs with chromosome haplotypes containing novel genetic variation.

Karyotype

A karyotype is the characteristic chromosome complement of a eukaryote species. The preparation and study of karyotypes is part of cytology and, more specifically, cytogenetics.

Although the replication and transcription of DNA is highly standardized in eukaryotes, the same cannot be said for their karotypes, which are highly variable between species in chromosome number and in detailed organization despite being constructed out of the same macromolecules. In some cases there is even significant variation within species. This variation provides the basis for a range of studies in what might be called evolutionary cytology.

Paralogous

The term is used to describe the relationship among duplicated genes or portions of chromosomes that derived from a common ancestral DNA. Paralogous segments of DNA may arise spontaneously by errors during DNA replication, copy and paste transposons, or whole genome duplications.

Paleopolyploidy

Ancient genome duplications probably occurred in the evolutionary history of all life. Duplication events that occurred long ago in the history of various evolutionary lineages can be difficult to detect because of subsequent diploidization (such that a polyploid starts to behave cytogenetically as a diploid over time) as mutations and gene translations gradually make one copy of each chromosome unlike its other copy.

In many cases, these events can be inferred only through comparing sequenced genomes. Examples of unexpected but recently confirmed ancient genome duplications include the baker's yeast (Saccharomyces cerevisiae), mustard weed/thale cress (Arabidopsis thaliana), rice (Oryza sativa), and an early evolutionary ancestor of the vertebrates (which includes the human lineage) and another near the origin of the teleost fishes. Angiosperms (flowering plants) have paleopolyploidy in their ancestry. All eukaryotes probably have experienced a polyploidy event at some point in their evolutionary history.

Ploidy

Ploidy is the number of homologous sets of chromosomes in a biological cell. The ploidy of cells can vary within an organism. In humans, most cells are diploid (containing one set of chromosomes from each parent), but sex cells (sperm and egg) are haploid. In contrast, tetraploidy (four sets of chromosomes) is a type of polyploidy and is common in plants, and not uncommon in amphibians, reptiles, and various species of insects.

The number of chromosomes in one of the mutually-homologous sets is called the monoploid number (x). This is the same number for every set in every cell of a given organism.

Euploidy is the state of a cell or organism having an integral multiple of the monoploid number, possibly excluding the sex-determining chromosomes. For example, a human cell has 46 chromosomes, which is an integer multiple of the monoploid number, 23. A human with abnormal, but integral, multiples of this full set (e.g. 69 chromosomes) would also be considered as euploid. Aneuploidy is the state of not having euploidy. In humans, examples include having a single extra chromosome (such as Down syndrome), or missing a chromosome (such as Turner syndrome). Aneuploidy is not normally considered -ploidy but -somy, such as trisomy or monosomy.

Haploid and Monoploid

The haploid number is the number of chromosomes in a gamete of an individual. This is distinct from the monoploid number which is the number of unique chromosomes in a single complete set.

In humans, the monoploid number (x) equals the haploid number (the number in a gamete, n), that is, x = n = 23. In some species (especially plants), these numbers differ. Commercial common wheat is an allopolyploid with six sets of chromosomes, two sets coming originally from each of three different species, with six copies of chromosomes in each cell. The gametes of common wheat are considered as haploid since they contain half the genetic information of somatic cells, but are not monoploid as they still contain three complete sets of chromosomes from the original three different species (n = 3x).

Most fungi and a few algae are monoploid organisms, and male bees, wasps, and ants are haploid because of the way they develop from unfertilized, haploid eggs. The Australian bulldog ant, Myrmecia pilosula, a haplodiploid species has n = 1, the lowest known (and lowest theoretically possible) n. A monoploid cell is likely to be identical to the cell it was copied from however in haploid cells one of two differing copies of the same chromosome is in the haploid set.

Plants and some algae switch between a haploid and a diploid or polyploid state, with one of the stages emphasized over the other. This is called alternation of generations. Most diploid organisms produce monoploid sex cells that can combine to form a diploid zygote, for example animals are primarily diploid but produce monoploid gametes. During meiosis, germ cell precursors have their number of chromosomes halved by randomly "choosing" one homologue, resulting in haploid germ cells (sperm and ovum).

Diploid

Diploid cells have two homologous copies of each chromosome, usually one from the mother and one from the father. The exact number of chromosomes may be one or two different from the 2 number yet the cell may still be classified as diploid (although with aneuploidy). Nearly all mammals are diploid organisms (the Plains Viscacha Rat is an exception), although all individuals have some small fraction of cells that display polyploidy. Human diploid cells have 46 chromosomes and human haploid gametes (egg and sperm) have 23 chromosomes.

Retroviruses that contain two copies of their RNA genome in each viral particle are also said to be diploid. Examples include human foamy virus, human T-lymphotropic virus, and HIV.

Haploidisation

Haploidisation (haploidization) is the process of creating a haploid cell (usually from a diploid cell).

A laboratory procedure called haploidisation forces a normal cell to expel half of its chromosomal complement. In mammals this renders this cell chromosomally equal to sperm or egg. This was one of the procedures used by Japanese researchers to produce Kaguya, a fatherless mouse.

Haploidisation sometimes occurs in plants when meiotically reduced cells (usually egg cells) develop by parthenogenesis.

Polyploidy

Polyploidy is the state where all cells have multiple pairs of chromosomes beyond the basic set. These may be from the same species or from closely related species. In the latter case these are known as allopolyploids, amphidiploids or allotetraploids. Allopolyploids can be formed from the hybridisation of two separate species followed by their subsequent chromosome doubling. A good example is the so-called Brassica triangle where three different parent species have hybridized in each pair combination to form three different allopolyploid species. Polyploid plants are probably most often formed from the pairing of meiotically unreduced gametes (Ramsey and Schemske, 2002).

Polyploidy occurs commonly in plants, but rarely in animals. Even in diploid organisms many somatic cells are polyploid due to a process called endoreduplication where duplication of the genome occurs without mitosis (cell division).

The extreme in polyploidy occurs in the fern-ally genus Ophioglossum, the adder's-tongues, in which polyploidy results in chromosome counts in the hundreds, or in at least one case, well over one thousand. Interestingly, these plants seem to have simplified structures in their phenotype.

Variable or indefinite ploidy

Depending on growth conditions, prokaryotes such as bacteria may have a chromosome copy number of 1 to 4, and that number is commonly fractional, counting portions of the chromosome partly replicated at a given time. This is because under logarithmic growth conditions the cells are able to replicate their DNA faster than they can divide.

Mixoploidy

Mixoploidy refers to the presence of two cell lines, one diploid and one polyploid. Though polyploidy in humans is not viable, mixoploidy has been found in live adults and children. There are two types: diploid-triploid mixoploidy, in which some cells have 46 chromosomes and some have 69, and diploid-tetraploid mixoploidy, in which some cells have 46 and some have 92 chromosomes.

Dihaploidy and Polyhaploidy

Dihaploid and polyhaploid cells are formed by haploidisation of polyploids, i.e., by halving the chromosome constitution.

Dihaploids (which are diploid) are important for selective breeding of tetraploid crop plants (notably potatoes), because selection is faster with diploids than with tetraploids. Tetraploids can be reconstituted from the diploids, for example by somatic fusion.

The term “dihaploid” was coined by Bender (1963) to combine in one word the number of genome copies (diploid) and their origin (haploid). The term is well established in this original sense (e.g., Nogler 1984; Pehu 1996), but it has also been used for doubled monoploids or doubled haploids, which are homozygous and used for genetic research (Sprague et al, 1960).

Aneuploidy

Aneuploidy is defined as an abnormal number of chromosomes. Syndromes caused by an extra or missing chromosome are among the most widely recognized genetic disorders in humans. Different organisms have widely varying chromosome complements and thus the term "aneuploidy" does not refer to a particular number of chromosomes, but rather the situation in which the chromosome content within a given cell is abnormal.

Chromosomes

Every cell in the human body, apart from enucleated red blood cells and the haploid gametes, has 23 pairs of chromosomes (for a total of 46). One copy of each pair is inherited from the mother and the other copy is inherited from the father. The first 22 pairs of chromosomes (referred to as autosomes) are numbered from 1 to 22, and are arranged from largest to smallest in a karyotype (see figure). The 23rd pair of chromosomes are the sex chromosomes. Females typically have two X chromosomes, while males typically have one X chromosome and one Y chromosome.

Complete aneuploidy for most autosomes (numbered chromosomes) is incompatible with life and will lead to spontaneous miscarriage during pregnancy. The most frequent meiotic aneuploidy in humans is trisomy 16, although fetuses affected with this chromosome abnormality do not survive to term. The most common form of meiotic aneuploidy in live-born humans is trisomy 21, which is found in Down syndrome.

Changes in chromosome number may not necessarily be present in all cells in an individual. When aneuploidy is detected in a fraction of cells in an individual, it is called chromosomal mosaicism. In general, individuals who are mosaic for a chromosomal aneuploidy tend to have a less severe form of the syndrome compared to those with full trisomy. For many of the autosomal trisomies, only mosaic cases survive to term. However, mitotic aneuploidy may be more common than previously recognized in somatic tissues, and aneuploidy is a characteristic of many types of tumorigenesis.

Terminology

Strictly, a chromosome complement having a number of chromosomes other than 46 (in humans) is considered heteroploid while an exact multiple of the haploid chromosome complement is considered euploid.

Number of chromosomes	Name	Description
1	Monosomy	Monosomy refers to lack of one chromosome of the normal complement. Partial monosomy can occur in unbalanced translocations or deletions, in which only a portion of the chromosome is present in a single copy (see deletion (genetics)). Monosomy of the sex chromosomes (45,X) causes Turner syndrome.
2	Disomy	Disomy is the presence of two copies of a chromosome. For organisms such as humans that have two copies of each chromosome (those that are diploid), it is the normal condition. For organisms that normally have three or more copies of each chromosome (those that are triploid or above), disomy is an aneuploid chromosome complement. In uniparental disomy, both copies of a chromosome come from the same parent (with no contribution from the other parent).
3	Trisomy	Trisomy refers to the presence of three copies, instead of the normal two, of a particular chromosome. The presence of an extra chromosome 21, which is found in Down syndrome, is called trisomy 21. Trisomy 18 and Trisomy 13 are the two other autosomal trisomies recognized in live-born humans. Trisomy of the sex chromosomes can be seen in females (47,XXX) or males (47,XXY which is found in Klinefelter's syndrome; or 47,XYY).
4/5	tetrasomy/pentasomy	Tetrasomy and pentasomy are the presence of four or five copies of a chromosome, respectively. Although rarely seen with autosomes, sex chromosome tetrasomy and pentasomy have been reported in humans, including XXXX, XXXY, XXYY, XYYY, XXXXX, XXXXY, XXXYY, XXYYY and XYYYY.

Mechanisms

1. Nondisjunction usually occurs as the result of a weakened mitotic checkpoint, as these checkpoints tend to arrest or delay cell division until all components of the cell are ready to enter the next phase. If a checkpoint is weakened, the cell may fail to 'notice' that a chromosome pair is not lined up on the mitotic plate, for example. In such a case, most chromosomes would separate normally (with one chromatid ending up in each cell), while others could fail to separate at all. This would generate a daughter cell lacking a copy and a daughter cell with an extra copy.
2. Completely inactive mitotic checkpoints may cause non-disjunction at multiple chromosomes, possibly all. Such a scenario could result in each daughter cell possessing a disjoint set of genetic material.
3. Merotelic attachment occurs when one kinetochore is attached to both mitotic spindle poles. One daughter cell would have a normal complement of chromosomes, the second would lack one. A third daughter cell may end up with the 'missing' chromosome.
4. Multipolar spindle: more than two spindle poles form. Such a mitotic division would result in one daughter cell for each spindle pole; each cell may possess an unpredictable complement of chromosomes.
5. Monopolar spindle: only a single spindle pole forms. This produces a single daughter cell with its copy number doubled.
6. A tetraploid intermediate may be produced as the end result of the monopolar spindle mechanism. In such a case, the cell has double the copy number of a normal cell, and produces double the number of spindle poles as well. This results in four daughter cells with an unpredictable complement of chromosomes, but in the normal copy number.

Somatic mosaicism in the nervous system

It was recently discovered that mosaicism for aneuploid chromosome content may be part of the constitutional make-up of the mammalian brain. This observation was then extended to normal human brain, where brain samples from six individuals ranging from 2-86 years of age were found to have mosaicism for chromosome 21 aneuploidy (average of 4% of neurons analyzed). This low-level aneuploidy appears to arise from chromosomal segregation defects during cell division in neuronal precursor cells, and neurons containing such aneuploid chromosome content reportedly integrate into normal circuits. These results suggest the possibility that somatic mosaicism in the brain (and perhaps, by extension, other tissues) may contribute to the diversity between individuals.

Somatic mosaicism in cancer

Somatic mosaicism also occurs in many cancer cells, including trisomy 12 in chronic lymphocytic leukemia (CLL) and trisomy 8 in acute myeloid leukemia (AML). However, these forms of mosaic aneuploidy occur through mechanisms distinct from those typically associated with genetic syndromes involving complete or mosaic aneuploidy.

In addition, genetic syndromes in which an individual is predisposed to breakage of chromosomes (chromosome instability syndromes) are frequently associated with increased risk for various types of cancer, thus highlighting the role of somatic aneuploidy in carcinogenesis.

Partial aneuploidy

The terms "partial monosomy" and "partial trisomy" are used to describe an imbalance of genetic material caused by loss or gain of part of a chromosome. In particular, these terms would be used in the situation of an unbalanced translocation, where an individual carries a derivative chromosome formed through the breakage and fusion of two different chromosomes. In this situation, the individual would have three copies of part of one chromosome (two normal copies and the portion that exists on the derivative chromosome) and only one copy of part of the other chromosome involved in the derivative chromosome.

Detection

Example of Trisomy 21 detected via qPCR Short Tandem Repeat assay

Germline aneuploidy is typically detected through karyotyping, a process in which a sample of cells is fixed and stained to create the typical light and dark chromosomal banding pattern and a picture of the chromosomes is analyzed. Other techniques include Fluorescence In Situ Hybridization (FISH), Quantitative Polymerase Chain Reaction (PCR) of Short Tandem Repeats, Quantitative Fluorescence PCR (QF-PCR), Quantitative Real-time PCR (RT-PCR) dosage analysis, Quantitative Mass Spectrometry of Single Nucleotide Polymorphisms, and Comparative Genomic Hybridization (CGH).

These tests can also be performed prenatally to detect aneuploidy in a pregnancy, either through amniocentesis or chorionic villus sampling. Pregnant women of 35 years or older are offered prenatal diagnosis because the chance of chromosomal aneuploidy increases as the mother's age increases. For more information, see prenatal diagnosis.

Fanconi anemia

Fanconi anemia (FA) is a genetic disease that affects children and adults from all ethnic backgrounds. The disease is named after the Swiss pediatrician who originally described this disorder, Guido Fanconi. It should not be confused with Fanconi syndrome, a kidney disorder also named after Fanconi.

FA is characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemias, bone marrow failure (aplastic anemia), and cellular sensitivity to DNA damaging agents such as mitomycin C.

Fanconi Anemia

Genetic prevalence

Fanconi anemia has an autosomal recessive pattern of inheritance.

FA is primarily an autosomal recessive genetic disorder. There are at least 13 genes of which mutations are known to cause FA: FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM and FANCN. FANCB is the one exception to FA being autosomal recessive, as this gene is on the X chromosome. For an autosomal recessive disorder, both parents must be carriers in order for a child to inherit the condition. If both parents are carriers, there is a 25% risk with each pregnancy for the mother to have an affected child. Approximately 1,000 persons worldwide currently suffer from the disease. The carrier frequency in the Ashkenazi Jewish population is about 1/90. Genetic counseling and genetic testing is recommended for families that may be carriers of Fanconi anemia.

Because of the failure of hemotologic components to develop - leukocytes, red blood cells and platelets - the body's capabilities to fight infection, deliver oxygen, and form clots are all diminished. Bone marrow transplantation is the accepted treatment to repair the hematological problems associated with FA. However, even with a bone marrow transplant, patients face an increased risk of acquiring cancer and other serious health problems throughout their lifetime.

Prognosis

Many patients eventually develop acute myelogenous leukemia (AML). Older patients are extremely likely to develop head and neck, esophageal, gastrointestinal, vulvar and anal cancers. Patients who have had a successful bone marrow transplant and, thus, are cured of the blood problem associated with FA still must have regular examinations to watch for signs of cancer. Many patients do not reach adulthood.

The overarching medical challenge that Fanconi patients face is a failure of their bone marrow to produce blood cells. In addition, Fanconi patients normally are born with a variety of birth defects. For instance, 90% of the Jewish children born with Fanconi's have no thumbs. A good number of Fanconi patients have kidney problems, trouble with their eyes, developmental retardation and other serious defects, such as microcephaly (small head).

Good care is available for treating Fanconi anemia. Since research is on-going, there is hope that as knowledge gained through clinical trials and research grows, a cure may be developed. One study published by faculty at Northwestern University, however, suggested that Fanconi anemia is an incurable condition.

Hematological abnormalities

Clinically, hematological abnormalities are the most serious symptoms in FA. By the age of 40, 98% of FA will have developed some type of hematological abnormality. It is interesting to note however the few cases in which older patients have died without ever developing them. Symptoms appear progressively and often lead to complete bone marrow (BM) failure. While at birth blood count is usually normal, macrocytosis/megaloblastic anemia, defined as unusually large red blood cells, is the first detected abnormality, often within the first decade of life (median age of onset is 7 years). Within the next 10 years, over 50% of patients presenting haematological abnormalities will have developed pancytopenia, defined as abnormalities in two or more blood cell lineage. Most commonly, a low platelet count (thrombocytopenia) precedes a low neutrophil count (neutropenia), with both appearing with relative equal frequencies. The deficiencies cause increase risk of hemorrhage and recurrent infections, respectively.

As FA is now known to affect the DNA repair and given the current knowledge about dynamic cell division in the BM, it is not surprising to find out that patients are more likely to develop BM failure, myelodysplastic syndromes(MDS) and acute myeloid leukemia (AML). The next sections will detail those pathologies.

Myelodysplastic syndromes

MDS, formerly known as pre-leukemia, are a group of BM neoplastic diseases that share many of the morphologic features of AML with some important differences. First, the percentage of undifferentiated progenitor cells, blasts cells, is always less than 20% and there is considerably more dysplasia, defined as cytoplasmic and nuclear morphologic changes in erythroid, granulocytic and megakaryocytic precursors, than what is usually seen in cases of AML. These changes reflect delayed apoptosis or a failure of programmed cell death. When left untreated, MDS can lead to AML in about 30% of cases. Due the nature of the FA pathology, MDS diagnosis cannot be made solely through cytogenetic analysis of the BM. Indeed, it is only when morphologic analysis of BM cells is performed, that a diagnosis of MDS can be ascertained. Upon examination, MDS-afflicted FA patients will show many clonal variations, appearing either prior or subsequent to the MDS. Furthermore, cells will show chromosomal aberrations, the most frequent being monosomy 7 and partial trisomies of chromosome 3q 15. Observation of monosomy 7 within the BM is well correlated with an increased risk of developing AML and with a very poor prognosis, death generally ensuing within 2 years.

Acute myeloid leukemia

As stated earlier, FA patients also have elevated risks of developing AML, defined as presence of 20% or more of myeloid blasts in the BM or 5 to 20% myeloid blasts in the blood. All of the subtypes of AML can occur in FA with the exception of promyelocytic. However, myelomonocytic and acute monocytic are the most common subtypes observed. It is also interesting to note that many MDS patients will evolve into AML given they survive long enough. Furthermore, the risk of developing AML increases with the onset of BM failure.

While the risk of developing either MDS or AML before the age of 20 is only 27%, this risk increases to 43% by the age of 30 and 52% by the age of 40. Even with BM transplant, about one fourth of patients will die from MDS/ALS related causes within 2 years.

Bone marrow failure

The last major haematological complication associated with FA is BM failure, defined as inadequate blood cell production. Several types of BM failure are observed in FA patients and are generally precede MDS and AML. Detection of decreasing blood count is generally the first sign used to assess necessity of treatment and possible BM transplant. While most FA patients are initially responsive to androgen therapy and haemopoietic growth factors, these have been shown to promote leukemia, especially in patients with clonal cytogenetic abnormalities, and have severe side effects, including hepatic adenomas and adenocarcinomas. The only treatment left would be BM transplant; however, such an operation has a relatively low success rate in FA patients when the donor is unrelated (30% 5-year survival) 16. It is therefore imperative to transplant from HLA-identical sibling. Furthermore, due to the increased susceptibility of FA patients to chromosomal damage, pre-transplant conditioning cannot include high doses of radiations or immunosuppressants, and thus increase chances of patients developing graft-versus-host disease. If all precautions are taken, and the BM transplant is performed within the first decade of life, 2-year probability of survival can be as high as 89%. However, if the transplant is performed at ages older than 10, 2-year survival rates drop to 54%.

