TRINUCLEOTIDE REPEAT EXPANSION IN NEUROLOGICAL DISEASE

Expansion of trinucleotide repeats is now recognized as a major cause of neurological disease. At least seven disorders result from trinucle otide repeat expansion: X-linked spinal and bulbar muscular atrophy (S BMA), two fragile X syndromes of mental retardation (FRAXA and FRAXE), myotonic dystrophy, Huntington's disease, spinocerebellar ataxia type 1 (SCA1), and dentatorubral-pallidoluysian atrophy (DRPLA). The expan ded trinucleotide repeats are unstable; and the phenomenon of anticipa tion, i.e., worsening of disease phenotype over successive generations , correlates with increasing expansion size. In this review, we compar e the clinical and molecular features of the trinucleotide repeat dise ases, which may be classified into two types. Fragile X and myotonic d ystrophy are multisystem disorders usually associated with large expan sions of untranslated repeats, while the four neurodegenerative disord ers, SBMA, Huntington's disease, SCA1, and DRPLA, are caused by smalle r expansions of CAG repeats within the protein coding portion of the g ene. CAG repeats encode polyglutamine tracts. Polyglutamine tract expa nsion thus appears to be a common mechanism of inherited neurodegenera tive disease. Although polyglutamine tract lengthening presumably has a toxic gain of function effect in the CAG trinucleotide repeat disord ers, the basis of this neuronal toxicity remains unknown.