Huntington disease and the related disorder, dentatorubral-pallidoluysian atrophy (DRPLA)

Huntington disease (HD) and dentatorubral-pallidoluysian atrophy (DRPLA) are autosomal dominant, progressive neurodegenerative disorders characterized by involuntary movements, incoordination, dementia, psychiatric syndromes, seizures (particularly in the juvenile-onset form), and death 10-30 years after the onset of symptoms. The mutation responsible for each disorder is an expansion of a CAG repeat, placing HD and DRPLA in a growing class of polyglutamine neurodegenerative diseases. Unstable transmission of the expanded CAG repeats explains the anticipation observed in HD and DRPLA. Cloning of the HD and DRPLA genes allows direct testing for the presence of the mutation, of particular relevance to presymptomatic individuals desiring to know their gene status. The pathology of HD and DRPLA involves selective neuronal dysfunction and death in overlapping regions of the basal ganglia, cerebral cortex, cerebellum, and brainstem. Both disorders appear to result from a so-called gain-of-function mechanism in which the elongated stretch of glutamine residues confers toxic new properties to the protein. Recent histologic and immunocytochemical findings suggest that this gain of function results in intranuclear inclusions containing aggregates of polyglutamine fragments, a potential common pathway of pathogenesis for HD, DRPLA, and related disorders.