A recent report by Zhang et al investigates the mechanism of BM failure in FANCC-/- cells. They hypothesize and successfully demonstrate that continuous cycles of hypoxia-reoxygenation, such as those seen by haemopoietic and progenitor cells as they migrate between hyperoxic blood and hypoxic BM tissues, leads to premature cellular senescence and therefore inhibition of BM haemopoietic function. Senescence, together with apoptosis, may constitute a major mechanism of haemopoietic cell depletion occurred in BM failure.

Molecular basis of FA

Due to the similarities in the phenotypes of the different FA complementation groups, it was reasonable to assume that all affected genes interacted in a common pathway. Up until the late 90s, nothing was known about the proteins encoded by FA genes. However, more recently, studies have shown that eight of these proteins, FANCA, -B, -C, -E, -F, -G, -L and –M assemble to form a core protein complex in the nucleus. This complex has also been suggested to exist in cytoplasm and its translocation into the nucleus is dependent on the nuclear localization signals on FANCA and FANCE. Assembly is thought to be activated by replicative stress, particularly that resulting from DNA damage caused by cross-linking agents(mitomycin C or cisplatin) or reactive oxygen species (ROS). Indeed, FANCA and FANCG have been observed to multimerize when a cell is faced with oxidative stress-induced damage. Following assembly, the protein core complex activates FANCL protein which acts as an E3 ubiquitin-ligase and monoubiquitinates FANCD2. It was previously thought that BRCA1, with its zinc finger ubiquitin ligase domain was responsible for the post-transcriptional modification of FANCD2, however, this has since been invalidated and BRCA1 interaction with the FA protein complex is still being investigated.

Monoubiquitinated FANCD2, also know as FANCD2-L, then goes on to interact with a BRCA1/BRCA2 complex. Again, details of this interaction have yet to be discovered. However, it is already known that similar complexes are involved in genome surveillance and associated with a variety of proteins implicated in DNA repair and chromosomal stability. With a crippling mutation in any FA protein in the complex, DNA repair has been shown to be much less effective, as can be seen from the damage caused by cross-linking agents such as cisplatin, diepoxybutane and Mitomycin C. It follows that tissues, as is the case in bone marrow, in which successful cell replication is vital, will be severely affected by FA protein dysfunction where FA leads to decreased haemopoiesis and bone marrow failure due to progenitor and stem cell senescence.

In another pathway responding to ionizing radiation, FANCD2 is thought to be phosphorylated by protein complex ATM/ATR activated by double-strand DNA breaks, and takes part in S-phase checkpoint control. This pathway was proven by the presence of radioresistant DNA synthesis, the hallmark of a defect in the S phase checkpoint, in patients with FA-D1 or FA-D2. Such a defect readily leads to uncontrollable replication of cells and might also explain the increase frequency of AML in these patients.

Other FA protein interactions

Although the above described pathway seems to be the most integral part of the DNA damage response in cells and explains the pathology of FA, novel approaches have determined that most FA proteins have an alternate role. Indeed, recent investigations on FANCC, one of the intensively studied proteins, have shown that it plays an important role in cellular responses to oxidative stress. For example, it has been found to interact with NADPH cytochrome P450 reductase, associated with increased production of ROS, and glutathione S-transferase, responsible for production of the anti-oxidant glutathione. These two enzymes are both involved in either triggering or detoxifying ROS. Not surprisingly, mice with Cu/Zn superoxide dismutase and FANCC mutations demonstrate defective haemopoiesis. FANCC was also shown to bind STAT1 and help receptor docking and phosphorylation of STAT135, which helps in tumor suppression. This leads to the conclusion that FANCC participates in cell growth arrest and cell cycle progression, inhibiting apoptosis, a possible cause of bone marrow failure due to depletion of haemopoietic progenitors. Another FA protein linked to protection against oxidative damage is FANCG. Indeed, this protein interacts with cytochrome P450 2E1 suggesting a possible role in detoxifying cytochrome ROS, produced readily by the members of this superfamily36. Furthermore, FANCG is identical to post-replication repair protein XRCC9, hinting at the possibility that FANCG also interacts directly with DNA by means of its internal leucine zipper. Thus it is readily seen that FA proteins also acts outside of the Fanconi pathway, either by helping neutralize ROS or by taking part in DNA repair. Such mechanisms help understand the causes behind bone marrow failure, where reoxygenation-induced oxidative stress is very common19. Furthermore, it is known that cross-linking agents produce ROS and it is possible that FA cell hypersensitivity to cross-linkers is not due directly to them, but rather to the cell’s impaired ability to cope with increased ROS production.

Xeroderma pigmentosum

Xeroderma pigmentosa, or XP, is an autosomal recessive genetic disorder of DNA repair in which the ability to repair damage caused by ultraviolet (UV) light is deficient. This disorder leads to multiple basaliomas and other skin malignancies at a young age. In severe cases, it is necessary to avoid sunlight completely. The two most common causes of death for XP victims are metastatic malignant melanoma and squamous cell carcinoma. XP is about six times more common in Japanese people than in other groups.

Cause

Xeroderma pigmentosum has an autosomal recessive pattern of inheritance.

The most common defect in xeroderma pigmentosum is a genetic defect whereby nucleotide excision repair (NER) enzymes are mutated, leading to a reduction in or elimination of NER. Unrepaired damage can lead to mutations, altering the information of the DNA in individual cells. If mutations affect important genes, like tumour suppressor genes (e.g. p53) or proto oncogenes then this disorder may lead to cancer. Patients exhibit elevated risk of developing cancer, such as basal cell carcinoma.

Normally, damage to DNA in epidermal cells occurs during exposure to UV light. The absorption of the high energy light leads to the formation of pyrimidine dimers, namely CPD's (cyclobutane-pyrimidine-dimers) and 6-4PP's (pyrimidine-6-4-pyrimidone photoproducts). The normal repair process entails nucleotide excision. The damage is excised by endonucleases, then the gap is filled by a DNA polymerase and "sealed" by a ligase.

Types

There are 7 complementation groups, plus one variant form :

Type	Diseases Database	OMIM	Gene	Locus	Also known as/Description
Type A, I, XPA	29877	278700	XPA	9q22.3	Xeroderma pigmentosum group A. Classical form of XP.
Type B, II, XPB	29878	133510	XPB	2q21	Xeroderma pigmentosum group B.
Type C, III, XPC	29879	278720	XPC	3p25	Xeroderma pigmentosum group C.
Type D, IV, XPD	29880	278730 278800	XPD ERCC6	19q13.2-q13.3 , 10q11	Xeroderma pigmentosum group D or De Sanctis-Cacchione syndrome. De Sanctis-Cacchione syndrome can be considered a subtype of XPD.
Type E, V, XPE	29881	278740	DDB2	11p12-p11	Xeroderma pigmentosum group E.
Type F, VI, XPF	29882	278760	ERCC4	16p13.3-p13.13	Xeroderma pigmentosum group F.
Type G, VII, XPG	29883	278780 133530	RAD2 ERCC5	13q33	Xeroderma pigmentosum group G.
Type V, XPV		278750	POLH	6p21.1-p12	Xeroderma pigmentosum variant. XPV patients suffer from mutation in a gene that codes for a specialized DNA polymerase called polymerase-η (eta). Polymerase-η can replicate over the damage and is needed when cells enter S-phase in the presence of a DNA-damage.

Symptoms

Some of the most common symptoms of XP include:

• An unusually severe sunburn after a short sun exposure. The sunburn may last for several weeks. The sunburn usually occurs during a child's first sun exposure.
• Development of many freckles at an early age .
• Irregular dark spots on the skin .
• Thin skin .
• Excessive dryness of skin .
• Rough-surfaced growths (solar keratoses), and skin cancers .
• Eyes that are painfully sensitive to the sun and may easily become irritated, bloodshot, and clouded, .
• Blistering or freckling on minimum sun exposure.
• Premature aging of skin, lips, eyes, mouth and tongue.
• Crusting skin
• Spidery blood vessels
• Scaly skin
• Oozing raw skin surface
• Limited growth of hair on chest and legs.

Treatment

The most important part of managing the condition is reducing exposure to the sun. The number of keratoses can be reduced with Isotretinoin (though there are significant side-effects.) Existing keratoses can be treated using cryotherapy or fluorouracil.

In Popular Culture

Christopher Snow, the protagonist and narrator of Dean Koontz' Moonlight Bay Trilogy of novels (Fear Nothing, Seize The Night and the to-be-completed Ride The Storm), has severe enough XP that he must avoid sunlight and as much artificial light as possible at all costs, living his life at night and then only by dim bulbs and candlelight, though always maintaining a positive and envigorated attitude about life, even authoring a best-selling autobiographical book on living with XP.

In Jodi Picoult's novel 'Second Glance' nine year old character Ethan Wakeman suffers from XP so severe he can only leave the house after sunset.

Alejandro Amenábar's Award-winning film, The Others, centers around a woman (Nicole Kidman) whose children suffer from XP and must be kept indoors, behind closed curtains, at all times.

Yui stars in a romantic Japanese movie Taiyō no Uta, where she plays the lead character, a street musician named Kaoru Amane, who is diagnosed with Xeroderma Pigmentosum and only performs at night because of this disease. Even with this diagnosis, she chases her dreams of becoming a singer and meets Kōji Fujishiro (Takashi Tsukamoto), who also has a passion for music and whom Kaoru eventually falls in love with. This story was also the basis for a Japanese TV drama series, also called "Taiyō no Uta", starring Erika Sawajiri and Takayuki Yamada in the roles of Kaoru and Kōji.

Werner syndrome

Werner Syndrome (WRN) is a very rare, autosomal recessive disorder characterized by the appearance of premature aging.

Werner's syndrome more closely resembles accelerated aging than any other segmental progeria. For this reason, Werner syndrome is often referred to as a progeroid syndrome, as it partly mimics the symptoms of Progeria.

Pathophysiology

The defect is on a gene that codes DNA helicase and it is located on the short arm of the 8th chromosome. The disorder is directly caused by shorter-than-normal length telomere maintenance. As a result DNA replication is impaired.

Symptoms

Individuals with this syndrome typically develop normally until they reach puberty. Following puberty they age rapidly, so that by age 40 they often appear several decades older. The age of onset of Werner syndrome is variable, but an early sign is the lack of a teenage growth spurt, which results in short stature. Other signs and symptoms appear when affected individuals are in their twenties or thirties and include loss and graying of hair, hoarseness of the voice, thickening of the skin, and cloudy lenses (cataracts) in both eyes. Overall, people affected by Werner syndrome have thin arms and legs and a thick torso.

Affected individuals typically have a characteristic facial appearance described as "bird-like" by the time they reach their thirties. Patients with Werner syndrome also exhibit genomic instability, hypogonadism, and various age-associated disorders; these include cancer, heart disease, atherosclerosis, diabetes mellitus, and cataracts. However, not all characteristics of old-age are present in Werner patients; for instance, senility is not seen in individuals with Werner syndrome. People affected by Werner syndrome usually do not live past their late forties or early fifties, often dying from the results of cancer or heart disease.

Genetics

Werner syndrome has an autosomal recessive pattern of inheritance.

Werner syndrome is an autosomal recessive disorder. The gene associated with Werner Syndrome lies on chromosome 8 in humans.

History

Werner's syndrome is named after Otto Werner, a German scientist, who, as a student, described the syndrome as part of his doctoral thesis in 1904.

Trichothiodystrophy

Trichothiodystrophy is a rare genetic condition caused by mutations in either of the ERCC2/XPD and ERCC3/XPB genes. The symptoms of the disease result from a loss of nucleotide excision repair (NER) mechanisms, resulting in high sensitivity to UV light. Patients suffer from brittle hair and nails, ichthyotic or dry and scaly skin as well as physical and mental retardation. Skin cancers have been reported in several cases, associated with Trichothiodystrophy, which is also known as Tay syndrome.

In some cases, it can be diagnosed prenatally.

Rothmund-Thomson syndrome

Rothmund-Thomson Syndrome is a rare autosomal recessive skin condition originally described by August von Rothmund (1830-1906) in 1868. Matthew Sydney Thomson (1894-1969) published further descriptions in 1936.

There have been several reported cases associated with osteosarcoma. A hereditary genetic basis, mutations in the DNA Helicase RECQL4 gene, has been implicated in the syndrome.

Rothmund-Thomson syndrome has an autosomal recessive pattern of inheritance.

Key features

• Abnormal rash termed poikiloderma skin pigmentation
Telangiectasia
• Juvenile cataracts
• Saddle nose
• Congenital bone defects, particularly radial ray anomalies and short stature
• Hair growth problems (absent eyelashes, eyebrows and/or hair)
• Hypogonadism has not been well documented
• Hypodontia
• Calcium problems (not documented in journals)
• Ear problems (not documented in journals but identified by patients in support groups)
Osteosarcoma

Progeria

Progeria is a condition that resembles premature aging which usually refers specifically to Hutchinson-Gilford Progeria syndrome.

Hutchinson-Gilford Progeria syndrome is an extremely rare condition where symptoms resembling some aspects of aging are manifested at an early age, and few affected children live past age 13. About 1 in 8 million babies are born with this condition. It is a genetic condition, but occurs sporadically and is usually not inherited in families.

Scientists are particularly interested in progeria because it might reveal clues about the normal process of aging.

Symptoms

The earliest symptoms include failure to thrive (FTT) and a localized scleroderma-like skin condition. As the child ages past infancy, additional conditions become apparent. Limited growth, alopecia, and a distinctive appearance with small face and jaw and pinched nose all are characteristic of progeria. The people diagnosed with this disease usually have small, fragile bodies like those of elderly people.

Later the condition causes wrinkled skin, atherosclerosis and cardiovascular problems.

Cause

Hutchinson-Gilford Progeria Syndrome (HGPS) is a childhood disorder caused by mutations in one of the major architectural proteins of the cell nucleus.

Unlike most other "accelerated aging diseases" (such as Werner's syndrome, Cockayne's syndrome or xeroderma pigmentosum), progeria is not caused by defective DNA repair. Because these "accelerated aging" diseases display different aspects of aging, but never every aspect, they are often called "segmental progerias".

Diagnosis

In HGPS patients, the cell nucleus has dramatically aberrant morphology (bottom, right) rather than the uniform shape typically found in healthy individuals (top, right)

Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. It can be confirmed through a genetic test.

Treatment

No treatments have been proven effective. Most treatment focuses on reducing complications such as cardiovascular disease, such as heart bypass surgery or low-dose aspirin. Children may also benefit from a high-calorie diet.

Growth hormone treatment has been attempted.

A type of anti-cancer drug, the farnesyltransferase inhibitors (FTIs), have been proposed, but their use has been mostly limited to animal models. A phase II clinical trial using the FTI Lonafarnib began in May 2007.

Prognosis

There is no known cure. Few people with progeria exceed 13 years of age. At least 90% of patients die from complications of atherosclerosis, such as heart attacks or strokes.

Mental development is not affected. The development of symptoms is comparable to aging at a rate six to eight times faster than normal, although certain age-related conditions do not occur. Specifically, patients show no neurodegeneration or cancer predisposition. They do not develop "wear and tear" conditions commonly associated with aging, like cataracts and osteoarthritis.

Epidemiology

One study from the Netherlands has shown an incidence of 1 in 4 million births. Currently, there are 48 known cases in the world. Approximately 100 cases have been formally identified in medical history.

Classical Hutchinson–Gilford Progeria Syndrome is almost never passed on from parent to child. It is usually caused by a new (sporadic) mutation during the early division of the cells in the child. There has been one case in which became evident that a healthy parent can carry the LMNA-mutation that causes progeria in her or his egg- or spermcells. In this case two siblings were born with HGPS. But Hutchinson–Gilford Progeria Syndrome is usually genetically dominant, therefore parents who are healthy will normally not pass it on to their children. Affected children do not live long enough to have children themselves.

However, there are milder cases in which either the gene is not expressed in parents, or a different gene is responsible for a different form of progeria, and healthy parents can pass on their children.

Four families have been identified as having more than one child with the disease.

Research areas

Several discoveries have been made that have led to greater understanding and perhaps eventual treatment.

A 2003 report in Nature said progeria may be a de novo dominant trait. It develops during cell division in a newly conceived child or in the gametes of one of the parents. It is caused by mutations in LMNA (Lamin A protein) gene on chromosome 1; The mutated form of Lamin A is commonly known as progerin. One of the authors, Leslie Gordon, was a physician who didn't know anything about progeria, until her own son, Sam, was diagnosed at 21 months. Gordon and her husband, pediatrician Scott Berns, founded the Progeria Research Foundation.

Lamin A

Nuclear lamina is a protein scaffold on the inner edge of the nucleus that helps organize nuclear processes such as RNA and DNA synthesis.

preLamin A contains a CAAX box at the C-terminus of the protein (where C is a cysteine and A is any aliphatic amino acids). This ensures that the cysteine is farnesylated, and this allows preLamin A to bind membranes, specifically the nuclear membrane. After Prelamin A has been localized to the cell nuclear membrane the C-terminal amino acids, including the farnesylated cysteine, are cleaved off by a specific protease. The resulting protein is now Lamin A, is no longer membrane-bound and carries out functions inside the nucleus.

In HGPS the recognition site that the enzyme requires for cleavage of Prelamin A to Lamin A is mutated. Lamin A cannot be produced and preLamin A builds up on the nuclear membrane, causing a characteristic nuclear blebbing. This results in the premature aging symptoms of progeria, although the mechanism connecting the misshapen nucleus to the symptoms is not known.

A study which compared HGPS patient cells with the skin cells from LMNA young and elderly human subjects found similar defects in the HGPS and elderly cells, including down-regulation of certain nuclear proteins, increased DNA damage and demethylation of histone leading to reduced heterochromatin. Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but neurons and gametes. These studies suggest that lamin A defects contribute to normal aging.

Mouse model of progeria

A mouse model of progeria exists, though in the mouse the LMNA preLamin A is not mutated, but instead ZMPSTE24, the specific protease that is required to remove the C-terminus of preLamin A is missing. Both cases result in the build up of farnesylated preLamin A on the nuclear membrane and in the characteristic nuclear LMNA blebbing. Fong et al use a farnesyl transferase inhibitor (FTI) in this mouse model to inhibit protein farnesylation of preLamin A. Treated mice had greater grip strength, lower likelihood of rib fracture and may live longer than untreated mice.

This method does not directly 'cure' the underlying cause of progeria. This method prevents Prelamin A going to the nucleus in the first place so no preLamin A can build up on the nuclear membrane, but equally there is no production of normal Lamin A in the nucleus. Luckily Lamin A does not appear to be essential, indeed mouse models in which the genes for preLamin A and C are knocked out show no symptoms. This also shows that it is the build up of Prelamin A in the wrong place, rather than the loss of the normal function of Lamin A that causes the disease.

It was hypothesized that part of the reason that treatment with an FFI such as alendronate is inefficient due to prenylation by geranylgeranyltransferase. Since statins inhibit geranylgeranyltransferase, the combination of an FFI and statins was tried, and markedly improved "the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects".

History

Progeria was first described in 1886 by Jonathan Hutchinson and also described independently in 1897 by Hastings Gilford. The condition was later named Hutchinson-Gilford Progeria syndrome (HGPS).

Cockayne syndrome

Cockayne syndrome (also called Weber-Cockayne syndrome, or Neill-Dingwall Syndrome) is a rare autosomal recessive congenital disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight (photosensitivity), and premature aging. Hearing loss and eye abnormalities (pigmentary retinopathy) are other common features, but problems with any or all of the internal organs are possible.

It is named after English physician Edward Alfred Cockayne (1880-1956).

Forms of Cockayne syndrome

• CS Type I, the classic form, is characterized by normal fetal growth with the onset of abnormalities in the first two years of life. Impairment of vision, hearing, and the central and peripheral nervous system progressively degenerate until death in the first or second decade of life.
• CS Type II, otherwise known as connatal CS, involves very little neurological development after birth. Death usually occurs by age 7.
• CS Type III is rare and is characterized by late onset. It is milder than Type I and II.
• Xeroderma-pigmentosum-Cockayne syndrome (XP-CS) occurs when an individual also suffers from Xeroderma pigmentosum, another DNA repair disease. Some symptoms of each disease are expressed.

Genetics

Cockayne syndrome is classified genetically as follows:

• Online 'Mendelian Inheritance in Man' (OMIM) 216400 (TYPE A)
• Online 'Mendelian Inheritance in Man' (OMIM) 133540 (TYPE B)
• Online 'Mendelian Inheritance in Man' (OMIM) 216411 (TYPE C)

Cockayne syndrome has an autosomal recessive pattern of inheritance.

Mutations in the ERCC6 and ERCC8 genes are the cause of Cockayne syndrome. The proteins made by these genes are involved in repairing damaged DNA via the transcription-coupled repair mechanism, particularly the DNA in active genes. If either the ERCC6 or the ERCC8 gene is altered, DNA damage is not repaired. As this damage accumulates, it can lead to malfunctioning cells or cell death.

