Trinucleotide Repeats: Mechanisms and Pathophysiology

Within the closing decade of the twentieth century, 14 neurological disorders were shown to result from the expansion of unstable trinucleotide repeats, establishing this once unique mutational mechanism as the basis of an expanding class of diseases. Trinucleotide repeat diseases can be categorized into two subclasses based on the location of the trinucleotide repeats: diseases involving noncoding repeats (untranslated sequences) and diseases involving repeats within coding sequences (exonic). The large body of knowledge accumulating in this fast moving field has provided exciting clues and inspired many unresolved questions about the pathogenesis of diseases caused by expanded trinucleotide repeats. This review summarizes the current understanding of the molecular pathology of each of these diseases, starting with a clinical picture followed by a focused description of the disease genes, the proteins involved, and the studies that have lent insight into their pathophysiology.