Huntington Disease-Like 1

A number sign (#) is used with this entry because of evidence that this phenocopy of Huntington disease (HDL1) is a familial prion disease caused by 8 extra octapeptide repeats in the PRNP gene (176640.0001) on chromosome 20p13.

Clinical Features

Andrew et al. (1994) found that 30 of 1,022 persons (2.9%) diagnosed as having Huntington disease (HD; 143100) did not have an expanded CAG repeat in the disease range in the huntingtin gene (HTT; 613004). After excluding errors in misdiagnosis, sample mix-up, or clerical error, 12 patients (1.2% of the total sample) represented possible phenocopies for HD. In at least 4 cases, family studies of these phenocopies excluded 4p16.3 as the region responsible for the phenotype. Andrew et al. (1994) concluded that on rare occasions mutations in other genes can present a clinical phenotype very similar to that of HD.

Xiang et al. (1998) presented follow-up on 1 of the families reported by Andrew et al. (1994) in whom linkage to 4p was excluded. There were 7 affected members in 3 generations. Age at onset ranged from 23 to 41 years, characterized by personality changes, cognitive decline, and difficulties in coordination and gait. Personality changes included aggression, anxiety, and depression. One patient had delusions. Motor disturbances included chorea, rigidity, ataxia, and dysarthria. Three patients had seizures. Neuropathologic findings in 3 patients showed atrophy of the basal ganglia, and variable frontal and temporal lobe atrophy. No plaques or tangles were identified.

Laplanche et al. (1999) described a 5-generation French kindred in which 11 members were affected by a form of spongiform encephalopathy which was originally diagnosed as Gerstmann-Straussler-Scheinker disease (137440). Mean age at onset was 28 years (range, 21 to 34 years). In 6 instances, the patients were hospitalized in psychiatric institutions with various diagnoses, the most frequent being mania or mania-like symptoms. Dementia occurred progressively after a lengthy course. Histologic studies showed atrophy of the cerebellar molecular layer, which contained kuru and multicentric plaques labeled with anti-prion protein antibodies. Spongiosis was not prominent and remained largely limited to the periphery of plaques; it was more marked in the thalamus, where plaques were scarce.

Mapping

In an affected family with normal numbers of huntingtin CAG repeats, Xiang et al. (1998) found linkage to marker D20S482 on 20p (lod score of 3.01). Haplotype analysis indicated the gene responsible for the disease was likely located in a 2.7-cM region between D20S193 and D20S895.

Molecular Genetics

In 4 symptomatic subjects from a French kindred with a neurodegenerative disease with prominent psychiatric manifestations, Laplanche et al. (1999) identified a heterozygous 192-bp insertion (8 extra repeats of 24 bp each) in the octapeptide coding region of the PRNP gene (176640.0001). The insert was present within the 129met codon, and all patients were also homozygous for the met129 allele (176640.0005). Early age at onset, the prominence of psychiatric symptoms, and the long course of the disease were noticeable clinical features distinguishing the disorder from other prion diseases. Laplanche et al. (1999) noted the families reported by Goldfarb et al. (1991) and van Gool et al. (1995) in which an 8-octapeptide repeat in the PRNP gene occurred within a codon-129 valine allele and caused Creutzfeldt-Jakob disease (see 176640.0009).

In studies of the HD phenocopy pedigree with linkage to 20p12 reported by Xiang et al. (1998), Moore et al. (2001) found that affected individuals were heterozygous for the 192-nucleotide insertion within the coding region of the PRNP gene, resulting in an expanded prion protein with 8 extra octapeptide repeats. Thus, this HD phenocopy is a familial prion disease. The mutation found was the same as that described in the French family by LaPlanche et al. (1999) and referred to as 'early-onset prion disease with prominent psychiatric features.'