Physical appearance

Small head size, short stature, sunken eyes, "aged" look.

DNA repair-deficiency disorder

An DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair.

DNA repair defects are seen in nearly all of the diseases described as accelerated aging disease, in which various tissues, organs or systems of the human body age prematurely. Because the accelerated aging diseases display different aspects of aging, but never every aspect, they are often called segmental progerias by biogerontologists.

Examples

Some of the examples include:

• Ataxia telangiectasia
  
• Bloom syndrome
• Cockayne's syndrome
• 
  
• Progeria (Hutchinson-Gilford Progeria syndrome)
• Rothmund-Thomson syndrome
  
• Trichothiodystrophy
• Werner syndrome
• Xeroderma pigmentosum

DNA repair defects distinguished from "accelerated aging"

Most of the DNA repair deficiency diseases show varying degrees of "accelerated aging" or cancer (usually some of both). But elimination of any gene essential for base excision repair kills the embryo -- it is too lethal to display symptoms (much less symptoms of cancer or "accelerated aging"). Rothmund-Thomson syndrome and xeroderma pigmentosum display symptoms dominated by vulnerability to cancer, whereas progeria and Werner syndrome show the most features of "accelerated aging". Hereditary nonpolyposis colorectal cancer (HNPCC) is very often caused by a defective MSH2 gene leading to defective mismatch repair, but displays no symptoms of "accelerated aging". Some DNA repair defects manifest as neurodegeneration rather than as cancer or "accelerated aging".

Debate concerning "accelerated aging"

Some biogerontologists question that such a thing as "accelerated aging" actually exists, at least partly on the grounds that all of the so-called accelerated aging diseases are segmental progerias. Many disease conditions such as diabetes, high blood pressure, etc. are associated with increased mortality. Without reliable biomarkers of aging it is hard to justify the claim that a disease condition represents more than accelerated mortality.

Against this position other biogerontologists argue that premature aging phenotypes are identifiable symptoms associated with mechanisms of molecular damage. The fact that these phenotypes are widely recognized justifies classification of the relevant diseases as "accelerated aging". Such conditions, it is argued, are readily distinguishable from genetic diseases associated with increased mortality, but not associated with an aging phenotype, such as cystic fibrosis and sickle cell anemia. It is further argued that segmental aging phenotype is a natural part of aging insofar as genetic variation leads to some people being more disposed than others to aging-associated diseases such as cancer and Alzheimer's disease.

Bloom syndrome

Bloom syndrome (BLM) is a rare autosomal recessive chromosomal disorder characterized by a high frequency of breaks and rearrangements in an affected person's chromosomes. The condition was discovered and first described by dermatologist Dr. David Bloom in 1954.

Presentation

Bloom syndrome is characterized by short stature and a facial rash that develops shortly after first exposure to sun. This rash can make a butterfly-shaped patch of reddened skin on the cheeks. The rash can develop on other sun-exposed areas such as the backs of the hands. Other clinical features include (1) a high-pitched voice; (2) a distinct facies, including a long, narrow face, a small lower jaw, and prominent nose and ears; (3) other pigmentation changes of the skin, including hypo- and hyper-pigmented areas and "cafe-au-lait" spots; (4) telangiectasias (dilated blood vessels) which can appear on the skin but also in the eyes; (5) a moderate immune deficiency, characterized by deficiency in certain immunoglobulin classes, that apparently leads to recurrent pneumonia and ear infections; (6) hypo-gonadism characerized by a failure to produce sperm, hence infertility in males, and premature cessation of menses (premature menopause), hence sub-fertility in females. However, several women with Bloom syndrome have had children.

Complications of the disorder may include chronic lung problems, diabetes, and learning disabilities. In a small number of persons, there is mental retardation. The most striking complication of the disorder is susceptibility to cancer, as described in more detail in the next section.

Relationship to cancer

A greatly elevated rate of mutation in Bloom syndrome results in a high risk of cancer in affected individuals. The cancer predisposition is characterized by 1) broad spectrum, including leukemias, lymphomas, and carcinomas, 2) early age of onset relative to the same cancer in the general population, and 3) multiplicity. Persons with Bloom syndrome may develop cancer at any age. The average age of cancer diagnoses in the cohort is approximately 25 years old.

Pathophysiology

Mutations in the BLM gene, which is a member of the DNA helicase family, are associated with Bloom syndrome. DNA helicases are enzymes that unwind the two strands of a duplex DNA molecule. DNA unwinding is required for most processes that involve the DNA, including copied, RNA transcription, DNA repair, etc.

When a cell prepares to divide to form two cells, the chromosomes are duplicated so that each new cell will get a complete set of chromosomes. The duplication process is called DNA replication. Errors made during DNA replication can lead to mutations. The BLM protein is important in maintaining the stability of the DNA during the replication process. The mutations in the BLM gene associated with Bloom syndrome inactivate the BLM protein's DNA helicase activity or nullify the protein expression (the protein is not made). Lack of BLM protein or protein activity leads to an increase mutations; however, the molecular mechanism(s) by which BLM maintains stability of the chromosomes is still a very active area of research.

Persons with Bloom syndrome have an enormous increase in exchange events between homologous chromosomes or sister chromatids (the two DNA molecules that are produced by the DNA replication process); and there are increases in chromosome breakage and rearrangements compared to persons who do not have Bloom syndrome. Direct connections between the molecular processes in which BLM operates and the chromosomes themselves are under investigation. The relationships between molecular defects in Bloom syndrome cells, the chromosome mutations that accumulate in somatic cells (the cells of the body), and the many clinical features seen in Bloom syndrome are also areas of intense research.

Bloom syndrome has an autosomal recessive pattern of inheritance.

Bloom syndrome is inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. The carrier frequency in individuals of Eastern European Jewish (Ashkenazi Jewsish) ancestry is about 1/100. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of Bloom syndrome. For families in which carrier status is known, prenatal testing is available using cytogenetic or molecular methods. Molecular DNA testing for the mutation that is common in the Ashkenazi Jewish population is also available.

Refsum's disease

Refsum's disease (Refsum-Thiébaut disease, Refsum-Thiébaut-Klenk-Kahlke disease), named after Norwegian neurologist Sigvald Bernhard Refsum (1907-1991), is neurological disease that results in the malformation of myelin sheaths around nerve cells. It is a peroxisomal disorder.

Causes

Refsum's disease is caused by faulty enzymes during the alpha-oxidation of phytanic acid resulting in buildup of phytanic acid and its unsaturated fatty acid derivatives in the plasma and tissues.

This in turn can be due to deficiencies of phytanoyl-CoA hydroxylase (chromosome 10) or peroxin-7 (chromosome 6).

Presentation

Patients with Refsum's Disease present with neurologic damage, cerebellar degeneration, and peripheral neuropathy. Onset is most commonly in childhood/adolescence with a progressive course, although periods of stagnation/remission occur. Symptoms also include night blindness, ataxia, scaly skin (ichthyosis), difficulty hearing, and eye problems including cataracts.

Treatment

The most effective therapy in the classic Refsum disease is dietary treatment with a phytanic acid-restricted diet, such as exclusively avoiding consumption of beef, lamb, fatty fish such as tuna, cod, and haddock. Recent research has shown that CYP4 isoform enzymes could eliminate the phytanic acid storage in vivo and patients could try alternative natural remedies with either eatable marine invertebrates or with clofibrate supplement of which the component is usually rich in the excretion of high plant. Currently, there is no clinical data to approve using this xenonbiotic drug for the treatment, perhaps due to its serious adverse effect and the major medical treatment of the disease only relies on the plasmapheresis.

Reaction

Phytol (from chlorophyll in plant foods) ---> phytanic acid -x-> pristanic acid ---> propionyl CoA due to the composition of starch and the chemical and molecular breakdown of fatty acids refsum's disease can be treated by creating glucose in an excess amount

Nijmegen breakage syndrome

Nijmegen breakage syndrome (NBS) (also known as Berlin breakage syndrome and Seemanova syndrome) is a rare syndrome characterised by chromosomal instability, probably as a result of a defect in the Double Holliday junction DNA repair mechanism.

The name derives from the Dutch city Nijmegen where the condition was first described.

Most people with NBS have West Slavic origins. The largest number of them live in Poland.

Presentation

It is characterized by microcephaly, a distinct facial appearance, short stature, immunodeficiency, radiation sensitivity and a strong predisposition to lymphoid malignancy.

Causes

It is caused by a mutation in the NBS1 gene.

Niemann-Pick disease

Niemann-Pick disease (pronounced nē′mahn pik) refers to a group of fatal inherited metabolic disorders that are included in the larger family of lysosomal storage diseases (LSDs). Niemann Pick diseases are classified in a subgroup of LSDs called sphingolipidoses or lipid storage diseases in which harmful quantities of a fatty substances, called lipids, accumulate in the spleen, liver, lungs, bone marrow, and brain.

Symptoms may be related to the organs in which they accumulate. Enlargement of the liver and spleen (heptosplenomegaly) may cause reduced appetite, abdominal distension and pain, and the enlarged spleen may trap platelets and other blood cells, leading to reduced numbers of these cell in the circulation. Storage in specific areas of the nervous system, causes specific symptoms. For example, storage in the cerebellum causes unsteady gait (ataxia), slurring of speech (dysarthria) and incoordinated swallowing (dysphagia). Basal ganglia dysfunction causes abnormal posturing of the limbs, trunk and face (dystonia) and upper brainstem disease causes impaired voluntary rapid eye movements (supranuclear gaze palsy) and sleep related disorders, including gelastic cataplexy (sudden loss of muscle tone associated with laughter), and sleep inversion (sleepiness during the day and wakefulness at night). More widespread disease involving the cerebral cortex and subcortical structures is responsible for gradual loss of intellectual abilities causing dementia and seizures.

Albert Niemann published the first description of what is now known as Niemann-Pick disease, type A, in 1914 and Ludwig Pick, a German neuropathologist, described the pathology of the disease in a series of papers in the 1930s.

Pick's disease is sometimes confused with Niemann-Pick disease but is a different disease, one of the frontotemporal dementias, described by Arnold Pick.

Genetics

Mutations in the SMPD1 gene cause Niemann-Pick disease types A and B, and mutations in NPC1 and NPC2 cause type C (NPC). Type D was originally separated from type C to delineate a group of otherwise identical patients who shared a common Nova Scotian ancestry. Patients in this group are now known to share a specific mutation in the NPC 1 gene, and NPC is now used to embrace both groups. The terms "Niemann-Pick type I" and "Niemann-Pick type II" were proposed to separate the high and low sphingomyelin forms of the disease in the early 1980s, before the molecular defects were described.

Niemann-Pick disease is inherited in an autosomal recessive pattern, which means both copies, or alleles, of the gene must be mutated (altered in such a way that function is impaired, in contrast to a polymorphism, in which the nucleotide sequence is altered but causes no functional disruption) for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene. If both parents are carriers, there is a 25% chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of Niemann-Pick.

Autosomal recessive inheritence

Classification

In 1961, the following classification was introduced:

• type A - classic infantile
• type B - visceral
• type C - subacute/juvenile
• type D - Nova Scotian

Now that the genetics are better understood, the condition can be classified as follows:

• Niemann-Pick disease, SMPD1-associated, which includes types A and B

• Niemann-Pick disease, type C, which includes types C1 and C2. (Type D is caused by the same gene as type C1.)

Hartnup disease

Hartnup disease, or Hartnup disorder, is an autosomal recessive metabolic disorder affecting the absorption of neutral amino acids (particularly tryptophan that can be, in turn, converted into Serotonin, Melatonin and Niacin). Niacin is a precursor to nicotinamide, a necessary component of NAD+.

The causative gene, SLC6A19, is located on chromosome 5.

Hartnup disease
Tryptophan

Diagnosis

The defective gene controls the absorption of certain amino acids from the intestine and the reabsorption of those amino acids in the kidneys. Consequently, a person with Hartnup disease cannot absorb amino acids properly from the intestine and cannot reabsorb them properly from tubules in the kidneys. Excessive amounts of amino acids, such as tryptophan, are excreted in the urine. The body is thus left with inadequate amounts of amino acids, which are the building blocks of proteinches With too little tryptophan in the blood, the body is unable to make a sufficient amount of the B-complex vitamin niacinamide, particularly under stress when more vitamins are needed.

Causes

Hartnup disease is inherited as an autosomal recessive trait. Heterozygotes are normal. Consanguinity is common. In 2004, a causative gene, SLC6A19, was located on band SLC6A19 is a sodium-dependent and chloride-independent neutral amino acid transporter, expressed predominately in the kidneys and intestine.

Symptoms

Hartnup disease manifest during infancy with variable clinical presentation: failure to thrive, photosensitivity, intermittent ataxia, nystagmus and tremor.

Nicotinamide is necessary for neutral amino acid transporter production in the proximal renal tubules found in the kidney, and intestinal mucosal cells found in the small intestine. Therefore, a symptom stemming from this disorder results in increased amounts of amino acids in the urine.

Pellagra is also caused by low nicotinamide; this disorder results in dermatitis, diarrhea and dementia.

Hartnup disease is a disorder of amino acid transport in the intestine and kidneys; otherwise, the intestine and kidneys function normally, and the effects of the disease occur mainly in the brain and skinches Symptoms may begin in infancy or early childhood, but sometimes they begin as late as early adulthood Symptoms may be triggered by sunlight, fever, drugs, or emotional or physical stress. A period of poor nutrition nearly always precedes an attack. The attacks usually become progressively less frequent with age. Most symptoms occur sporadically and are caused by a deficiency of niacinamide. A rash develops on parts of the body exposed to the sun. Mental retardation, short stature, headaches, an unsteady gait, and collapsing or fainting are common. Psychologic problems (such as anxiety, rapid mood changes, delusions, and hallucinations) may also result.

Treatment

A high-protein diet can overcome the deficient transport of neutral amino acids in most patients. Poor nutrition leads to more frequent and more severe attacks of the disease, which is otherwise asymptomatic Advise all patients who are symptomatic to use physical and chemical protection from sunlight. Avoiding excessive exposure to sunlight, wearing protective clothing, and using physical and chemical sunscreens are mandatory. Recommend sunscreens with a skin protection factor of 15 or greater. Advise patients to avoid other aggravating factors, such as photosensitizing drugs, as much as possible. In patients with niacin deficiency and symptomatic disease, daily supplementation with nicotinic acid or nicotinamide reduces the number and the severity of attacks. Neurologic and psychiatric treatment is needed in patients with severe CNS involvement.

Gaucher's disease

Gaucher's disease is the most common of the lysosomal storage diseases. It is caused by a deficiency of the enzyme glucocerebrosidase, leading to an accumulation of its substrate, the fatty substance glucocerebroside (also known as glucosylceramide). Fatty material can collect in the spleen, liver, kidneys, lungs, brain and bone marrow. Symptoms may include enlarged spleen and liver, liver malfunction, skeletal disorders and bone lesions that may be painful, severe neurologic complications, swelling of lymph nodes and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelets and yellow fatty deposits on the sclera. Persons affected most seriously may also be more susceptible to infection. The disease shows autosomal recessive inheritance and therefore affects both males and females. It is named after the French doctor Philippe Gaucher who originally described it in 1882. The biochemical basis for the disease would be elucidated in 1965 by Brady et al. The first effective treatment for the disease, the drug Ceredase, was approved by the FDA in June 1995. An improved drug, Cerezyme, was approved by the FDA in 2001 and has replaced the use of Ceredase.

Subtypes

Gaucher's disease has three common clinical subtypes.

• Type I (or nonneuropathic type) is the most common form of the disease, occurring in approximately 1 in 50,000 live births. It occurs most often among persons of Ashkenazi Jewish heritage. Symptoms may begin early in life or in adulthood and include enlarged liver and grossly enlarged spleen (together hepatosplenomegaly); the spleen can rupture and cause additional complications. Skeletal weakness and bone disease may be extensive. Spleen enlargement and bone marrow replacement cause anemia, thrombocytopenia and leukopenia. The brain is not affected, but there may be lung and, rarely, kidney impairment. Patients in this group usually bruise easily (due to low levels of platelets) and experience fatigue due to low numbers of red blood cells. Depending on disease onset and severity, type 1 patients may live well into adulthood. Many patients have a mild form of the disease or may not show any symptoms.

• Type II (or acute infantile neuropathic Gaucher's disease) typically begins within 6 months of birth and has an incidence rate of approximately 1 in 100,000 live births. Symptoms include an enlarged liver and spleen, extensive and progressive brain damage, eye movement disorders, spasticity, seizures, limb rigidity, and a poor ability to suck and swallow. Affected children usually die by age 2.

• Type III (the chronic neuropathic form) can begin at any time in childhood or even in adulthood, and occurs in approximately 1 in 100,000 live births. It is characterized by slowly progressive but milder neurologic symptoms compared to the acute or type 2 version. Major symptoms include an enlarged spleen and/or liver, seizures, poor coordination, skeletal irregularities, eye movement disorders, blood disorders including anemia and respiratory problems. Patients often live into their early teen years and adulthood.

These subtypes have come under some criticism for not taking account of the spectrum of observable symptoms (the phenotypes.) There are also compound heterozygous variations which considerably increase the complexity of predicting disease course.

Signs and symptoms

• Painless hepatomegaly and splenomegaly; the size of the spleen can be 1500-3000 ml, as opposed to the normal size of 50-200 ml.
• Hypersplenism: the rapid and premature destruction of blood cells, leading to anemia, neutropenia and thrombocytopenia (with an increased risk of infection and bleeding)
• Cirrhosis of the liver is rare
• Neurological symptoms occur only in some types of Gaucher's (see below):
  • Type II: serious convulsions, hypertonia, mental retardation, apnea.
  • Type III: muscle twitches known as myoclonus, convulsions, dementia, ocular muscle apraxia.
• Osteoporosis: 75% develop visible bony abnormalities due to the accumulated glucosylceramide. A deformity of the distal femur in the shape of an Erlenmeyer flask is commonly described.
• Yellowish-brown skin pigmentation

Diagnosis

A definitive diagnosis is made with genetic testing. As there are numerous different mutations, sequencing of the beta-glucosidase gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available, and is useful when there is a known genetic risk factor.

A diagnosis can also be implied by biochemical abnormalities such as high alkaline phosphatase, angiotensin-converting enzyme (ACE) and immunoglobulin levels, or by cell analysis showing "crinkled paper" cytoplasm and glycolipid-laden macrophages.

Pathophysiology

Acid beta-glucosidase

The disease is caused by a defect in the housekeeping gene lysosomal gluco-cerebrosidase (also known as beta-glucosidase, EC 3.2.1.45, PDB 1OGS) on the first chromosome (1q21). The enzyme is a 55.6 KD, 497 amino acids long protein that catalyses the breakdown of glucocerebroside, a cell membrane constituent of red and white blood cells. The macrophages that clear these cells are unable to eliminate the waste product, which accumulates in fibrils, and turn into Gaucher cells, which appear on light microscopy to resemble crumpled-up paper.

Different mutations in the beta-glucosidase determine the remaining activity of the enzyme, and, to a large extent, the phenotype.

In the brain (type II and III), glucocerebroside accumulates due to the turnover of complex lipids during brain development and the formation of the myelin sheath of nerves.

Research suggests that heterozygotes for particular acid beta-glucosidase mutations are at an increased risk of Parkinson's disease. A study of 1525 Gaucher patients in the United States suggested that while cancer risk is not elevated, particular malignancies (non-Hodgkin lymphoma, melanoma and pancreatic cancer) occurred at a 2-3 times higher rate.

Classification and genetics

The three types of Gaucher's disease are inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of mutations.

Each type has been linked to particular mutations. In all, there are about 80 known mutations, grouped into three main types:

• Type I (N370S homozygote), the most common, also called the "non-neuropathic" type occurs mainly in Ashkenazi Jews, at 100 times the occurence in the general populace. The median age at diagnosis is 28 years of age, and life expectancy is mildly decreased. There are no neurological symptoms.
• Type II (1 or 2 alleles L444P) is characterized by neurological problems in small children. The enzyme is hardly released into the lysosomes. Prognosis is dismal: most die before reaching the third birthday.
• Type III (also 1-2 copies of L444P, possibly delayed by protective polymorphisms) occurs in Swedish patients from the Norrbotten region. This group develops the disease somewhat later, but most die before their 30th birthday.

Diaz et al suggest that the Gaucher-causing mutations entered the Ashkenazi Jewish gene pool in the early Middle Ages (48-55 generations ago).

Epidemiology

• The National Gaucher Foundation states that around 1 in 100 people in the general U.S. population is a carrier for type 1 Gaucher's disease, giving a prevalence of 1 in 40,000: among Ashkenazi Jews the rate of carriers is considerably higher, at roughly 1 in 15.
• Type 2 Gaucher's disease shows no particular preference for any ethnic group.
• Type 3 Gaucher's disease is especially common in the population of the Northern Swedish region of Norrbotten where the incidence of the disease is 1 in 50,000.

