Molecular pathology of dentatorubral-pallidoluysian atrophy

Dentatorubral - pallidoluysian atrophy (DRPLA) is an autosomal dominant dis order characterized clinically by myoclonus, epilepsy, cerebellar ataxia, c horeoathetosis and dementia. Cardinal pathological features of DRPLA are a combined degeneration of both the dentatorubral and the pallidoluysian syst ems. Although the early sporadic cases were reported by Western neuropathol ogists, a strong heritability and an age of onset-dependent variability of the clinical features were carefully deduced by Japanese clinicians. The di sease is fairly common in Japan , but extremely rare in Caucasians. Since t he gene was identified in 1994, DRPLA is known as one of the CAG repeat exp ansion diseases, in which the responsible gene is located on chromosome 12p and its product is called atrophin 1. DRPLA shows prominent 'anticipation' , which is genetically clearly explained by a marked instability of the exp anded CAG repeat length during spermatogenesis. Moreover, the instability o f the CAG repeat length also seems to occur in the somatic cells, resulting in 'somatic mosaicism'. Possible mechanism(s) underlying the neuronal cell death in DRPLA are discussed in terms of molecular pathological points of view.