Trinucleotide Repeat Disorders

Repeat expansion disorders are a category of inherited diseases that predominantly affect the central nervous system and are caused by repeated sequences of deoxyribonucleic acid (DNA) (usually 3–6 nucleotides) that expand beyond a certain length. Repeat expansion disorders include Huntington’s disease, ataxias, myotonic dystrophies, and many other neurological diseases. Depending on the repeat motif and the location of the repeat within the gene in which they reside, the repeat expansion disorders can be classified into four different categories: loss-of-function, gain-of-function due to a protein with a polyglutamine tract expansion, gain-of-function due to ribonucleic acid (RNA) containing an expanded CG-rich repeat tract, and gain-of-function due to a protein containing a polyalanine tract expansion. An overview of the different repeat disease categories and current understanding of the molecular basis of these disorders are provided in this article. Recent advances in the field, including the discovery of an yet-to-be classified hexanucleotide repeat expansion within the C9orf72 gene, which is emerging as a major cause of inherited amyotrophic lateral sclerosis and frontotemporal dementia, as well as a likely risk factor for sporadic occurrences of these disorders are also considered in this article.