Treatment

For type 1 and most type 3 patients, enzyme replacement treatment with intravenous recombinant glucocerebrosidase can dramatically decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations. The rarity of the disease means that dose-finding studies have been difficult to conduct, so there remains controversy over the optimal dose and dosing frequency. Due to the low incidence, this has become an orphan drug in many countries, meaning that a government recognizes and accomodates the financial constraints that limit research into drugs that address a small population.

Successful bone marrow transplantation cures the non-neurological manifestations of the disease, because it introduces a monocyte population with active beta-glucosidase. However, this procedure carries significant risk and is rarely performed in Gaucher patients. Surgery to remove the spleen (splenectomy) may be required on rare occasions if the patient is anemic or when the enlarged organ affects the patient’s comfort. Blood transfusion may benefit some anemic patients. Other patients may require joint replacement surgery to improve mobility and quality of life. Other treatment options include antibiotics for infections, antiepileptics for seizures, bisphosphonates for bone lesions, and liver transplants. Substrate reduction therapy may prove to be effective in stopping Type 2, as it can cross through the blood barrier into the brain. There is currently no effective treatment for the severe brain damage that may occur in patients with types 2 and 3 Gaucher disease. Gene therapy may be a future step.

Gaucher's disease has recently become a target for more than one effort at pharmacological chaperoning, which involves the use of orally administered drugs that operate at a molecular level.

The currently existing treatment of Gaucher's disease, Cerezyme (imiglucerase for injection), costs up to $550,000 annually for a single patient and the treatment should be continued for life. This recombinant beta-glucosidase is given intravenously. Miglustat is another drug approved for this disease in 2003.

Cerebral palsy

Cerebral palsy

Cerebral palsy (CP) is an umbrella term encompassing a group of non-progressive, non-contagious conditions that cause physical disability in human development.

Cerebral refers to the cerebrum, which is the affected area of the brain (although the disorder most likely involves connections between the cortex and other parts of the brain such as the cerebellum), and palsy refers to disorder of movement. CP is caused by damage to the motor control centers of the young developing brain and can occur during pregnancy (about 75 percent), during childbirth (about 5 percent) or after birth (about 15 percent) up to about age three.

It is a non-progressive disorder, meaning the brain damage does not worsen, but secondary orthopedic difficulties are common. There is no known cure for CP. Medical intervention is limited to the treatment and prevention of complications arising from CP's effects.

Onset of arthritis and osteoporosis can occur much sooner in adults with cerebral palsy. Further research is needed on adults with CP, as the current literature body is highly focused on the pediatric patient. CP's resultant motor disorder(s) are sometimes, though not always, accompanied by "disturbances of sensation, cognition, communication, perception, and/or behavior, and/or by a seizure disorder".

A 2003 study put the economic cost for CP suffers in the US at $921,000 per case, including lost income. In another study, the incidence in six countries surveyed was 2.12–2.45 per 1000 live births; there has been a slight increase in recent years. Although improvements in neonatal nursing help reduce the number of babies who develop cerebral palsy, they also mean that babies with very low birth weights survive, and these babies are more likely to have cerebral palsy.

Classification

CP is divided into four major classifications to describe the different movement impairments. These classifications reflect the area of brain damaged. The four major classifications are:

• Spastic
• Athetoid/Dyskinetic
• Ataxic
• Mixed

In 30 percent of all cases of CP, the spastic form is found along with one of the other types. There are a number of other, less prevalent types of CP, but these are the most common.

A general classification is as follows:

Spastic

Spastic cerebral palsy is by far the most common type, occurring in 70% to 80% of all cases. People with this type are hypertonic and have a neuromuscular condition stemming from damage to the corticospinal tract or the motor cortex that affects the nervous system's ability to receive gamma amino butyric acid in the area(s) affected by the disability . Spastic CP is further classified by topography dependent on the region of the body affected; these include:

• Spastic hemiplegia (one side being affected). Generally, injury to the left side of the brain will cause a right body deficit, and vice versa. Typically, people that suffer from this type of cerebral palsy are the most ambulatory, although they generally have dynamic equinus on the affected side and are primarily prescribed ankle-foot orthoses to prevent said equinus.
• Spastic diplegia (the lower extremities are affected more than the upper extremities). Most people with disabled diplegia do eventually walk. The gait of a person with Cerebral Palsy diplegia is typically characterised by a crouched gait. Toe walking and flexed knees are common. Hip problems, dislocations, and side effects like strabismus (crossed eyes) are common. Strabismus affects three quarters of people with spastic diplegia. This is due to weakness of the muscles that control eye movement. In addition, these individuals are often nearsighted. In many cases the intelligence of a person with spastic diplegia is unaffected by the condition.
• Spastic quadriplegia (Whole body affected; all four limbs affected equally). Some children with quadriplegia also have hemiparetic tremors; an uncontrollable shaking that affects the limbs on one side of the body and impairs normal movement. A common problem for children with quadriplegia is fluid buildup. Diuretics and steroids are medications administered to decrease any buildup of fluid in the spine that is caused by leakage from dead cells. Hardened feces in a quadriplegia patient are important to monitor because it can cause high blood pressure. Autonomic dysreflexia can be caused by hardened feces, urinary infections, and other problems, resulting in the overreaction of the nervous system and can result in high blood pressure, heart attacks, and strokes. Blockage of tubes inserted into the body to drain or enter fluids also needs to be monitored to prevent autonomic dysreflexia in quadriplegia. The proper functioning of the digestive system needs to be monitored as well.

Occasionally, terms such as monoplegia, paraplegia, triplegia, and pentaplegia may also be used to refer to specific manifestations of the spasticity.

Ataxic

Ataxia (ICD-10 G80.4) type symptoms can be caused by damage to the cerebellum. Forms of ataxia are less common types of Cerebral Palsy, occurring in at most 10% of all cases. Some of these individuals have hypotonia and tremors. Motor skills like writing, typing, or using scissors might be affected, as well as balance, especially while walking. It is common for individuals to have difficulty with visual and/or auditory processing of objects.

Athetoid/dyskinetic

Athetoid or dyskinetic is mixed muscle tone—sometimes hypertonia and sometimes hypotonia (Hypotonia will usually occur before 1 year old; the muscle tone will be increased with age and progress to Hypertonia). People with athetoid CP have trouble holding themselves in an upright, steady position for sitting or walking, and often show involuntary motions. For some people with athetoid CP, it takes a lot of work and concentration to get their hand to a certain spot (like scratching their nose or reaching for a cup). Because of their mixed tone and trouble keeping a position, they may not be able to hold onto objects (such as a toothbrush or pencil). About one quarter of all people with CP have athetoid CP. The damage occurs to the extrapyramidal motor system and/or pyramidal tract and to the basal ganglia. It occurs in 40% of all cases.

Incidence and prevalence

In the industrialised world, the incidence of cerebral palsy is about 2 per 1000 live births. The incidence is higher in males than in females; the Surveillance of Cerebral Palsy in Europe (SCPE) reports a M:F ratio of 1.33:1. Variances in reported rates of incidence across different geographical areas in industrialised countries are thought to be caused primarily by discrepancies in the criteria used for inclusion and exclusion. When such discrepancies are taken into account in comparing two or more registers of patients with cerebral palsy (for example, the extent to which children with mild cerebral palsy are included), the incidence rates converge toward the average rate of 2:1000.

In the United States, approximately 10,000 infants and babies are diagnosed with CP each year, and 1200-1500 are diagnosed at preschool age.

Overall, advances in care of pregnant mothers and their babies has not resulted in a noticeable decrease in CP. This is generally attributed to medical advances in areas related to the care of premature babies (which results in a greater survival rate). Only the introduction of quality medical care to locations with less-than-adequate medical care has shown any decreases. The incidence of CP increases with premature or very low-weight babies regardless of the quality of care.

Prevalence of cerebral palsy is best calculated around the school entry age of about six years, the prevalence in the U.S. is estimated to be 2.4 out of 1000 children

The SCPE reported the following incidence of comorbidities in children with CP (the data are from 1980-1990 and included over 4,500 children over age 4 whose CP was acquired during the prenatal or neonatal period):

• Mental retardation (IQ <>
• Active seizures: 21%
• Mental retardation (IQ <>
• Blindness: 11%

The SCPE noted that the incidence of comorbidities is difficult to measure accurately, particularly across centers. For example, the actual rate of mental retardation may be difficult to determine, as the physical and communicational limitations of people with CP would likely lower their scores on an IQ test if they were not given a correctly modified version.

Apgar scores have sometimes been used as one factor to predict whether or not an individual will develop CP.

Symptoms

All types of CP are characterized by abnormal muscle tone(i.e. slouching over while sitting), reflexes, or motor development and coordination. There can be joint and bone deformities and contractures (permanently fixed, tight muscles and joints). The classical symptoms are spasticity, spasms, other involuntary movements (e.g. facial gestures), unsteady gait, problems with balance, and/or soft tissue findings consisting largely of decreased muscle mass. Scissor walking (where the knees come in and cross) and toe walking (which can contribute to a gait reminiscent of a marionette) are common among people with CP who are able to walk, but taken on the whole, CP symptomatology is very diverse. The effects of cerebral palsy fall on a continuum of motor dysfunction which may range from virtually unnoticeable to "clumsy" and awkward movements on one end of the spectrum to such severe impairments that coordinated movements are almost impossible on the other end of the spectrum.

Babies born with severe CP often have an irregular posture; their bodies may be either very floppy or very stiff. Birth defects, such as spinal curvature, a small jawbone, or a small head sometimes occur along with CP. Symptoms may appear, change, or become more severe as a child gets older. Some babies born with CP do not show obvious signs right away.

Secondary conditions can include seizures, epilepsy, speech or communication disorders, eating problems, sensory impairments, mental retardation, learning disabilities, and/or behavioral disorders.

History

CP, then known as "Cerebral Paralysis", was first identified by English surgeon William Little in 1860. Little raised the possibility of asphyxia during birth as a chief cause of the disorder. It was not until 1897 that Sigmund Freud, then a neurologist, suggested that a difficult birth was not the cause but rather only a symptom of other effects on fetal development. Research conducted during the 1980s by the National Institute of Neurological Disorders and Stroke (NINDS) suggested that only a small number of cases of CP are caused by lack of oxygen during birth.

Causes

Despite years of debate, the cause of the majority of cases of CP is uncertain.

Some contributing causes of CP are asphyxia, hypoxia of the brain, birth trauma, premature birth, central nervous system infections and certain infections in the mother during and before birth. CP is also more common in multiple birth.

Studies at the University of Liverpool have led to the hypothesis that many cases of cerebral palsy, and other conditions that an infant has at birth, are caused by the death in very early pregnancy of an identical twin. This may occur when twins have a joint circulation through sharing the same placenta. Not all identical twins share the same blood supply (monochorionic twins), but if they do, the suggestion is that perturbations in blood flow between them can cause the death of one and damage to the development of the surviving fetus. It is common knowledge amongst obstetricians and midwives that a small dead fetus (fetus papyraceus) may sometimes be found attached to a placenta following birth. In the past, this has not been considered important and knowledge of the so called ‘vanishing twin’ has been suppressed to avoid triggering feelings of loss, grief, or guilt in mothers. The pathological consequences depend on the severity and the stage of development of the fetus when the imbalances in blood flow between the fetuses occur. It has been proposed that such pathology could account, not just for cerebral palsy, but for developmental abnormalities of the eye, heart, and gut, and other specific brain abnormalities such as neuronal migration disorders e.g. lissencephaly and holoprosencephaly, which occur during very early fetal development.

Between 40% and 50% of all children who develop cerebral palsy were born prematurely. Premature infants are vulnerable, in part because their organs are not fully developed, increasing the risk of hypoxic injury to the brain that may manifest as CP. A problem in interpreting this is the difficulty in differentiating between CP caused by damage to the brain that results from inadequate oxygenation and CP that arises from prenatal brain damage that then precipitates premature delivery.

Recent research has demonstrated that intrapartum asphyxia is not the most important cause, probably accounting for no more than 10 percent of all cases; rather, infections in the mother, even infections that are not easily detected, may triple the risk of the child developing the disorder, mainly as the result of the toxicity to the fetal brain of cytokines that are produced as part of the inflammatory response. Low birthweight is a risk factor for CP--and premature infants usually have low birth weights, less than 2.0 kg, but full-term infants can also have low birth weights. Multiple-birth infants are also more likely than single-birth infants to be born early or with a low birth weight.

After birth, other causes include toxins, severe jaundice, lead poisoning, physical brain injury, shaken baby syndrome, incidents involving hypoxia to the brain (such as near drowning), and encephalitis or meningitis. The three most common causes of asphyxia in the young child are: choking on foreign objects such as toys and pieces of food; poisoning; and near drowning.

Some structural brain anomalies such as lissencephaly may present with the clinical features of CP, although whether that could be considered CP is a matter of opinion (some people say CP must be due to brain damage, whereas these people never had a normal brain). Often this goes along with rare chromosome disorders and CP is not genetic or hereditary.

Diagnosis

The diagnosis of cerebral palsy has historically rested on the patient's history and physical examination. Once diagnosed with cerebral palsy, further diagnostic tests are optional. The American Academy of Neurology published an article in 2004 reviewing the literature and evidence available on CT and MRI imaging. They suggested that neuroimaging with CT or MRI is warranted when the etiology of a patient's cerebral palsy has not been established - an MRI is preferred over CT due to diagnostic yield and safety. When abnormal, the neuroimaging study can suggest the timing of the initial damage. The CT or MRI is also capable of revealing treatable conditions, such as hydrocephalus, porencephaly, arteriovenous malformation, subdural hematomas and hygromas, and a vermian tumor (which a few studies suggest are present 5 to 22%). Furthermore, an abnormal neuroimaging study indicates a high likelihood of associated conditions, such as epilepsy and mental retardation.

Presentation: bones

In order for bones to attain their normal shape and size, they require the stresses from normal musculature. Osseous findings will therefore mirror the specific muscular deficits in a given person with CP. The shafts of the bones are often thin (gracile). When compared to these thin shafts (diaphyses) the metaphyses often appear quite enlarged (ballooning). With lack of use, articular cartilage may atrophy, leading to narrowed joint spaces. Depending on the degree of spasticity, a person with CP may exhibit a variety of angular joint deformities. Because vertebral bodies need vertical gravitational loading forces to develop properly, spasticity and an abnormal gait can hinder proper and/or full bone and skeletal development. People with CP tend to be shorter in height than the average person because their bones are not allowed to grow to their full potential. Sometimes bones grow at different lengths, so the person may have one leg longer than the other.

Prognosis

CP is not a progressive disorder (meaning the actual brain damage does not worsen), but the symptoms can become worse over time due to 'subdual damage.' A person with the disorder may improve somewhat during childhood if he or she receives extensive care from specialists, but once bones and musculature become more established, orthopedic surgery may be required for fundamental improvement. People who have CP tend to develop arthritis at a younger age than normal because of the pressure placed on joints by excessively toned and stiff muscles.

The full intellectual potential of a child born with CP will often not be known until the child starts school. People with CP are more likely to have some type of learning disability, but this is not related to a person's intellect or IQ level. Intellectual level among people with CP varies from genius to mentally retarded, as it does in the general population, and experts have stated that it is important to not underestimate CP sufferer's capabilities and to give them every opportunity to learn.

The ability to live independently with CP also varies widely depending on the severity of the disability. Some individuals with CP will require personal assistant services for all activities of daily living. Others can live semi-independently, needing support only for certain activities. Still others can live in complete independence. The need for personal assistance often changes with increasing age and associated functional decline. However, in most cases persons with CP can expect to have a normal life expectancy; survival has been shown to be associated with the ability to ambulate, roll, and self-feed. As the condition does not directly affect reproductive function, some persons with CP have children and parent successfully.

According to OMIM, only 2% of cases of CP are inherited (with glutamate decarboxylase-1 as one known enzyme involved.) There is no evidence of an increased chance of a person with CP having a child with CP.

Treatment

There is no cure for CP, but various forms of therapy can help a person with the disorder to function and live more effectively. In general, the earlier treatment begins the better chance children have of overcoming developmental disabilities or learning new ways to accomplish the tasks that challenge them. The earliest proven intervention occurs during the infant's recovery in the neonatal intensive care unit (NICU). Treatment may include one or more of the following: physical therapy; occupational therapy; speech therapy; drugs to control seizures, alleviate pain, or relax muscle spasms (e.g. benzodiazepienes, baclofen and intrathecal phenol/baclofen); hyperbaric oxygen; the use of Botox to relax contracting muscles; surgery to correct anatomical abnormalities or release tight muscles; braces and other orthotic devices; rolling walkers; and communication aids such as computers with attached voice synthesizers. For instance, the use of a standing frame can help reduce spasticity and improve range of motion for people with CP who use wheelchairs. Nevertheless, there is only some benefit from therapy. Treatment is usually symptomatic and focuses on helping the person to develop as many motor skills as possible or to learn how to compensate for the lack of them. Non-speaking people with CP are often successful availing themselves of augmentative and alternative communication systems such as Blissymbols.

Early Nutritional Support In one cohort study of 490 premature infants discharged from the NICU, the rate of growth during hospital stay was related to neurological function at 18 and 22 months of age. The study found a signficant decrease in the incidence of cerebral palsy in the group of premature infants with the highest growth velocity. This study suggests that adequate nutrition and growth play a protective role in the development of cerebral palsy.

Physical therapy (PT) programs are designed to encourage the patient to build a strength base for improved gait and volitional movement, together with stretching programs to limit contractures. Many experts believe that life-long physical therapy is crucial to maintain muscle tone, bone structure, and prevent dislocation of the joints.

Occupational therapy helps adults and children maximise their function, adapt to their limitations and live as independently as possible.

Orthotic devices such as ankle-foot orthoses (AFOs) are often prescribed to minimise gait irregularities. AFOs have been found to improve several measures of ambulation, including reducing energy expenditure and increasing speed and stride length.

Speech therapy helps control the muscles of the mouth and jaw, and helps improve communication. Just as CP can affect the way a person moves their arms and legs, it can also affect the way they move their mouth, face and head. This can make it hard for the person to breathe; talk clearly; and bite, chew and swallow food. Speech therapy often starts before a child begins school and continues throughout the school years.

Advanced Biomechanical Rehabilitation (ABR) ABR is a unique biomechanically based rehabilitation approach for children and young adults with brain injury that brings predictable recovery of musculoskeletal structure and motor functions. ABR improves musculoskeletal structure so significantly that normal motor functions recover spontaneously, making special training and management for "motor disabled" unnecessary.

Hyperbaric oxygen therapy Recent studies have demonstrated a dramatic improvement in CP symptomology when hyperbaric oxygen therapy is used as a treatment. In 1989, researchers in Brazil reported an alleviation in symptomology and other characteristics in a study involving 218 cerebral palsy patients. Significant enhancements were documented showing improved vision, hearing and speech as well as a reduction of spasticity by 50%, which occurred in 94% of study patients. Since the publication of the São Paulo review, other studies on the efficacy of hyperbaric oxygenation have been published though the number of subjects have remained low. An editorial published by the Undersea and Hyperbaric Medical Society in 2007 reviewed all publications to date and called for further research that will include "basic science research to determine a reasonable mechanism of action" for hyperbaric oxygenation as well as "clinical studies of the highest possible methodological rigor".

Nutritional counseling may help when dietary needs are not met because of problems with eating certain foods.

Both massage therapy and hatha yoga are designed to help relax tense muscles, strengthen muscles, and keep joints flexible. Hatha yoga breathing exercises are sometimes used to try to prevent lung infections. More research is needed to determine the health benefits of these therapies for people with CP.

Surgery for people with CP usually involves one or a combination of:

• Loosening tight muscles and releasing fixed joints, most often performed on the hips, knees, hamstrings, and ankles. In rare cases, this surgery may be used for people with stiffness of their elbows, wrists, hands, and fingers.

• The insertion of a Baclofen Pump usually during the stages while a patient is a young adult. This is usually placed in the left abdomen. It is a pump that is connected to the spinal cord, whereby it sends bits of Baclofen aleiviating the continuous muscle flexation. Baclofen in an of itself is a muscle relaxer and is often given PO to patients to help counter the effects of spasticity.

• Straightening abnormal twists of the leg bones, i.e. femur (termed femoral anteversion or antetorsion) and tibia (tibial torsion). This is a secondary complication caused by the spastic muscles generating abnormal forces on the bones, and often results in intoeing (pigeon-toed gait). The surgery is called derotation osteotomy, in which the bone is broken (cut) and then set in the correct alignment.

• Cutting nerves on the limbs most affected by movements and spasms. This procedure, called a rhizotomy, "rhizo" meaning root and "tomy" meaning "a cutting of" from the Greek suffix 'tomia' reduces spasms and allows more flexibility and control of the affected limbs and joints.

