Trinucleotide repeat disorder

Trinucleotide repeat disorders are a set of genetic disorders caused by trinucleotide repeat expansion, a kind of mutation where trinucleotide repeats in certain genes or introns exceed the normal, stable threshold, which differs per gene. The mutation is a subset of unstable microsatellite repeats that occur throughout all genomic sequences. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. If the repeat is present in an intron it can cause toxic effects by forming spherical clusters called RNA foci in cell nuclei. Trinucleotide repeat disorders are a set of genetic disorders caused by trinucleotide repeat expansion, a kind of mutation where trinucleotide repeats in certain genes or introns exceed the normal, stable threshold, which differs per gene. The mutation is a subset of unstable microsatellite repeats that occur throughout all genomic sequences. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. If the repeat is present in an intron it can cause toxic effects by forming spherical clusters called RNA foci in cell nuclei. Trinucleotide repeats are sometimes classified as insertion mutations and sometimes as a separate class of mutations. Since the early 1990s, a new class of molecular disease has been characterized based upon the presence of unstable and abnormal expansions of DNA-triplets (trinucleotides). The first triplet disease to be identified was fragile X syndrome, which has since been mapped to the long arm of the X chromosome. At this point, there are from 230 to 4000 CGG repeats in the gene that causes fragile X syndrome in these patients, as compared with 60 to 230 repeats in carriers and 5 to 54 repeats in unaffected individuals. The chromosomal instability resulting from this trinucleotide expansion presents clinically as intellectual disability, distinctive facial features, and macroorchidism in males. The second, related DNA-triplet repeat disease, fragile X-E syndrome, was also identified on the X chromosome, but was found to be the result of an expanded CCG repeat. Identifying trinucleotide repeats as the basis of disease has brought clarity to our understanding of a complex set of inherited neurological diseases. As more repeat expansion diseases have been discovered, several categories have been established to group them based upon similar characteristics. Category I includes Huntington's disease (HD) and the spinocerebellar ataxias that are caused by a CAG repeat expansion in protein-coding portions of specific genes. Category II expansions tend to be more phenotypically diverse with heterogeneous expansions that are generally small in magnitude, but also found in the exons of genes. Category III includes fragile X syndrome, myotonic dystrophy, two of the spinocerebellar ataxias, juvenile myoclonic epilepsy, and Friedreich's ataxia. These diseases are characterized by typically much larger repeat expansions than the first two groups, and the repeats are located outside of the protein-coding regions of the genes. Some TRD manifest problems through causing alternations in the coding sequence of the protein, while others are caused via altered gene regulation. In over half of these disorders, the repeated codon is CAG, which in a coding region, codes for glutamine (Q), resulting in a polyglutamine tract. These diseases are commonly referred to as polyglutamine (or PolyQ) diseases. The remaining disorders repeated codons do not code for glutamine and are classified as non-polyglutamine diseases. A common symptom of PolyQ diseases is characterized by a progressive degeneration of nerve cells usually affecting people later in life. Although these diseases share the same repeated codon (CAG) and some symptoms, the repeats for the different polyglutamine diseases can occur on different chromosomes. The non-PolyQ diseases do not share any specific symptoms and are unlike the PolyQ diseases. Trinucleotide repeat disorders generally show genetic anticipation, where their severity increases with each successive generation that inherits them. This is likely explained by the addition of further CAG repeats in the gene in the progeny of affected individuals. For example, Huntington's disease occurs when there are more than 35 CAG repeats on the gene coding for the protein HTT. A parent with 35 repeats would be considered 'normal' and never exhibit any symptoms of the disease. That parent's offspring, however, would be at an increased risk compared to the general population of developing Huntington's, as it would take only the addition of one more CAG codon to cause the production of mHTT (mutant HTT), the protein responsible for disease. Huntington's very rarely occurs spontaneously; it is almost always the result of inheriting the defective gene from an affected parent. Sporadic cases of Huntington's do occur, and those individuals with a parent who already has a significant number of CAG repeats in their HTT gene, especially if it approaches the number (36) required for the disease to manifest, are at an increased risk of developing Huntington's despite the lack of any history of the disease in their family. Also, the more repeats, the more severe the disease and the earlier its onset. This explains why individuals that have had Huntington's running in their family for a longer period of time show an earlier age of disease onset and faster disease progression, as mutations that add additional CAG codons become more likely with each successive generation.