Huntington disease phenocopy is a familial prion disease

Huntington disease (HD) is a common autosomal dominant neurodegenerative di sease with early adult-onset motor abnormalities and dementia. Many studies of HD show that huntingtin (CAG) n repeat-expansion length is a sensitive and specific marker for HD. However, there are a significant number of exam ples of HD in the absence of a huntingtin (CAG) n expansion, suggesting tha t mutations in other genes can provoke HD-like disorders. The identificatio n of genes responsible for these "phenocopies" may greatly improve the reli ability of genetic screens for HD and may provide further insight into neur odegenerative disease. We have examined an HD phenocopy pedigree with linka ge to chromosome 20p12 for mutations in the prion protein (PrP) gene (PRNP) . This reveals that affected individuals are heterozygous for a 192-nucleot ide (nt) insertion within the PrP coding region, which encodes an expanded PrP with eight extra octapeptide repeats. This reveals that this HD phenoco py is, in fact, a familial prion disease and that PrP repeat-expansion muta tions can provoke an HD "genocopy." PrP repeat expansions are well characte rized and provoke early-onset, slowly progressive atypical prion diseases w ith an autosomal dominant pattern of inheritance and a remarkable range of clinical features, many of which overlap with those of HD. This observation raises the possibility that an unknown number of HD phenocopies are, in fa ct, familial prion diseases and argues that clinicians should consider scre ening for PrP mutations in individuals with HD-like diseases in which the c haracteristic HD (CAG) n repeat expansions are absent.