• Botulinum Toxin A (Botox) injections into muscles that are either spastic or have contractures, the aim being to relieve the disability and pain produced by the inappropriately contracting muscle.

Another way is that a new study has found that cooling the bodies and blood of high-risk full-term babies shortly after birth may significantly reduce disability or death.

Cord Blood Therapy: There are no published randomized controlled trials or meta-analysis of this treatment modality in cerebral palsy. In March 2008 a boy that was diagnosed with cerebral palsy appeared on the Today Show with his family. The parents noted that he could not walk on his own and appeared to be "swallowing his tongue" at times. He was eventually diagnosed with cerebral palsy and could only walk with the aid of a walker for a short time. Earlier this year he participated in a clinical trial involving his own cord blood that his parents had saved when he was born. Within 5 days after the procedure he was walking on his own and talking, something his mother said he was not capable of on his own and it was doubtful he would ever be able to do on his own. The doctors also told his parents that if his rate of progress continues uninterrupted until he is 7 he will be pronounced cured. The parents message to the audience was "Bank your babies cord blood or donate it if you do not want to keep it. But you never know when you may need it."

Conductive education (CE) was developed in Hungary from 1945 based on the work of András Pető. It is a unified system of rehabilitation for people with neurological disorders including cerebral palsy, Parkinson's disease and multiple sclerosis, amongst other conditions. It is theorised to improve mobility, self-esteem, stamina and independence as well as daily living skills and social skills. The conductor is the professional who delivers CE in partnership with parents and children. Skills learned during CE should be applied to everyday life and can help to develop age-appropriate cognitive, social and emotional skills. It is available at specialised centres.

Biofeedback is an alternative therapy in which people with CP learn how to control their affected muscles. Some people learn ways to reduce muscle tension with this technique. Biofeedback does not help everyone with CP.

Neuro - cognitive therapy. A new approach to treating cerebral palsy from [Snowdrop]. It is based upon two proven principles. (1). Neural Plasticity. The brain is capable of altering its own structure and functioning to meet the demands of any particular environment. Consequently if the child is provided with an appropriate neurological environment, he will have the best chance of making progress. (2)Learning can lead development. As early as the early 1900s, this was being proven by a psychologist named Lev Vygotsky. He proposed that children's learning is a social activity, which is achieved by interaction with more skilled members of society. There are many studies, which provide evidence for this claim. there are however, as yet no controlled studies on neuro - cognitive therapy.

Patterning is a controversial form of alternative therapy for people with CP. The method is promoted by The Institutes for the Achievement of Human Potential (IAHP), a Philadelphia nonprofit, but has been criticized by the American Academy of Pediatrics. The IAHP's methods have been endorsed by Linus Pauling, as well as some parents of children treated with their methods.

Cultural aspects

Use of terms when referring to people with CP

Many people would rather be referred to as a person with a disability instead of handicapped. "Cerebral Palsy: A Guide for Care" at the University of Delaware offers the following guidelines:

Impairment is the correct term to use to define a deviation from normal, such as not being able to make a muscle move or not being able to control an unwanted movement. Disability is the term used to define a restriction in the ability to perform a normal activity of daily living which someone of the same age is able to perform. For example, a three year old child who is not able to walk has a disability because normal three year old can walk independently. Handicap is the term used to describe a child or adult who, because of the disability, is unable to achieve the normal role in society commensurate with his age and socio-cultural milieu. As an example, a sixteen-year- old who is unable to prepare his own meal or care for his own toileting or hygiene needs is handicapped. On the other hand, a sixteen-year- old who can walk only with the assistance of crutches but who attends a regular school and is fully independent in activities of daily living is disabled but not handicapped. All disabled people are impaired, and all handicapped people are disabled, but a person can be impaired and not necessarily be disabled, and a person can be disabled without being handicapped.

The term "spastic" describes the attribute of spasticity in types of spastic CP. In 1952 a UK charity called The Spastics Society was formed. The term "spastics" was used by the charity as a term for people with CP. The word "spaz" has since been used extensively as a general insult to disabled people, which some see as extremely offensive. It is also frequently used to insult able-bodied people when they seem overly anxious or unskilled in sports. The charity changed its name to Scope in 1994. In the United States the word spaz has the same usage as an insult, but is not generally associated with CP.

Misconceptions

A common misconception about those born with Cerebral Palsy is that they are less intelligent than those born without it. Cerebral Palsy is defined as damage to the part of the brain that controls movement; areas of the brain that define a person's intelligence are not affected by CP.

Spastic Cerebral Palsy, the most common form of CP, causes the muscles to be tense, rigid and movements are slow and difficult. This can be misinterpreted as cognitive delay due to difficulty of communication. Individuals with cerebral palsy can have learning difficulties, but sometimes it is the sheer magnitude of problems caused by the underlying brain injury that prevents the individual from expressing what cognitive abilities they do possess.

Public perception

Those with CP are sometimes stigmatized and shunned. This has lessened since the 1950s thanks to public education and to United Cerebral Palsy in the U.S. and similar organizations in other countries. Prior to that time the great majority were often sent to asylums or confined to attics. They were perceived to be the products of incest and partial smothering.

Thomas Galton believed that there was a correlation between physical disability and aptitude, and this attitude remained prevalent as concerned CP until the 1970s.

Only individuals with brain damage in the hippocampus or the frontal cerebral cortex develop mental retardation. While learning difficulties and CP may be associated, it is common for individuals with CP to lead normal lives.

Ataxia telangiectasia

Ataxia-telangiectasia (AT) (Boder-Sedgwick syndrome or Louis-Bar syndrome) is a rare, neurodegenerative, inherited disease which affects many parts of the body and causes severe disability. Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both of which are hallmarks of the disease.

AT affects the cerebellum (the body's motor control centre) and also weakens the immune system in about 70% of cases, leading to respiratory disorders and increased risk of cancer. It first appears in early childhood (the toddler stage) with symptoms such as lack of balance, slurred speech, and increased infections. Because all children at this age take time to develop good walking skills, coherent speech, and an effective immune system, it may be some years before AT is properly diagnosed.

Classification

So far there appear to be three forms of AT:

1. Pure AT where patients present with all/most of the diagnostic symptoms.
2. Attenuated AT where sufferers do not possess all of the diagnostic symptoms.
3. Carrier AT where individuals with a single ATM mutation show an increased risk of cancer

These are sometimes classified into ‘types’ from I to IV.

• Type I is the classic syndrome with all manifestations.
• Type II lacks some of the typical findings but shows radiosensitivity.
• Type III has the classic clinical findings but is not radiosensitive.
• Type IV shows only some clinical features and is not radiosensitive.

Differential diagnosis

There are several other disorders with similar symptoms that physicians may consider when diagnosing AT. These include:

• Ataxia oculomotor apraxia type 1
  
• Ataxia oculomotor apraxia type 2
• Cerebral palsy
• Gaucher disease
• Hartnup disease
• Niemann-Pick disease
• Nijmegen breakage syndrome (NBS)
• Refsum disease

Ataxia-telangiectasia like disorder (ATLD) is an extremely rare condition which could be considered in the differential diagnosis of AT. ATLD patients are very similar to AT patients in showing a progressive cerebellar ataxia, hypersensitivity to ionising radiation and genomic instability. However, ATLD can be distinguished from AT by the absence of telangiectasias, normal immunoglobulin levels, a later onset of the condition and a slower progression of the disease. It is not known whether ATLD individuals are also predisposed to tumours. The gene mutated in ATLD is hMre11 and is located on chromosome 11q21.

Interestingly, the proteins expressed by the hMre11 (defecting in ATLD) and Nbs1 (defective in NBS) genes exist in the cell as a complex, along with a third protein expressed by the hRad50 gene. This complex, known as the MRN complex, plays an important role in DNA damage repair and signalling and is required to recruit ATM to the sites of DNA double strand breaks. Mre11 and Nbs1 are also targets for phosphorylation by the ATM kinase. Thus, the similarity of the three diseases can be explained in part by the fact that the protein products of the three genes mutated in these disorders interact in common pathways in the cell.

Signs and Symptoms

AT is characterised by:

• Early-onset progressive cerebellar ataxia (difficulty with control of movement)
• Telangiectasias of the eyes and skin
• Immunodeficiency mostly thorough lowering of IgA, IgG and IgE levels.
• Chromosomal instability
• Hyper-sensitivity to ionising radiation
• Increased incidence of malignancies (primarily hematologic).
• Raised alpha-fetoprotein levels.

Initially it may be hard to be sure that anything is amiss and some children seem to improve from 3 to 5 years, but eventually it becomes obvious that balance control is abnormal. Towards the end of the first decade and the start of the second other problems come to light; these can be as handicapping as the loss of body balance control. Because AT can have somewhat incomplete penetrance, some patients have a mild form of the disease that starts later and has less severe symptoms.

Ataxia

The first indications of AT usually occur during the toddler years. These first signs indicate difficulty with control of the body posture and body movement (truncal ataxia). The child may start to walk later than usual (after 18 months), may be reluctant to let go of supporting people or objects, may continue to walk unsteadily for longer than normal, may be unable to stand still without tottering, and may fall frequently.

Walking becomes more strenuous and appears awkward, doors and walls are frequently used for support. Running may, for a time, seem less affected; this is because less balance is needed for quick movements than slower graceful ones. At the beginning of the second decade of their lives most people with AT begin to use a wheelchair.

Co-ordination of limbs becomes abnormal ("peripheral ataxia") later in the disease. Involuntary movements may start in some patients, and generally become worse over time. They may include small jerks of the hands and feet which look like fidgeting (chorea), slower twisting movements of the upper body (athetosis), adoption of stiff and twisted postures (dystonia), occasional uncontrolled jerks (myoclonic jerks), and shaking episodes of a limb which are like shivering (tremors).

Slurring of speech (dysarthria) may develop in the first decade, becoming worse for 5 to 10 years and then remaining a static problem. Patients generally can be understood, although conversation may be a slow process. Eye movements become restricted (vertical and horizontal sacchadic apraxia). Reading and following moving objects becomes difficult.

Telangiectasia

Prominent blood vessels in the whites of the eyes (telangiesctasias) usually occur by the age of 5 years. These are the ocular telangiectasia of the condition and resemble those vessels seen in the eyes of much older people. They can occasionally be present at birth yet in others may not develop until the teenage years. Although potentially a cosmetic problem they do not bleed or itch. It is their constant nature, not changing with time, weather or emotion, which marks them as different from other eye blood vessels.

Immune problems

About half the people with AT have immune problems. These usually take the form of repeated colds and runny noses (sinopulmonary infections). The immune system is complex and difficult to assess, but if the child is suffering more than his/her fair share of infections a physician should undertake this assessment. Some people with A-T need additional immunisations (DPT, Hib and Pneumovax), others need continued antibiotics to provide "background cover" and some need injections of immunoglobulins (proteins that the body makes to fight infections). Others are never troubled. The impression is that bacterial, rather than viral, infections are the most trouble.

Other features

People with AT have an increased incidence (probably 1% risk per year) of tumours, particularly lymphomas and leukaemia. It has been reported that there is a small increased risk of breast cancer in mothers of children with AT. This finding is the subject of much debate and research at present. Mammography before 50 years however is not recommended unless there is a strong family history of breast cancer.

Although people with AT have an increased sensitivity to ionising radiation (X-rays and gamma rays), they cope with other forms of radiation normally, i.e. obtaining a suntan from ultraviolet light. Also, the tumours seen in AT are not thought to be radiation induced. Finally, normal X-rays of arms and chest and any necessary dental X-rays are not thought to produce enough radiation to be harmful.

Mental retardation is not seen in AT. However, many children seem to have slower thinking speed. Some children are placed in special schools while others remain in mainstream schools, even graduating from university.

AT patients are often very thin. This may be due to a poor appetite, to the energy expended with involuntary movements, or the inherent characteristics of the disorder. Some people with A-T, both males and females, have a delayed puberty. This seems more common in those who are thin or are prone to infections.

Genetics

AT is inherited in an autosomal recessive fashion.

A-T usually runs in families. The mode of inheritance is autosomal recessive, so in a family with two parents who are carriers of the AT allele, there is 1 chance in 4 that each child born to the parents will have the disorder. Prenatal diagnosis can be carried out in most families, but this is complex and must be arranged before conception.

AT is caused by mutations in the ATM gene located on chromosome 11q22-23. It was characterised in June 1995 and is made up of 66 exons spread across 150kb of genomic DNA. It encodes a 13kb mature transcript with an open reading frame of 9168 nucleotides. The ATM protein is about 370kDa and is ubiquitously expressed and is localised to the cell nucleus. The ATM protein is a large serine-threonine kinase thought to play a role in regulating cell cycle checkpoints, repair of double stranded DNA and meiosis (similar to the BRCA genes). ATM is also known to play a role in regulating p53, BRCA1 and CHEK2. Part of ATM’s role in DNA repair is known to be that of telomere repair as telomeres degrade more rapidly in people affected with AT.

Mutations in the ATM gene are thought to come in two types:

• Null mutations are those which cause complete loss of function of the protein and are therefore inherited in a recessive manner and cause AT.
• ‘Missense’ mutations which produce stable, full sized protein with reduced function e.g. substitutions, short in-frame insertions and deletions etc. These mutations act by dominantly interfering with the normal copy of the protein.

The majority of AT sufferers, 65-70%, have truncating mutations, with exon skipping mutations being particularly common. This results in very low or undetectable levels of ATM protein. Missense mutations are the most common type of mutation found in carriers with breast cancer. Individuals with two missense mutations are believed to have a milder form of AT, which may account for cases of attenuated AT. Therefore it is thought that "subtle constitutional alterations of ATM may impart an increased risk of developing breast cancer and therefore act as a low penetrance, high prevalence gene in the general population" (Maillet et al 2002).

Oculo-cutaneous telangiectasia combined with ataxia are the defining features of the condition. However, some patients with AT, even those with two null mutations who produce no ATM protein at all, may never present with oculo-cutaneous telangiectasia.

ATM Carriers

Carriers of ATM missense mutations are believed to have a 60% penetrance by age 70 and a risk of breast cancer 16 times higher that of the normal population, with a 5-8 fold increased risk of cancer. On average carriers die 7-8 years earlier than the normal population, often from heart disease. Some papers state a lifetime risk for people with both null and missense mutations of 10-38%, which is still a hundredfold increase from population risk.

Individuals with a single ATM mutation are also at a higher risk from lung, gastric and lymphoid tumours, as well as breast cancer. S707P is known to be particularly common in breast cancer patients and F1463S is known to be associated with Hodgkin’s lymphoma. If pulmonary infections could be completely eradicated AT is consistent with survival into the 5th or 6th decade.

Diagnosis

Diagnosis is usually achieved clinically by examination and identification of both ataxia and oculo-telangiectasia. This is then followed by laboratory tests for serum AFP level, the response of white blood cells to X-rays and measurement of the level of ATM protein. Sufferers may also have a low lymphocyte count and other immunological abnormalities. This can then be followed by cytogenetic and molecular testing to confirm the diagnosis. MRI and CT scans may show signs of cerebellar atrophy.

Molecular diagnosis of AT can be carried out by sequencing all 66 exon of the gene or by linkage if there is a significant family history. Protein functionality testing is also available. However AT testing is usually carried out cytogenetically as specific breakpoints and cytogenetic instability are major characteristic features of the disorder. This must be carried out on lymphocytes. 10% of patients with AT show balanced translocations, 2/3rds of which involve the immunoglobulin genes on chromosomes 7 and 14. Some patients show expansions in their immunoglobulin genes which can expand during mitosis resulting in prolymphocyte leukaemia.

Antenatal diagnosis can be carried out using linkage and microsatellite markers. However, direct gene analysis between known sufferers and the foetus is more common.

Pathophysiology

The responsible gene in AT, ataxia-telangiectasia mutated (ATM), was discovered in 1995 by Savitsky et al. a team led by Yosef Shiloh of Tel Aviv University in Israel. Researchers linked the hyper-sensitivity of AT patients to ionizing radiation (IR) and predisposition to cancer, to "chromosomal instability, abnormalities in genetic recombination, and defective signaling to programmed cell death and several cell cycle checkpoints activated by DNA damage". Earlier observations predicted that the gene altered in AT played a role in DNA damage recognition. These predictions were confirmed when a single gene on chromosome 11 (11q 22-23) was discovered. Since its discovery, the protein product of the ATM gene has been shown to be a part of eukaryotic cell cycle control, DNA repair, and DNA recombination (Lavin, 2004). Specifically, the AT gene serves as a tumor suppressor gene by contributing to a network of genes that link double stranded breaks in DNA to cell cycle arrest and apoptosis (programmed cell death). Patients with ATM have a defective AT gene, which leaves them susceptible to contracting cancer. For example, female ATM patients have a two-fold higher chance of ever having breast cancer, which often occur before the age of 50. ATM patients must try avoiding x-rays at all costs since the radiation induces double-stranded breaks.

Management

Treatment is symptomatic and supportive. Physical and occupational therapy may help maintain flexibility. Speech therapy may also be needed. Gamma-globulin injections may be given to help supplement a weakened immune system. High-dose vitamin regimens may also be used. Antibiotics are used to treat infections. Some physicians recommend low doses of chemotherapy to reduce the risk of cancer but this is controversial. It is also recommended that heterozygote family members are regularly monitored for cancers. Recently deferoxamine was shown to increase the stability of AT cells and may prove to be an effective treatment for the disorder.

People with A-T have an increased incidence (probably 1% risk per year) of tumours, particularly lymphomas and leukaemia, but due to sufferers' hyper-sensitivity to ionising radiation, radiotherapy and chemotherapy are rarely used.

Prognosis

Those with AT usually die in their teens or early 20s although some individuals have been known to live to over 40. Mortality is mainly due to the compromised immune system which results in recurrent respiratory infections, predisposition to cancer, and the high rate of pulmonary problems which are associated with the disease.

Epidemiology

The incidence of AT in Caucasians is about 3 per million so the disorder is very rare, with probably fewer than 200 affected people in the UK.

Society and Culture

All families in the United Kingdom with a child who has A-T have access to a specialist clinic in Nottingham where a multi-disciplinary team (involving a neurologist, a geneticist and therapists) has seen many families with A-T.

Chromosome instability syndrome

Chromosome instability syndromes are a group of inherited conditions associated with chromosomal instability and breakage. They often lead to an increased tendency to develop certain types of malignancies.

The following chromosome instability syndromes are known:

• Ataxia telangiectasia
  
• Ataxia telangiectasia-like disorder
• Bloom syndrome
• Fanconi anaemia
• Nijmegen breakage syndrome

Isochromosome

An isochromosome is a chromosome that has lost one of its arms and replaced it with an exact copy of the other arm. This is sometimes seen in some females with Turner syndrome or in tumor cells.

The chromosome arm is already copied during S phase of the cell cycle. During mitosis (or meiosis I or II), the sister chromatid sets line up along the midline in metaphase. The affected chromosome simply lines up at a right angle to its normal position, and as anaphase begins, the centromere is divided in the opposite plane from all the other chromosomes. This leaves the two long arms together and the two short arms together. The two new mirror-image chromosomes are pulled into opposite daughter cells. This produces two cells, each lacking one arm (e.g. the short arm) and containing an extra arm (e.g. the long arm) of the affected chromatid (or vice versa).

If the chromosomal material contains imprinted genes, there will either be a deletion of duplication of the genetic material (genes on the arm lost are deleted, genes on the arm mirrored are duplicated).

Epilepsy Phenome/Genome Project

The Epilepsy Phenome/Genome Project (EPGP) is a government-funded study to identify genes that influence the development of epilepsy and genes that affect the response to treatment. The study involves 13 major epilepsy centers and more than 150 scientists and clinical staff around the United States. The goal is to create a repository of clinical and genetic information on a select group of patients with epilepsy. The hope is that this information will reveal new insights and improve diagnosis and treatment.

EPGP is funded by the National Institutes of Health via The National Institute for Neurological Disorders and Stroke (NINDS).

The long-term goal of EPGP is to identify potential molecular targets that could be the basis of much more specific and effective treatments for patients who have epilepsy, and the prevention of epilepsy in those at risk.

Background on Genes and Epilepsy

Although heredity has been known since antiquity to cause epilepsy, the progress to date in identifying the genetic basis of epilepsy has been limited primarily to the discovery of single gene mutations that cause epilepsy in relatively rare families. For the more common types of epilepsy, heredity plays a subtler role, and it is thought that a combination of mutations in multiple genes likely determine an individual’s susceptibility to seizures, as well as the responsiveness to antiepileptic medications.

EPGP Phenotyping

The approach to teasing apart the more complicated genetic factors in epilepsy requires a very large number of patients whose epilepsy has been extremely well-characterized. EPGP investigators will be enrolling 3,750 patients and 3,000 controls over the course of the study.

