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A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion
R L Margolis1, E O'Hearn, A Rosenblatt
1Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. rmargoli@jhmi.edu
Insights
Researchers identified a novel CAG expansion mutation causing a Huntington's disease-like disorder. This finding offers new insights into the pathogenesis of neurodegenerative diseases.
Area of Science:
- Neurogenetics
- Neurodegenerative Diseases
Background:
- Huntington's disease (HD) is an autosomal dominant disorder linked to CAG trinucleotide repeat expansion, causing movement, cognitive, and emotional abnormalities.
- The precise mechanisms by which the CAG mutation leads to HD pathology are not fully understood.
Observation:
- A large family presented with an autosomal dominant disorder clinically resembling HD, but caused by a distinct CAG expansion mutation.
- Affected individuals exhibited late-onset movement disorders, psychiatric symptoms, dementia, and progressive atrophy of the striatum and cerebral cortex.
Findings:
- The novel disorder, termed Huntington's disease-like 2 (HDL2), is associated with a CAG repeat expansion of 50-60 triplets.
- Genetic testing excluded known HD mutations and linkage to specific chromosomes, confirming the novelty of this mutation.
- Autopsy and MRI revealed striatal neurodegeneration with a dorsal-to-ventral gradient and intranuclear inclusions.
Implications:
- Studying the HDL2 mutation may elucidate pathogenic pathways relevant to Huntington's disease.
- This discovery expands the genetic landscape of CAG repeat expansion disorders.
- Identifying novel mutations aids in understanding the molecular basis of neurodegeneration.
Abstract:
Huntington's disease (HD) is an autosomal dominant disorder characterized by abnormalities of movement, cognition, and emotion and selective atrophy of the striatum and cerebral cortex. While the etiology of HD is known to be 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 arises from a different CAG expansion mutation. The disorder is characterized by onset in the fourth decade, involuntary movements and abnormalities of voluntary movement, psychiatric symptoms, weight loss, dementia, and a relentless course with death about 20 years after disease onset. Brain magnetic resonance imaging scans and an autopsy revealed marked striatal atrophy and moderate cortical atrophy, with striatal neurodegeneration in a dorsal to ventral gradient and occasional intranuclear inclusions. All tested affected individuals, and no tested unaffecteds, have a CAG trinucleotide repeat expansion of 50 to 60 triplets, as determined by the repeat expansion detection assay. Tests for the HD expansion, for all other known CAG expansion mutations, 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.