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J Med Genet 2004;41:230-232. doi: 10.1136/jmg.2003.015602
Huntington's disease (HD) is characterized by movement abnormalities and psychiatric symptoms. Prominent features include choreiform movements, dysarthria, ataxia, depression, dementia, and personality changes. The disease usually manifests during the third or fourth decade of live and progresses with dysphagia and subsequent cachexia causing death some 20 years later. Neuropathologically, the disease is characterized by atrophy of the caudate and putamen and, to a lesser extent, of the cortex, globus pallidum, thalamus, subthalamic region, and substantia nigra. (1)
A CAG repeat expansion in the HD gene resulting in an expanded polyglutamine chain in the huntingtin protein was identified as the major cause of HD. (2) Phenocopies of HD have been described and designated as Huntington disease-like (HD-like). These disorders are genetically heterogeneous. In a consanguineous family of Saudi Arabian ancestry a juvenileonset choreiform disease resembling HD was described, inherited as an autosomal recessive trait. The chromosomal mapping might point to 4p15.3, but still is controversial. (3) (4) In senile chorea, CAG repeat expansions in the HD gene have been excluded but a gene locus for this HD-like condition is not known. (5) Several families have been reported with clinical features closely resembling HD and autosomal dominant inheritance. Among these, an early-onset non-progressive chorea with benign course has been associated with mutations in TITF-1 mapped to chromosome 14q, (6) and a progressive form has been described in a Swedish family, and has been designated as HDL-1 localizing to chromosome 20p. (7) Moore and co-workers and Laplanche and co-workers identified a 192-nucleotide insertion in the prion-protein gene (PRNP) that segregated with this phenotype in the family of Xiang and in one French family. (8) (9) More recently, a second family of African-American ethnicity with HD-like features showed repeat expansion in a gene mapping to chromosome 16q23 and the locus was designated HDL-2. (10) Subsequently, a CAG/CTG repeat expansion in the junctophilin-3 gene was identified in this family and was shown to cosegregate with the disease in …