Details about seizure types, EEGs, imaging studies, and effects of treatment will be collected and archived in a central data repository, and all participants will be asked to submit a sample of blood as a source of their DNA. Once this first phase of the study is completed, genomic analyses will be used to identify potential connections between patterns of DNA sequences and specific characteristics of epilepsy in the study population.

EPGP Genotyping

Aim 1: Identify Genetic Variants of Common Forms of Epilepsy

We hypothesize that a substantial portion of the inherited risk of epilepsy and pharmacoresistance is due to a small to moderate number of common frequency (frequency > 1%) allelic variants with modest to moderate relative risks.

SubAim 1.1 will identify loci contributing to the occurrence and type of epilepsy.

SubAim 1.2 will identify loci associated with pharmacoresponse to AEDs.

Aim 2: Determine Genetic Influence in Rare, Severe Epilepsy

We will determine the role of de novo copy number polymorphisms (CNPs) in IS, LGS, and PMG/PVNH. We will evaluate the role of inherited CNPs in IS, LGS, and PMG/PVNH.

EPGP Clinical Centers

13 clinical centers around the US will enroll patients for EPGP. They are:

• Baylor College of Medicine (Houston, TX)
• Children's Hospital of Philadelphia (Philadelphia, PA)
• Cincinnati Children's Hospital Medical Center (Cincinnati, OH)
• The Albert Einstein College of Medicine (Bronx, NY)
• Emory School of Medicine (Atlanta, GA)
• Johns Hopkins School of Medicine (Baltimore, MD)
• Mayo Clinic College of Medicine (Rochester, MN)
• New York University School of Medicine (New York, NY)
• Rush University Medical Center (Chicago, IL)
• St. Barnabas Medical Center (West Orange, NJ)
• University of Alabama at Birmingham School of Medicine (Birmingham, AL)
• University of California, San Francisco (San Francisco, CA)

Postictal state

Symptoms

Jerome Engel defines the postictal state as “manifestations of seizure-induced reversible alterations in neuronal function but not structure.” Following a seizure it is common to experience feelings of exhaustion, both mental and physical, that can last for a day or two. Patients’ most common complaint after a seizure is an inability to think clearly, specifically “poor attention and concentration, poor short term memory, decreased verbal and interactive skills, and a variety of cognitive defects specific to individuals.” This collection of symptoms is known as the postictal state, though the word postictal means nothing more than “after the seizure”.

Postictal migraines are a major complaint among epilepsy patients, and can have a variety of etiologies. One possible cause of these migraines is high intracranial pressure resulting from postictal cerebral edema. At times, patients may be unaware that they had a seizure, and the characteristic migraine is their only clue. Depression is also very common after a seizure. There are social and psychological reasons for depression immediately following a seizure, but it is also believed that there are biological causes as well, perhaps the result of changing neurotransmitter systems, as discussed later in this paper.

Other symptoms associated with the postictal state are less common. Todd’s paresis (TP) is a temporary regional loss of function in whatever region just experienced the seizure, and its manifestation depends on where the seizure was located. Loss of motor function is most common, and can range from weakness to full paralysis. About 6% of patients who had tonic-clonic seizures experienced TP afterward, with loss of motor function sometimes accompanied with temporary numbness, blindness, or deafness. TP can also cause anterograde amnesia if the seizure included the bilateral hippocampi, and aphasia if the seizures began in the language-dominant hemisphere. Symptoms typically lasts about 15 hours, but can last as long as 36 hours, and the clinician must resolve whether the loss of motor function is due to TP or ischemia.

Postictal psychosis (PP) is a rare but serious complication following seizures, characterized by auditory and visual hallucinations, delusions, paranoia, affective change, and aggression. Interestingly, the onset of PP doesn’t begin until hours or days after the seizure has ended. Following the conclusion of the seizure, the patient feels the typical confusion and lethargy of the postictal state, and then gradually recovers to a normal state. This is called the lucid phase. In patients who experience PP, the lucid phase usually lasts between 2 hours and a week (usually more than 6 hours) before psychosis sets in. In about 12-50% of seizure patients, the lucid phase is followed by a period of psychosis that can last for 12 hours to more than 3 months (mean, 9-10 days). This psychosis is treatable with standard antipsychotic drugs, and stops when the patient no longer experiences seizures.

Some of these postictal symptoms are almost always present for a period of a few hours to a day or two. In fact, confusion and lack of responsiveness after a seizure is so common and expected that if a patient doesn’t show these symptoms after a seizure, it can be a signal to clinicians that the event may not be an actual seizure at all. Usually such false seizures are instead related to syncope or have a psychogenic origin. The postictal state can also be useful for the clinician when determining the focus of the seizure. Decreased verbal memory (short term) tends to result from a seizure in the dominant hemisphere, whereas seizures in the nondominant hemisphere tend to manifest with decreased visual memory. Inability to read suggests seizure foci in the language areas of the speech-dominant hemisphere, and “after a seizure semivoluntary events as mundane as nose wiping tend to be done with the hand ipsilateral to the seizure focus.”

Causes

While it might seem that the neurons become “exhausted” after the near-constant firing involved in a seizure, the ability of the neuron to carry an action potential following a seizure is not decreased. Neurons of the brain fire normally when stimulated, even after long periods of status epilepticus. Furthermore, the sodium gradient that allows the axon potential to be propagated is so large in comparison to the tiny number of ions that are let through each channel with each signal that it is highly unlikely that this gradient could be ‘used up’ by high activity during a seizure. Instead, there are four major hypotheses regarding what cellular and molecular mechanisms could cause the observed postictal systems: neurotransmitter depletion, changes in receptor concentration, active inhibition, and cerebral bloodflow changes. It is likely that these may in fact interact or more than one theory may contribute to postictal symptoms.

Neurotransmitter depletion

Neurotransmitters must be present in the axon terminal and then exocytosed into the synaptic cleft in order to propagate the signal to the next neuron. While neurotransmitters are not typically a limiting factor in neuronal signaling rates, it is possible that with extensive firing during seizures neurotransmitters could be used up faster than new ones could be synthesized in the nucleus and transported down the axon. There is currently no direct evidence for neurotransmitter depletion following seizures.

Changes in receptor concentration

In studies that stimulate seizures by subjecting rats to electroshock, seizures are followed by unconsciousness and slow waves on an electroencephalogram (EEG), signs of postictal catalepsy. Administering the opiate antagonist naloxone immediately reverses this state, providing evidence that increased responsiveness or concentration of the opiate receptors may be occurring during seizures and may be partially responsible for the weariness humans experience following a seizure. When humans were given naloxone in-between seizures, researchers observed increased activity on their EEGs, suggesting that opioid receptors may also be upregulated during human seizures. To provide direct evidence for this, Hammers et al did positron emission tomography (PET) scanning of radiolabelled ligands before, during, and after spontaneous seizures in humans. They found that opioid receptors were upregulated in the regions near the focus of the seizure during the ictal phase, gradually returning to baseline availability during the postictal phase. Hammers notes that cerebral bloodflow after a seizure can not account for the increase in PET activity observed. Regional bloodflow can increase by as much as 70-80% after seizures but normalizes after 30 minutes. The shortest postictal interval in their study was 90 minutes and none of the patients had seizures during the scanning. It has been predicted that a decrease in opioid activity following a seizure could cause withdrawal symptoms, contributing to postictal depression. The opioid receptor connection with mitigating seizures has been disputed, and opioids have been found to have different functions in different regions of the brain, having both proconvulsive and anticonvulsive effects.

Active inhibition

It is possible that seizures cease spontaneously, but it is much more probable that some changes in the brain create inhibitory signals that serve to tamp down the overactive neurons and effectively end the seizure. Opioid peptides have been shown to be involved in the postictal state and are at times anticonvulsive, and adenosine has also been implicated as a molecule potentially involved in terminating seizures. Evidence for the theory of active inhibition lies in the postictal refractory period, a period of weeks or even months following a series of seizures in which seizures cannot be induced (using animal models and a technique called kindling, in which seizures are induced with repeated electrical stimulation).

Leftover inhibitory signals are he most likely explanation for why there would be a period in which the threshold for provoking a second seizure is high, and lowered excitability may also explain some of the postictal symptoms. Inhibitory signals could be through GABA receptors (both fast and slow IPSPs), calcium-activated potassium receptors (which give rise to afterhyperpolarization), hyperpolarizing pumps, or other changes in ion channels or signal receptors. These changes would likely have a residual effect for a short time after successfully ending the high activity of neurons, perhaps actively inhibiting normal firing during the after the seizure has ended. However, most of these changes would be expected to last for seconds (in the case of IPSP and AHP) or maybe minutes (in the case of hyperpolarized pumps), but cannot account for the fog that lasts for hours after a seizure.

While not an example of active inhibition, acidosis of the blood could aid in ending the seizure and also depress neuron firing following its conclusion. As muscles contract during tonic-clonic seizures they outpace oxygen supplies and go into anaerobic respiration. With continued contractions under anaerobic conditions, the cells undergo lactic acidosis, or the production of lactic acid as a metabolic byproduct. This acidifies the blood (higher H+ concentration, lower pH), which has many impacts on the brain. For one, “hydrogen ions compete with other ions at the ion channel associated with N-methyl-d-aspartate (NMDA). This competition may partially attenuate NMDA receptor and channel mediated hyperexcitability after seizures.” It is unlikely that these effects would be long-lasting, but by decreasing the effectiveness of NMDA-type glutamate receptors , high H+ concentrations could increase the threshold needed to excite the cell, inhibiting the seizure and potentially slowing neuronal signaling after the event.

Cerebral bloodflow changes

Cerebral autoregulation typically ensures that the correct amount of blood reaches the various regions of the brain to match the activity of the cells in that region. In other words, perfusion typically matches metabolism in all organs, but especially in the brain, which gets the highest priority. However, following a seizure it has been shown that sometimes cerebral blood flow is not proportionate to metabolism. While cerebral blood flow didn’t change in the mouse hippocampus (the foci of seizures in this model) during or after seizures, increases in relative glucose uptake were observed in the region during the ictal and early postictal periods. Animal models are difficult for this type of study because each type of seizure model produces a unique pattern of perfusion and metabolism. Thus, in different models of epilepsy, researchers have had differing results as to whether or not metabolism and perfusion become uncoupled. Hosokawa’s model used EL mice, in which seizures begin in the hippocampus and present similarly to the behaviors observed in human epileptic patients. If humans show similar uncoupling of perfusion and metabolism, this would result in hypoperfusion in the affected area, a possible explanation for the confusion and ‘fog’ patients experience following a seizure. It is possible that these changes in blood flow could be a result of poor autoregulation following a seizure, or it could in fact be yet another factor involved in stopping seizures.

Treatments

Observing neuropeptide transcription levels during and after seizures provides a window into how the brain responds to seizures. Some neuropeptides (such as galanin, thyrotropin releasing hormone (TRH), neuropeptide Y, somatostatin, and cortistatin) are believed to have anticonvulsant and neuroprotective properties. In accordance with this perceived function, mouse studies using have used microarrays to show that transcription of these genes is increased many-fold following a seizure. The number of transcripts of these molecules typically peaks around 24 hours following the seizure, but can remain statistically significantly above normal levels for up to 72 hours.

Wilson observed a higher magnitude of increase in adult rats compared to immature rats, which is of note particularly because young mice have a much shorter postictal refractory period. Also, administering exogenous TRH, has been shown to improve postictal cognition in humans, as measured with neuropsychological tests. This evidence further suggests a natural role for these molecules in ending and/or recovering from seizures, and may give rise to pharmaceuticals that mitigate postictal symptoms in the future.

In support of the opioid theory of the postictal state, pretreatment of rats with morphine increased postictal symptoms and pretreatment with naloxone decreased postictal symptoms (as measured by the presence of EEG slow waves, increase in EEG spike activity, decreased memory, affective pain response, and explosive motor behavior). However, it is believed that opioid peptides serve a very useful purpose in ending the seizures, so pretreating humans with naloxone would put the patient at risk of status epilepticus. Naloxone may, however, prove a useful treatment for improving symptoms after seizures have ended. It is not known if this would also put the patient at risk of another seizure in the near future as a result of shortening the postictal refractory period.

Conclusion

There are few explanations for what could cause the long lasting symptoms of the postictal state, with patients complaining of difficulty thinking clearly and loss of short-term memory function for hours and even days. The cellular and molecular changes hypothesized to take place following a seizure would only have effects lasting for minutes. Todd’s paresis can last for 24 or 48 hours, and reversible neurological defects (typically short term memory) can last for months, suggesting that more permanent changes in neuron structure may take place following seizures. It should be noted that most patients do not display any long term neurological defects following seizures, and seizures are not believed to be damaging to the brain. It is possible in the small fraction of patients that do experience short term memory loss for weeks or months following a seizure, structural changes may take place that are eventually compensated for structurally or functionally, causing symptoms to eventually disappear.

ISAS (Ictal-Interictal SPECT Analysis by SPM)

The goal of ictal Single Photon Emission Computed Tomography (SPECT) is to localize the region of seizure onset for epilepsy surgery planning. ISAS (Ictal-Interictal SPECT Analysis by SPM) is an objective tool for analyzing ictal vs. interictal SPECT scans. ISAS was introduced and validated in two recent studies (Chang et al, 2002; McNally et al., 2005). This site is a technical supplement to (McNally et al., 2005), which should enable ISAS to be implemented at any center for further study and analysis.

Analysis

The basic idea of ISAS is to compute the difference between an ictal and interictal SPECT scan for a single patient. The differences of the ictal/inter-ictal comparison are checked against a healthy normal database to determine the normal expected variation. Significant increases and decreases in CBF (cerebral blood flow) between the interictal and ictal SPECT can then be detected. The analysis is conducted using SPM (statistical parametric mapping).

Cerebral blood flow is known to increase during seizures at the site of seizure onset. Since SPECT is an indicator of CBF, increases in the SPECT during seizures can be useful for seizure localization. CBF decreases are more complicated, and occur both during and following seizures in multiple locations. Details of ISAS interpretation can be found in McNally et al., 2005, but in summary:

1. For true ictal SPECT (patient injected before end of seizure), seizure onset can be reliably localized based on SPECT increases.

2. For post-ictal SPECT, seizure onset cannot be reliably localized to a single lobe based on SPECT increase or decreases. However, the side (L or R) of seizure onset can be reliably determined based on which hemisphere has greater overall SPECT decreases (hypoperfusion asymmetry index).

The requirements for implementing ISAS are relatively simple. All that is needed is a computer running MATLAB and an operator with sufficient imaging experience to download and implement the SPM (statistical parametric mapping) analysis.

NOTE: ISAS has been tested and confirmed to work with SPM2 and the following MATLAB versions - 6.1, 6.5.1, and 7.0.4. In order to ensure correctness, both Matlab and SPM should be kept updated with the latest service packs and patches. Refer to the software setup section of our site for more information.

The intent of ISAS and the ISAS website is to begin to fill the need for epilepsy SPECT image analysis, by providing a freely available method that can be implemented anywhere.

Selected References

1. McNally KA, Paige AL, Varghese G, Zhang H, Novotny EJ, Spencer SS, Zubal IG, Blumenfeld H. (2005). Seizure localization by ictal and postictal SPECT. Epilepsia , 46(9):1–15, 2005

This study, together with the ISAS website, provides a complete description of the ISAS method, and validates this approach with a group of mesial temporal and neocortical epilepsy patients.

2. Chang DJ, Zubal IG, Gottschalk C, Necochea A, Stokking R, Studholme C, Corsi M, Slawski J, Spencer SS, Blumenfeld H (2002). Comparison of Statistical Parametric Mapping and SPECT Difference Imaging in Patients with Temporal Lobe Epilepsy. Epilepsia , 43:68-74.

ISAS was introduced in this study, and compared to conventional SPECT difference imaging.

3. Lee JD, Kim HJ, Lee BI, Kim OJ, Jeon TJ, Kim MJ (2000). Evaluation of ictal brain SPET using statistical parametric mapping in temporal lobe epilepsy. European Journal of Nuclear Medicine 27:1658-1665.

This paper is the first use of ictal SPECT analysis by SPM for seizure localization.

4. O'Brien TJ, So EL, Mullan BP, Hauser MF, Brinkmann BH, Bohnen NI, Hanson D, Cascino GD, Jack CR, Jr., Sharbrough FW (1998). Subtraction ictal SPECT co-registered to MRI improves clinical usefulness of SPECT in localizing the surgical seizure focus. Neurology , 50:445-454.

This paper describes SISCOM (subtraction ictal SPECT coregistered with MRI), a widely used method of ictal-interictal difference imaging (see also below).

5. Zubal IG, Spencer SS, Imam K, Seibyl J, Smith EO, Wisniewski G, Hoffer PB (1995). Difference images calculated from ictal and interictal technetium-99m-HMPAO SPECT scans of epilepsy. Journal of Nuclear Medicine , 36:684-689.

This is the first paper which describes the use of ictal-interictal difference imaging coregistered with MRI for epilepsy surgery localization.

Generalised epilepsy

Generalised epilepsy is a form of epilepsy characterised by generalised seizures. Generalised seizures, as opposed to partial seizures, are a type of seizures that impair consciousness and distort the electrical activity of a larger portion of the brain (which can be seen, for example, on electroencephalography, EEG).

Generalised seizures can be either absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures or atonic seizures.

Generalised seizures occur in various seizure syndromes, including myoclonic epilepsy, familial neonatal convulsions, childhood absence epilepsy, absence epilepsy, myoclonic epilepsy, infantile spasms (West's syndrome) and Lennox-Gastaut syndrome.

Abdominal epilepsy

Abdominal epilepsy describes a group of gastrointestinal (GI) disturbances caused by epileptiform seizure activity seen on EEG tracing. While a causal relationship has not been proven, the GI symptoms cannot be explained by other pathophyisological mechanisms, and are seen to improve upon anticonvulsant treatment.

The phenomenon seems to be very rare, with a total of 36 case reports published in the English medical literature during the last 35 years. Trousseau is commonly credited as the first to describe the condition in 1868 in a boy with paroxysmal GI symptoms culminating in grand mal epileptic seizures.

The first account of abdominal epilepsy supported by EEG tracings came in 1944 in an article by M.T. Moore, followed by several subsequent case reports from the same group.

Epilepsy in animals

Epilepsy can occur in animals other than humans (see main article Epilepsy). It is characterized by recurrent unprovoked seizures. Canine epilepsy is often genetic. Epilepsy in cats and other pets is rarer, likely because there is no hereditary component to epilepsy in these animals.

Canine epilepsy

In dogs, epilepsy is often an inherited condition. The incidence of epilepsy/seizures in the general dog population is estimated at between 0.5% and 5.7%. In certain breeds, such as the Belgian Shepherd varieties, the incidence may be much higher.

Diagnosis

There are three types of epilepsy in dogs: reactive, secondary, and primary. Reactive epileptic seizures are caused by metabolic issues, such as low blood sugar or kidney or liver failure. Epilepsy caused by problems such as a brain tumor, stroke, or other trauma is known as secondary, or symptomatic, epilepsy.

In primary, or idiopathic, epilepsy, there is no known cause. This type of epilepsy is diagnosed by eliminating other possible causes for the seizures. Dogs with idiopathic epilepsy experience their first seizure between the ages of one and three. However, the age of diagnosis is only one factor in diagnosing canine epilepsy. One study found a cause for the seizures in one-third of dogs between the ages of one and three, indicating secondary or reactive rather than primary epilepsy.

When an animal who has suffered a seizure is presented to a veterinarian, the veterinarian will do an initial work-up. This work-up may include a physical and neurological exam, a complete blood count, serum chemistry profile, urinalysis, bile tests, and thyroid function tests. These tests will help the veterinarian determine whether the animal is in fact experiencing seizures, and may help determine a cause for the seizures if there is one. Veterinarians may also request that dog owners keep a "seizure log" documenting the timing, length, severity, and recovery of each seizure, as well as any other factors that might be helpful, such as dietary or environmental changes.

Treatment

Treatments can include the drugs phenobarbital, phenytoin, potassium bromide, levetiracetam, zonisamide, and diazepam. Potassium bromide and phenobarbital are often paired for the treatment of animals with epilepsy (other drugs such as gabapentin are only recently being introduced into the treatment of animals). A veterinarian will often prescribe Zentinol in an effort to minimize the damaging effects of bromides on the liver enzymes.

Feline epilepsy

Complex partial seizures are more common in cats than generalized convulsions. These partial seizures may be shown by either bizarre behavior or a complete lack of movement, accompanied by facial tics or excessive salivation. Cats may experience foaming round the mouth or loss of muscle and bladder control.

Epilepsy

Epilepsy is a common chronic neurological disorder that is characterized by recurrent unprovoked seizures. These seizures are transient signs and/or symptoms due to abnormal, excessive or synchronous neuronal activity in the brain. About 50 million people worldwide have epilepsy at any one time. Epilepsy is usually controlled, but not cured, with medication, although surgery may be considered in difficult cases. However, over 30% of people with epilepsy do not have seizure control even with the best available medications. Not all epilepsy syndromes are lifelong – some forms are confined to particular stages of childhood. Epilepsy should not be understood as a single disorder, but rather as a group of syndromes with vastly divergent symptoms but all involving episodic abnormal electrical activity in the brain.

