A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion

Huntington's disease (HD) is an autosomal dominant disorder characterized b y abnormalities of movement, cognition, and emotion and selective atrophy o f the striatum. and cerebral cortex. While the etiology of HD is known to b e a CAG trinucleotide repeat expansion, the pathways by which this mutation causes HD pathology remain unclear. We now report a large pedigree with an autosomal dominant disorder that is clinically similar to HD and that aris es from a different CAG expansion mutation. The disorder is characterized b y onset in the fourth decade, involuntary movements and abnormalities of vo luntary movement, psychiatric symptoms, weight loss, dementia, and a relent less course with death about 20 years after disease onset. Brain magnetic r esonance imaging scans and an autopsy revealed marked striatal atrophy and moderate cortical atrophy, with striatal neurodegeneration in a dorsal to v entral gradient and occasional intranuclear inclusions. All tested affected individuals, and no tested unaffecteds, have a CAG trinucleotide repeat ex pansion of 50 to 60 triplets, as determined by the repeat expansion detecti on assay. Tests for the HD expansion, for all other known CAG expansion mut ations, and for linkage to chromosomes 20p and 4p were negative, indicating that this mutation is novel. Cloning the causative CAG expansion mutation for this new disease, which we have termed Huntington's disease-like 2, may yield valuable insight into the pathogenesis of HD and related disorders.