[Dynamic mutations in hereditary neurodegenerative disorders]

Triplet repeat expansion diseases (TREDs) are characterized by co-incidence between neurological disease manifestation and amplification of specific trinucleotide repeats in different but defined loci. This class of mutations was first identified in 1991 as the cause of spinal and bulbar muscular atrophy (SBMA) and fragile X syndrome (FRAXA). Since then, TNR (tri-nucleotide repeat) expansions have been found to be the causative mechanism in 11 other neurodegenerative disorders. Short cytosine-adenine-guanine (CAG) expansions are characteristic for Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA) and spinocerebellar ataxia (SCA) type 1, 2, 3, 6 and 7. In the normal population, the TNR units are polymorphic but transmitted stably from one generation to the next. However, in the above disorders the TNRs are expanded into the disease range and subjected to meiotic instability in a length-dependent manner. Thus, disease-associated, expanded TNRs tend to increase in length from generation to generation. This explains the phenomenon of anticipation associated with these disorders. TNR expansions result in polyglutamine (Q)n expansions in the corresponding proteins. Such mutant proteins tend to precipitate as a result of self-aggregation leading to the formation of neuronal nuclear inclusions and, hence, selective degeneration and loss of neuronal cells.