Classification

Epilepsies are classified in five ways:

1. By their first cause (or etiology).
2. By the observable manifestations of the seizures, known as semiology.
3. By the location in the brain where the seizures originate.
4. As a part of discrete, identifiable medical syndromes.
5. By the event that triggers the seizures, as in primary reading epilepsy or musicogenic epilepsy.

In 1981, the International League Against Epilepsy (ILAE) proposed a classification scheme for individual seizures that remains in common use. This classification is based on observation (clinical and EEG) rather than the underlying pathophysiology or anatomy and is outlined later on in this article. In 1989, the ILAE proposed a classification scheme for epilepsies and epileptic syndromes. This can be broadly described as a two-axis scheme having the cause on one axis and the extent of localisation within the brain on the other. Since 1997, the ILAE have been working on a new scheme that has five axes: ictal phenomenon, seizure type, syndrome, etiology and impairment.

Diagnosis

The diagnosis of epilepsy requires the presence of recurrent, unprovoked seizures; accordingly, it is usually made based on the medical history. Imaging and measurement technologies such as electroencephalography (EEG), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetoencephalography (MEG) may be useful to discover an etiology for the epilepsy, discover the affected brain region, or classify the epileptic syndrome, but these studies are not useful in making the initial diagnosis.

Long-term video-EEG monitoring for epilepsy is the gold standard for diagnosis, but it is not routinely employed owing to its high cost, low availability and inconvenience.

Convulsive or other seizure-like activity, non-epileptic in origin, can be observed in many other medical conditions. These non-epileptic seizures can be hard to differentiate and may lead to misdiagnosis.

Epilepsy covers conditions with different etiologies, natural histories and prognoses, each requiring different management strategies. A full medical diagnosis requires a definite categorization of seizure and syndrome types.

Precipitants

The diagnosis of epilepsy usually requires that the seizures occur spontaneously. Nevertheless, certain epilepsy syndromes require particular precipitants or triggers for seizures to occur. These are termed reflex epilepsy. For example, patients with primary reading epilepsy have seizures triggered by reading. Photosensitive epilepsy can be limited to seizures triggered by flashing lights. Other precipitants can trigger an epileptic seizure in patients who otherwise would be susceptible to spontaneous seizures. For example, children with childhood absence epilepsy may be susceptible to hyperventilation. In fact, flashing lights and hyperventilation are activating procedures used in clinical EEG to help trigger seizures to aid diagnosis. Finally, other precipitants can facilitate, rather than obligately trigger, seizures in susceptible individuals. Emotional stress, sleep deprivation, sleep itself, and febrile illness are examples of precipitants cited by patients with epilepsy. Notably, the influence of various precipitants varies with the epilepsy syndrome. . Likewise, the menstrual cycle in women with epilepsy can influence patterns of seizure recurrence. Catamenial epilepsy is the term denoting seizures linked to the menstrual cycle.

Epidemiology

Epilepsy is one of the most common of the serious neurological disorders. Genetic, congenital, and developmental conditions are mostly associated with it among younger patients; tumors are more likely over age 40; head trauma and central nervous system infections may occur at any age. The prevalence of active epilepsy is roughly in the range 5–10 per 1000 people. Up to 5% of people experience non febrile seizures at some point in life; epilepsy's lifetime prevalence is relatively high because most patients either stop having seizures or (less commonly) die of it. Epilepsy's approximate annual incidence rate is 40–70 per 100,000 in industrialized countries and 100–190 per 100,000 in resource-poor countries; socioeconomically deprived people are at higher risk. In industrialized countries the incidence rate decreased in children but increased among the elderly during the three decades prior to 2003, for reasons not fully understood.

Beyond symptoms of the underlying diseases that can cause certain epilepsies, people with epilepsy are at risk for death from four main problems: status epilepticus (most often associated with anticonvulsant noncompliance), suicide associated with depression, trauma from seizures, and sudden unexpected death in epilepsy (SUDEP) Those at highest risk for epilepsy-related deaths usually have underlying neurological impairment or poorly controlled seizures; those with more benign epilepsy syndromes have little risk for epilepsy-related death.

Certain diseases also seem to occur in higher than expected rates in people with epilepsy, and the risk of these "comorbities" often varies with the epilepsy syndrome. These diseases include depression and anxiety disorders, migraine and other headaches, infertility and low sexual libido. Attention-deficit/hyperactivity disorder (ADHD) affects three to five times more children with epilepsy than children in the general population. Epilepsy is prevalent in autism.

Seizure types

Seizure types are organized firstly according to whether the source of the seizure within the brain is localized (partial or focal onset seizures) or distributed (generalized seizures). Partial seizures are further divided on the extent to which consciousness is affected. If it is unaffected, then it is a simple partial seizure; otherwise it is a complex partial (psychomotor) seizure. A partial seizure may spread within the brain - a process known as secondary generalization. Generalized seizures are divided according to the effect on the body but all involve loss of consciousness. These include absence (petit mal), myoclonic, clonic, tonic, tonic-clonic (grand mal) and atonic seizures.

Epilepsy syndromes

There are many different epilepsy syndromes, each presenting with its own unique combination of seizure type, typical age of onset, EEG findings, treatment, and prognosis. The most widespread classification of the epilepsies divides epilepsy syndromes by location or distribution of seizures (as revealed by the appearance of the seizures and by EEG) and by cause. Syndromes are divided into localization-related epilepsies, generalized epilepsies, or epilepsies of unknown localization.

Localization-related epilepsies, sometimes termed partial or focal epilepsies, arise from an epileptic focus, a small portion of the brain that serves as the irritant driving the epileptic response. Generalized epilepsies, in contrast, arise from many independent foci (multifocal epilepsies) or from epileptic circuits that involve the whole brain. Epilepsies of unknown localization remain unclear whether they arise from a portion of the brain or from more widespread circuits.

Epilepsy syndromes are further divided by presumptive cause: idiopathic, symptomatic, and cryptogenic. Idiopathic epilepsies are generally thought to arise from genetic abnormalities that lead to alteration of basic neuronal regulation. Symptomatic epilepsies arise from the effects of an epileptic lesion, whether that lesion is focal, such as a tumor, or a defect in metabolism causing widespread injury to the brain. Cryptogenic epilepsies involve a presumptive lesion that is otherwise difficult or impossible to uncover during evaluation.

Some epileptic syndromes are difficult to fit within this classification scheme and fall in the unknown localization/etiology category. People who only have had a single seizure, or those with seizures that occur only after specific precipitants ("provoked seizures"), have "epilepsies" that fall into this category. Febrile convulsions are an example of seizures bound to a particular precipitant. Landau-Kleffner syndrome is another epilepsy which, because of its variety of EEG distributions, falls uneasily in clear categories. More confusingly, certain syndromes like West syndrome featuring seizures such as Infantile spasms can be classified as idiopathic, syndromic, or cryptogenic depending on cause and can arise from both focal or generalized epileptic lesions.

Below are some common seizure syndromes:

• Benign centrotemporal lobe epilepsy of childhood or Benign rolandic epilepsy is an idiopathic localization-related epilepsy that occurs in children between the ages of 3 and 13 years with peak onset in prepubertal late childhood. Apart from their seizure disorder, these patients are otherwise normal. This syndrome features simple partial seizures that involve facial muscles and frequently cause drooling. Although most episodes are brief, seizures sometimes spread and generalize. Seizures are typically nocturnal and confined to sleep. The EEG may demonstrate spike discharges that occur over the centrotemporal scalp over the central sulcus of the brain (the Rolandic sulcus) that are predisposed to occur during drowsiness or light sleep. Seizures cease near puberty. Seizures may require anticonvulsant treatment, but sometimes are infrequent enough to allow physicians to defer treatment.

• Benign occipital epilepsy of childhood (BOEC) is an idiopathic localization-related epilepsy and consists of an evolving group of syndromes. Most authorities include two subtypes, an early subtype with onset between 3-5 years and an late onset between 7-10 years. Seizures in BOEC usually feature visual symptoms such as scotoma or fortifications (brightly colored spots or lines) or amaurosis (blindness or impairment of vision). Convulsions involving one half the body, hemiconvulsions, or forced eye deviation or head turning are common. Younger patients typically experience symptoms similar to migraine with nausea and headache, and older patients typically complain of more visual symptoms. The EEG in BOEC shows spikes recorded from the occipital (back of head) regions. Lately, a group of epilepsies termed Panayiotopoulos syndrome that share some clinical features of BOEC but have a wider variety of EEG findings are classified by some as BOEC.

• Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic localization-related epilepsy that is an inheirited epileptic disorder that causes seizures during sleep. Onset is usually in childhood. These seizures arise from the frontal lobes and consist of complex motor movements, such as hand clenching, arm raising/lowering, and knee bending. Vocalizations such as shouting, moaning, or crying are also common. ADNFLE is often misdiagnosed as nightmares. ADNFLE has a genetic basis. These genes encode various nicotinic acetylcholine receptors.

• Primary reading epilepsy is a reflex epilepsy classified as an idiopathic localization-related epilepsy. Reading in susceptible individuals triggers characteristic seizures.

• Childhood absence epilepsy (CEA) is an idiopathic generalized epilepsy that affects children between the ages of 4 and 12 years of age, although peak onset is around 5-6 years old. These patients have recurrent absence seizures, brief episodes of unresponsive staring, sometimes with minor motor features such as eye blinking or subtle chewing. The EEG finding in CAE is generalized 3 Hz spike and wave discharges. Some go on to develop generalized tonic-clonic seizures. This condition carries a good prognosis because children do not usually show cognitive decline or neurological deficits, and the seizures in the majority cease spontaneously with onging maturation.
  

  Generalized 3 Hz spike and wave discharges in EEG

• Juvenile absence epilepsy is an idiopathic generalized epilepsy with later onset that CAE, typically in prepubertal adolescence, with the most frequent seizure type being absence seizures. Generalized tonic-clonic seizures can occur. 3 Hz spike-wave or multiple spike discharges can be seen on EEG. Prognosis is mixed, with some patients going on to a syndrome that is poorly distinguishable from JME.

• Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy that occurs in patients aged 8 to 20 years. Patients have normal cognition and are otherwise neurologically intact. The most common seizures are myoclonic jerks, although generalized tonic-clonic seizures and absence seizures may occur as well. Myoclonic jerks usually cluster in the early morning after awakening. The EEG reveals generalized 4-6 Hz spike wave discharges or multiple spike discharges. Interestingly, these patients are often first diagnosed when they have their first generalized tonic-clonic seizure later in life when they experience sleep deprivation (e.g., freshman year in college after staying up late to study for exams). Alcohol withdrawal can also be a major contributing factor in breakthrough seizures as well. The risk of the tendency to have seizures is lifelong; however, the majority have well-controlled seizures with anticonvulsant medication and avoidance of seizure precipitants.

• Symptomatic localization-related epilepsies Symptomatic localization-related epilepsies are divided by the location in the brain of the epileptic lesion, since the symptoms of the seizures are more closely tied to the brain location rather than the cause of the lesion. Tumors, atriovenous malformations, cavernous malformations, trauma, and cerebral infarcts can all be causes of epileptic foci in different brain regions.

• Temporal lobe epilepsy (TLE), a symptomatic localization-related epilepsy, is the most common epilepsy of adults who experience seizures poorly controlled with anticonvulsant medications. In most cases, the epileptogenic region is found in the midline (mesial) temporal structures (e.g., the hippocampus, amygdala, and parahippocampal gyrus). Seizures begin in late childhood and adolescence. Most of these patients have complex partial seizures sometimes preceded by an aura, and some TLE patients also suffer from secondary generalized tonic-clonic seizures. If the patient does not respond sufficiently to medical treatment, epilepsy surgery may be considered.

• Frontal lobe epilepsy, usually a symptomatic or cryptogenic localization-related epilepsy, arises from lesions causing seizures that occur in the frontal lobes of the brain. These epilepsies can be difficult to diagnose because the symptoms of seizures can easily be confused with nonepileptic spells and, because of limitations of the EEG, be difficult to "see" with standard scalp EEG.

• Rasmussen's encephalitis is a symptomatic localization-related epilepsy that is a progressive, inflammatory lesion affecting children with onset before the age of 10. Seizures start as separate simple partial or complex partial seizures and may progress to epilepsia partialis continuata (simple partial status epilepticus). Neuroimaging shows inflammatory encephalitis on one side of the brain that may spread if not treated. Dementia and hemiparesis are other problems. The cause is hypothesized to involve an immulogical attack against glutamate receptors, a common neurotransmitter in the brain.

• West syndrome is a triad of developmental delay, seizures termed infantile spasms, and EEG demonstrating a pattern termed hypsarrhythmia. Onset occurs between 3 months and 2 years, with peak onset between 8-9 months. West syndrome may arise from idiopathic, symptomatic, or cryptogenic causes. The most common cause is tuberous sclerosis. The prognosis varies with the underlying cause. In general most surviving patients remain with significant cognitive impairment and continuing seizures and may evolve to another eponymic syndrome, Lennox-Gastaut syndrome.

• Dravet's syndrome Severe myoclonic epilepsy of infancy (SMEI). This generalized epilepsy syndrome is distinguished from benign myoclonic epilepsy by its severity and must be differentiated from the Lennox-Gastaut syndrome and Doose’s myoclonic-astatic epilepsy. Onset is in the first year of life and symptoms peak at about 5 months of age with febrile hemiclonic or generalized status epilepticus. Boys are twice as often affected as girls. Prognosis is poor. Most cases are sporadic. Family history of epilepsy and febrile convulsions is present in around 25 percent of the cases.

• Progressive myoclonic epilepsies define a group of symptomatic generalized epilepsies characterized by progressive dementia and myoclonic seizures. Tonic-clonic seizures may occur as well. Diseases usually classified in this group are Unverricht-Lundborg disease, myoclonus epilepsy with ragged red fibers (MERRF syndrome), Lafora disease, neuronal ceroid lipofucinosis, and sialdosis.

• Lennox-Gastaut syndrome (LGS) is a generalized epilepsy that consists of a triad of developmental delay or childhood dementia, mixed generalized seizures, and EEG demonstrating a pattern of approximately 2 Hz "slow" spike-wave. Onset occurs between 2-18 years. As in West syndrome, LGS result from idiopathic, symptomatic, or cryptogenic causes, and many patients first have West syndrome. Authorities emphasize different seizure types as important in LGS, but most have astatic seizures (drop attacks), tonic seizures, tonic-clonic seizures, atypical absence seizures, and sometimes, complex partial seizures. Anticonvulsants are usually only partially successful in treatment.

Treatment

Epilepsy is usually treated with medication prescribed by a physician; primary caregivers, neurologists, and neurosurgeons all frequently care for people with epilepsy. In some cases the implantation of a stimulator of the vagus nerve, or a special diet can be helpful. Neurosurgical operations for epilepsy can be palliative, reducing the frequency or severity of seizures; or, in some patients, an operation can be curative.

Responding to a seizure

In most cases, the proper emergency response to a generalized tonic-clonic epileptic seizure is simply to prevent the patient from self-injury by moving him or her away from sharp edges, placing something soft beneath the head, and carefully rolling the person into the recovery position to avoid asphyxiation. In some cases the person may seem to start snoring loudly following a seizure, before coming to. This merely indicates that the person is beginning to breathe properly and does not mean he or she is suffocating. Should the person regurgitate, the material should be allowed to drip out the side of the person's mouth by itself. If a seizure lasts longer than 5 minutes, or if the seizures begin coming in 'waves' one after the other - then Emergency Medical Services should be contacted immediately. Prolonged seizures may develop into status epilepticus, a dangerous condition requiring hospitalization and emergency treatment.

Objects should never be placed in a person's mouth by anybody - including paramedics - during a seizure as this could result in serious injury to either party. Despite common folklore, it is not possible for a person to swallow their own tongue during a seizure. However, it is possible that the person will bite their own tongue, especially if an object is placed in the mouth.

With other types of seizures such as simple partial seizures and complex partial seizures where the person is not convulsing but may be hallucinating, disoriented, distressed, or unconscious, the person should be reassured, gently guided away from danger, and sometimes it may be necessary to protect the person from self-injury, but physical force should be used only as a last resort as this could distress the person even more. In complex partial seizures where the person is unconscious, attempts to rouse the person should not be made as the seizure must take its full course. After a seizure, the person may pass into a deep sleep or otherwise they will be disoriented and often unaware that they have just had a seizure, as amnesia is common with complex partial seizures. The person should remain observed until they have completely recovered, as with a tonic-clonic seizure.

After a seizure, it is typical for a person to be exhausted and confused. Often the person is not immediately aware that they have just had a seizure. During this time one should stay with the person - reassuring and comforting them - until they appear to act as they normally would. Seldom during seizures do people lose bladder or bowel control. In some instances the person may vomit after coming to. People should not eat or drink until they have returned to their normal level of awareness, and they should not be allowed to wander about unsupervised. Many patients will sleep deeply for a few hours after a seizure - this is common for those having just experienced a more violent type of seizure such as a tonic-clonic. In about 50% of people with epilepsy, headaches may occur after a seizure. These headaches share many features with migraines, and respond to the same medications.

It is helpful if those present at the time of a seizure make note of how long and how severe the seizure was. It is also helpful to note any mannerisms displayed during the seizure. For example, the individual may twist the body to the right or left, may blink, might mumble nonsense words, or might pull at clothing. Any observed behaviors, when relayed to a neurologist, may be of help in diagnosing the type of seizure which occurred.

Pharmacologic treatment

The mainstay of treatment of epilepsy is anticonvulsant medications. Often, anticonvulsant medication treatment will be lifelong and can have major effects on quality of life. The choice among anticonvulsants and their effectiveness differs by epilepsy syndrome. Mechanisms, effectiveness for particular epilepsy syndromes, and side effects, of course, differ among the individual anticonvulsant medications. Some general findings about the use of anticonvulsants are outlined below.

History and Availability- The first anticonvulsant was bromide, suggested in 1857 by Charles Locock who used it to treat women with "hysterical epilepsy" (probably catamenial epilepsy). Potassium bromide was also noted to cause impotence in men. Authorities concluded that potassium bromide would dampen sexual excitement thought to cause the seizures, which in fact it did (athough we know now that impotence is a side effect of bromide treatment, not a treatment of epilepsy). Phenobarbital was first used in 1912 for both its sedative and antiepileptic properties. By the 1930s, the development of animal models in epilepsy research lead to the development of phenytoin by Tracy Putnam and H. Houston Merritt, which had the distinct advantage of treating epileptic seizures with less sedation. By the 1970s, an National Institutes of Health initiative, the Anticonvulsant Screening Program, headed by J. Kiffin Penry, served as a mechanism for drawing the interest and abilities of pharmaceutical companies in the development of new anticonvulsant medications.

Currently there are 19 medications approved by the Food and Drug Administration for the use of treatment of epileptic seizures in the US: carbamazepine (common US brand name Tegretol), clorazepate (Tranxene) clonazepam (Klonopin), ethosuximide (Zarontin), felbamate (Felbatol), fosphenytoin (Cerebyx), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine (Trileptal), phenobarbital (Luminal), phenytoin (Dilantin), pregabalin (Lyrica), primidone (Mysoline), tiagabine (Gabitril), topiramate (Topamax), valproate semisodium (Depakote), valproic acid (Depakene), and zonisamide (Zonegran). Most of these appeared after 1990.

Medications commonly available outside the US but still labelled as "investigational" within the US are clobazam (Frisium) and vigabatrin (Sabril).

Other drugs are commonly used to abort an active seizure or interrupt a seizure flurry; these include diazepam (Valium, Diastat) and lorazepam (Ativan). Drugs used only in the treatment of refractory status epilepticus include paraldehyde (Paral), midazolam (Versed), and pentobarbital (Nembutal).

Some anticonvulsant medications do not have primary FDA-approved uses in epilepsy but are used in limited trials, remain in rare use in difficult cases, have limited "grandfather" status, are bound to particular severe epilepsies, or are under current investigation. These include acetazolamide (Diamox), progesterone, adrenocorticotropic hormone (ACTH, Acthar), various corticotropic steroid hormones (prednisone), or bromide.

Effectiveness - The definition of "effective" varies. FDA-approval usually requires that 50% of the patient treatment group had at least a 50% improvement in the rate of epileptic seizures. About 20% of patients with epilepsy continue to have breakthrough epileptic seizures despite best anticonvulsant treatment.

Safety and Side Effects - 88% of patients with epilepsy, in a European survey, reported at least one anticonvulsant related side effect. Most side effects are mild and "dose-related" and can often be avoided or minimized by the use of the smallest effective amount. Some examples include mood changes, sleepiness, or unsteadiness in gait. Some anticonvulsant medications have "idiosyncratic" side-effects that can not be predicted by dose. Some examples include drug rashes, liver toxicity (hepatitis), or aplastic anemia. Safety includes the consideration of tetragenicity (the effects of medications on fetal development) when women with epilepsy become pregnant.

Principles of Anticonvulsant Use and Management - The goal for individual patients is, of course, no seizures and no side effects, and the job of the physician is to aid the patient to find the best balance between the two during the prescribing of anticonvulsants. Most patients can achieve this balance best with monotherapy, the use of a single anticonvulsant medication. Some patients, however, require polypharmacy; the use of two or more anticonvulsants.

Serum levels of AEDs can be checked to determine medication compliance, to assess the effects of new drug-drug interactions upon previous stable medication levels, or to help establish if particular symptoms such as instability or sleepiness can be considered a drug side-effect or are due to different causes. Children or impaired adults who may not be able to communicate side effects may benefit from routine screening of drug levels. Beyond baseline screening, however, trials of recurrent, routine blood or urine monitoring show no proven benefits and may lead to unnecessary medication adjustments in most older children and adults using routine anticonvulsants.

If a person's epilepsy cannot be brought under control after adequate trials of two or three (experts vary here) different drugs, that person's epilepsy is generally said to be medically refractory. A study of patients with previously untreated epilepsy demonstrated that 47% achieved control of seizures with the use of their first single drug. 14% became seizure free during treatment with a second or third drug. An additional 3% became seizure-free with the use of two drugs simultaneously. Other treatments, in addition to or instead of, anticonvulsant medications may be considered by those people with continuing seizures.

Surgical treatment

Epilepsy surgery is an option for patients whose seizures remain resistant to treatment with anticonvulsant medications who also have symptomatic localization-related epilepsy; a focal abnormality that can be located and therefore removed. The goal for these procedures is total control of epileptic seizures, although anticonvulsant medications may still be required.

The evaluation for epilepsy surgery is designed to locate the "epileptic focus" (the location of the epileptic abnormality) and to determine if resective surgery will affect normal brain function. Physicians will also confirm the diagnosis of epilepsy to make sure that spells arise from epilepsy (as opposed to non-epileptic seizures). The evaluation typically includes neurological examination, routine EEG, Long-term video-EEG monitoring, neuropsychological evaluation, and neuroimaging such as MRI, Single photon emission computed tomography (SPECT), positron emission tomography (PET). Some epilepsy centers use intracarotid sodium amobarbital test (Wada test), functional MRI or Magnetoencephalography (MEG) as supplementary tests.

Certain lesions require Long-term video-EEG monitoring with the use of intracranial electrodes if noninvasive testing was inadequate to identify the epileptic focus or distinguish the surgical target from normal brain tissue and function. Brain mapping by the technique of cortical electrical stimulation or Electrocorticography are other procedures used in the process of invasive testing in some patients.

The most common surgeries are the resection of lesions like tumors or arteriovenous malformations which, in the process of treating the underlying lesion, often result in control of epileptic seizures caused by these lesions.

Other lesions are more subtle and feature epilepsy as the main or sole symptom. The most common form of intractable epilepsy in these disorders in adults is temporal lobe epilepsy with hippocampal sclerosis, and the most common type of epilepsy surgery is the anterior temporal lobectomy, or the removal of the front portion of the temporal lobe including the amygdala and hippocampus. Some neurosurgeons recommend selective amygdalahippocampectomy because of possible benefits in postoperative memory or language function. Surgery for temporal lobe epilepsy is effective, durable, and results in decreased health care costs. Despite the efficacy of epilepsy surgery, some patients decide not to undergo surgery owing to fear or the uncertainty of having a brain operation.

Palliative surgery for epilepsy is intended to reduce the frequency or severity of seizures. Examples are callosotomy or commissurotomy to prevent seizures from generalizing (spreading to involve the entire brain), which results in a loss of consciousness. This procedure can therefore prevent injury due to the person falling to the ground after losing consciousness. It is performed only when the seizures cannot be controlled by other means. Multiple subpial transection can also be used to decrease the spread of seizures across the cortex especially when the epileptic focus is located near important functional areas of the cortex. Resective surgery can be considered palliative if it is undertaken with the expectation that it will reduce but not eliminate seizures.

Hemispherectomy involves removal or a functional disconnection of most or all of one half of the cerebrum. It is reserved for people suffering from the most catastrophic epilepsies, such as those due to Rasmussen syndrome. If the surgery is performed on very young patients (2-5 years old), the remaining hemisphere may acquire some rudimentary motor control of the ipsilateral body; in older patients, paralysis results on the side of the body opposite to the part of the brain that was removed. Because of these and other side effects it is usually reserved for patients who have exhausted other treatment options.

Other treatment

Ketogenic diet- a high fat, low carbohydrate diet developed in the 1920s, largely forgotten with the advent of effective anticonvulsants, and resurrected in the 1990s. The mechanism of action is unknown. It is used mainly in the treatment of children with severe, medically-intractable epilepsies.

Electrical stimulation- methods of anticonvulsant treatment with both currently approved and investigational uses. A currently approved device is vagus nerve stimulation (VNS). Investigational devices include the responsive neurostimulation system and deep brain stimulation.

Vagus nerve stimulation (VNS)- The VNS (US manufacturer = Cyberonics) consists of a computerized electrical device similar in size, shape and implant location to a heart pacemaker that connects to the vagus nerve in the neck. The device stimulates the vagus nerve at pre-set intervals and intensities of current. Efficacy has been tested in patients with localization-related epilepsies demonstrating that 50% of patients experience a 50% improvement in seizure rate. Case series have demonstrated similar efficacies in certain generalized epilepsies such as Lennox-Gastaut syndrome. Although success rates are not usually equal to that of epilepsy surgery, it is a reasonable alternative when the patient is reluctant to proceed with any required invasive monitoring, when appropriate presurgical evaluation fails to uncover the location of epileptic foci, or when there are multiple epileptic foci.

Responsive Neurostimulator System (RNS) (US manufacturer Neuropace) consists of an computerized electrical device implanted in the skull with electrodes implanted in presumed epileptic foci within the brain. The brain electrodes send EEG signal to the device which contains seizure-detection software. When certain EEG seizure criteria are met, the device delivers a small electrical charge to other electrodes near the epileptic focus and disrupt the seizure. The efficacy of the RNS is under current investigation with the goal of FDA approval.

Deep brain stimulation (DBS) (US manufacturer Medtronics) consists of computerized electrical device implanted in the chest in a manner similar to the VNS, but electrical stimulation is delivered to deep brain structures through depth electrodes implanted through the skull. In epilepsy, the electrode target is the anterior nucleus of the thalamus. The efficacy of the DBS in localization-related epilepsies is currently under investigation.

Noninvasive surgery- The use of the Gamma Knife or other devices used in radiosurgery are currently being investigated as alternatives to traditional open surgery in patients who would otherwise qualify for anterior temporal lobectomy

Avoidance therapy- Avoidance therapy consists of minimizing or eliminating triggers in patients whose seizures are particularly susceptible to seizure precipitants (see above). For example, sunglasses that counter exposure to particular light wavelengths can improve seizure control in certain photosensitive epilepsies.

Warning systems- A seizure response dog is a form of service dog that is trained to summon help or ensure personal safety when a seizure occurs. These are not suitable for everybody and not all dogs can be so trained. Rarely, a dog may develop the ability to sense a seizure before it occurs. Development of electronic forms of seizure detection systems are currently under investigation.

Alternative or complementary medicine- A number of systematic reviews by the Cochrane Collaboration into treatments for epilepsy looked at acupuncture, psychological interventions, vitamin and yoga and found there is no reliable evidence to support the use of these as treatments for epilepsy. Further studies are needed on the subject.

Pathophysiology

Mutations in several genes have been linked to some types of epilepsy. Several genes that code for protein subunits of voltage-gated and ligand-gated ion channels have been associated with forms of generalized epilepsy and infantile seizure syndromes. Several ligand-gated ion channels have been linked to some types of frontal and generalized epilepsies. Epilepsy-related mutations in some non-ion channel genes have also been identified.

Epileptogenesis is the process by which a normal brain develops epilepsy after an insult. One interesting finding in animals is that repeated low-level electrical stimulation to some brain sites can lead to permanent increases in seizure susceptibility: in other words, a permanent decrease in seizure "threshold." This phenomenon, known as kindling (by analogy with the use of burning twigs to start a larger fire) was discovered by Dr. Graham Goddard in 1967. Chemical stimulation can also induce seizures; repeated exposures to some pesticides have been shown to induce seizures in both humans and animals. One mechanism proposed for this is called excitotoxicity. The roles of kindling and excitotoxicity, if any, in human epilepsy are currently hotly debated.

Other causes of epilepsy are brain lesions, where there is scar tissue or another abnormal mass of tissue in an area of the brain.

History and stigma

The word epilepsy is derived from the Greek epilepsia, which in turn can be broken into epi- (upon) and lepsis (to take hold of, or seizure) In the past, epilepsy was associated with religious experiences and even demonic possession. In ancient times, epilepsy was known as the "Sacred Disease" because people thought that epileptic seizures were a form of attack by demons, or that the visions experienced by persons with epilepsy were sent by the gods. Among animist Hmong families, for example, epilepsy was understood as an attack by an evil spirit, but the affected person could become revered as a shaman through these otherworldly experiences.

However, in most cultures, persons with epilepsy have been stigmatized, shunned, or even imprisoned; in the Salpêtrière, the birthplace of modern neurology, Jean-Martin Charcot found people with epilepsy side-by-side with the mentally retarded, those with chronic syphilis, and the criminally insane. In Tanzania to this day, as with other parts of Africa, epilepsy is associated with possession by evil spirits, witchcraft, or poisoning and is believed by many to be contagious. In ancient Rome, epilepsy was known as the Morbus Comitialis ('disease of the assembly hall') and was seen as a curse from the gods.

Stigma continues to this day, in both the public and private spheres, but polls suggest it is generally decreasing with time, at least in the developed world; Hippocrates remarked that epilepsy would cease to be considered divine the day it was understood.

Notable people with epilepsy

Many notable people, past and present, have carried the diagnosis of epilepsy. In many cases, their epilepsy is a footnote to their accomplishments; for some, it played an integral role in their fame. Historical diagnoses of epilepsy are not always certain; there is controversy about what is considered an acceptable amount of evidence in support of such a diagnosis.

Legal implications

Most people diagnosed with epilepsy are forbidden by their local laws from operating vehicles. However, there are usually exceptions for those who can prove that they have stabilized their condition. Those few whose seizures do not cause impairment of consciousness, or whose seizures only arise from sleep, may be exempt from such restrictions, depending on local laws. There is an ongoing debate in bioethics over who should bear the burden of ensuring that an epilepsy patient does not drive a car or fly an airplane.

In the U.S., people with epilepsy can drive if their seizures are controlled with treatment and they meet the licensing requirements in their state. How long they have to be free of seizures varies in different states, but it is most likely to be between three months and a year. The majority of the 50 states place the burden on patients to report their condition to appropriate licensing authorities so that their privileges can be revoked where appropriate. A minority of states place the burden of reporting on the patient's physician. After reporting is carried out, it is usually the driver's licensing agency that decides to revoke or restrict a driver's license.

In the UK, it is the responsibility of the patients to inform the Driver and Vehicle Licensing Agency (DVLA) if they have epilepsy. The DVLA rules are quite complex, but in summary, those continuing to have seizures or who are within 6 months of medication change may have their licence revoked. A doctor who becomes aware that a patient with uncontrolled epilepsy is continuing to drive has, after reminding the patient of their responsibility, a duty to break confidentiality and inform the DVLA. The doctor should advise the patient of the disclosure and the reasons why their failure to notify the agency obliged the doctor to act.

The Epilepsy Foundation's Jeanne A. Carpenter
 Epilepsy Legal Defense Fund is dedicated to advancing the rights of people with epilepsy by changing discriminatory practices, policies and laws and to ending epilepsy-related discrimination and injustice through education and increased access to legal services for individuals with epilepsy through a system of managed referrals and legal support to a nationwide network of attorneys committed to this cause.

Additionally, the Epilepsy Foundation is a vigorous advocate for people with epilepsy. In the United States, the Foundation has been active in Congress, the executive branch, and the courts, focusing attention on the needs of those with epilepsy. Priorities for the Foundation include: the availability of affordable quality health care, the search for the cure, and the protection of civil rights for people with epilepsy.

Ring chromosome 20 syndrome

Ring chromosome 20, ring-shaped chromosome 20 or r(20) syndrome is a rare human chromosome abnormality where the two arms of chromosome 20 fuse to form a ring chromosome. The syndrome is associated with epileptic seizures, behaviour disorders and mental retardation.

When only one copy of chromosome 20 forms a ring, the individual suffers from ring 20 chromosomal mosaicism.

Ring chromosome

Formation of a ring chromosome.

A ring chromosome is a chromosome whose arms have fused together to form a ring. A ring chromosome is denoted by the symbol r. Ring chromosomes may form in cells following genetic damage by mutagens like radiation, they may also arise spontaneously during development.

Formation

Normally, the ends of a chromosome are lost, enabling the arms to fuse together. However, ring formation can also occur with only one end being lost. In rare cases, the telomeres at the ends of a chromosome fuse without any disappearing of material.

Associated diseases

Human genetic disorders can be caused by spontaneous ring chromosome formation; although ring chromosomes are very rare, they have been found in nearly all human chromosomes. Disorders arising from the formation of a ring chromosome include ring chromosome 20 syndrome where a ring formed by one copy of chromosome 20 is associated with epilepsy; ring chromosome 14 and ring chromosome 13 syndrome are associated with mental retardation and dysmorphic facial features; ring chromosome 15 is associated with mental retardation, dwarfism and microcephaly. Ring formation of an X-chromosome causes Turner syndrome. Symptoms seen in patients carrying ring chromosomes are more likely to be caused by the deletion of genes in the telomeric regions of affected chromosomes, rather than by the formation of a ring structure itself.

Complex rearrangements including segmental microdeletions and microduplications have been seen in numerous ring chromosomes providing important clues regarging the mechanisms of their formation.

Chromosomal inversion

A clay model showing why heterozygous inversion loops are visible in polytene chromosome preparations

An inversion loop in the A arm of a chromosome from an Axarus species midge

An inversion is a chromosome rearrangement in which a segment of a chromosome is reversed end to end. An inversion occurs when a single chromosome undergoes breakage and rearrangement within itself. Inversions are of two types: paracentric and pericentric.

Paracentric inversions do not include the centromere and both breaks occur in one arm of the chromosome. Pericentric inversions include the centromere and there is a break point in each arm.

Cytogenetic techniques may be able to detect inversions, or inversions may be inferred from genetic analysis. Nevertheless, in most species small inversions go undetected. In insects with polytene chromosomes, for example Drosophila, preparations of larval salivary gland chromosomes allow inversions to be seen when they are heterozygous. This useful characteristic of polytene chromosomes was first advertised by Theophilus Shickel Painter in 1933.

Inversions usually do not cause any abnormalities in carriers as long as the rearrangement is balanced with no extra or missing genetic information. However, in individuals which are heterozygous for an inversion, there is an increased production of abnormal chromatids (this occurs when crossing-over occurs within the span of the inversion). This leads to lowered fertility.

Families that may be carriers of inversions may be offered genetic counseling and genetic testing.

The most common inversion seen in humans is on chromosome 9, at inv(9)(p11q12). This inversion is generally considered to have no deleterious or harmful effects, but there is some evidence it leads to an increased risk for miscarriage for about 30% of affected couples.

Chronic myelogenous leukemia

Chronic myelogenous leukemia
The Philadelphia chromosome as seen by metaphase FISH.

Chronic myelogenous (or myeloid) leukemia (CML) is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which proliferation of mature granulocytes (neutrophils, eosinophils, and basophils) and their precursors is the main finding. It is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome. Historically, it has been treated with chemotherapy, interferon and bone marrow transplantation, although targeted therapies introduced at the beginning of the 21st century have radically changed the management of CML.

Signs and symptoms

Patients are often asymptomatic at diagnosis, presenting incidentally with an elevated white blood cell count on a routine laboratory test. In this setting, CML must be distinguished from a leukemoid reaction, which can have a similar appearance on a blood smear. Symptoms of CML may include: malaise, low-grade fever, gout, increased susceptibility to infections, anemia, and thrombocytopenia with easy bruising (although an increased platelet count (thrombocytosis) may also occur in CML). Splenomegaly may also be seen.

Diagnosis

CML is often suspected on the basis on the complete blood count, which shows increased granulocytes of all types, typically including mature myeloid cells. Basophils and eosinophils are almost universally increased; this feature may help differentiate CML from a leukemoid reaction. A bone marrow biopsy is often performed as part of the evaluation for CML, but bone marrow morphology alone is insufficient to diagnose CML.

Ultimately, CML is diagnosed by detecting the Philadelphia chromosome. This characteristic chromosomal abnormality can be detected by routine cytogenetics, by fluorescent in situ hybridization, or by PCR for the bcr-abl fusion gene.

Controversy exists over so-called Ph-negative CML, or cases of suspected CML in which the Philadelphia chromosome cannot be detected. Many such patients in fact have complex chromosomal abnormalities which mask the (9;22) translocation, or have evidence of the translocation by FISH or RT-PCR in spite of normal routine karyotyping. The small subset of patients without detectable molecular evidence of bcr-abl fusion may be better classified as having an undifferentiated myelodysplastic/myeloproliferative disorder, as their clinical course tends to be different from patients with CML.

Pathophysiology

CML was the first malignancy to be linked to a clear genetic abnormality, the chromosomal translocation known as the Philadelphia chromosome. This chromosomal abnormality is so named because it was first discovered and described in 1960 by two scientists from Philadelphia, Pennsylvania: Peter Nowell of the University of Pennsylvania and David Hungerford of the Fox Chase Cancer Center.

In this translocation, parts of two chromosomes (the 9th and 22nd by conventional karyotypic numbering) switch places. As a result, part of the BCR ("breakpoint cluster region") gene from chromosome 22 is fused with the ABL gene on chromosome 9. This abnormal "fusion" gene generates a protein of p210 or sometimes p185 weight (p is a weight measure of cellular proteins in kDa). Because abl carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase), the bcr-abl fusion gene product is also a tyrosine kinase.

The fused bcr-abl protein interacts with the interleukin 3beta(c) receptor subunit. The bcr-abl transcript is continuously active and does not require activation by other cellular messaging proteins. In turn, bcr-abl activates a cascade of proteins which control the cell cycle, speeding up cell division. Moreover, the bcr-abl protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the bcr-abl protein is the pathophysiologic cause of chronic myelogenous leukemia. With improved understanding of the nature of the bcr-abl protein and its action as a tyrosine kinase, targeted therapies have been developed (the first of which was imatinib mesylate) which specifically inhibit the activity of the bcr-abl protein. These tyrosine kinase inhibitors can induce complete remissions in CML, confirming the central importance of bcr-abl as the cause of CML.

Classification

CML is often divided into three phases based on clinical characteristics and laboratory findings. In the absence of intervention, CML typically begins in the chronic phase, and over the course of several years progresses to an accelerated phase and ultimately to a blast crisis. Blast crisis is the terminal phase of CML and clinically behaves like an acute leukemia. One of the drivers of the progression from chronic phase through acceleration and blast crisis is the acquisition of new chromosomal abnormalities (in addition to the Philadelphia chromosome). Some patients may already be in the accelerated phase or blast crisis by the time they are diagnosed.

Chronic phase

Approximately 85% of patients with CML are in the chronic phase at the time of diagnosis. During this phase, patients are usually asymptomatic or have only mild symptoms of fatigue or abdominal fullness. The duration of chronic phase is variable and depends on how early the disease was diagnosed as well as the therapies used. Ultimately, in the absence of curative treatment, the disease progresses to an accelerated phase.

Accelerated phase

Criteria for diagnosing transition into the accelerated phase are somewhat variable; the most widely used criteria are those put forward by investigators at M.D. Anderson Cancer Center, by Sokal et al, and the World Health Organization. The WHO criteria are perhaps most widely used, and include:

• 10–19% myeloblasts in the blood or bone marrow
• >20% basophils in the blood or bone marrow
• Platelet count <100,000,>
• Platelet count >1,000,000, unresponsive to therapy
• Cytogenetic evolution with new abnormalities in addition to the Philadelphia chromosome
• Increasing splenomegaly or white blood cell count, unresponsive to therapy

The patient is considered to be in the accelerated phase if any of the above are present. The accelerated phase is significant because it signals that the disease is progressing and transformation to blast crisis is imminent.

Blast crisis

Blast crisis is the final phase in the evolution of CML, and behaves like an acute leukemia, with rapid progression and short survival. Blast crisis is diagnosed if any of the following are present in a patient with CML:

• >20% myeloblasts or lymphoblasts in the blood or bone marrow
• Large clusters of blasts in the bone marrow on biopsy
• Development of a chloroma (solid focus of leukemia outside the bone marrow)

Treatment