Variant Huntington’s Disease
Abstract & Commentary
Source: Margolis RL, et al. A disorder similar to Huntington’s disease is associated with a novel CAG repeat expansion. Ann Neurol. 2001;50:373-380.
Huntington’s disease (HD) is an autosomal dominant disorder characterized by disorders of movement, cognition, and behavior. Symptoms typically begin between the ages of 35 and 50. Affected patients typically manifest a combination of chorea, dystonia, or parkinsonism, and there is an inexorable decline with progressive dementia and behavioral disinhibition. Medium spiny projection neurons are selectively lost in the striatum, with a characteristic dorsal-to-ventral gradient of cell loss. HD was the first neurodegenerative disorder linked to expansion of polyglutamine residues (the so-called CAG repeat expansions). Over the last decade, more than 15 spinocerebellar ataxias have been linked to triplet repeat expansions, and polyglutamine repeats are now known to cause dentatorubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias 1, 2, 3, 6, and 7. CAG-repeat expansions result in a "gain of function" of the affected protein, with accumulation of intranuclear polyglutamine protein aggregates in selected neuronal cell populations.
The availability of a gene test for HD has profoundly changed the way neurologists evaluate HD patients and family members who are at risk for HD. Patients with more than 40 CAG repeats in the IT-15 gene (the HD gene) will develop symptoms of HD with 100% certainty if they live long enough. More than 95% of patients who have symptoms of HD and magnetic resonace imaging (MRI) consistent with the disorder are proven to have CAG repeat expansions in the IT-15 gene. However, neurologists occasionally encounter patients who look like they have HD, but in whom gene testing is normal. In this paper, Margolis and colleagues describe such a patient and pedigree, and discuss the implications for HD and other neurodegenerative conditions.
Margolis et al’s pedigree is a 3-generation family with 17 affected individuals. The inheritance pattern is clearly autosomal dominant. Symptoms begin at age 35 in the youngest generation and age 45 in the oldest generation, suggesting the possibility of anticipation (ie, earlier disease onset with each succeeding generation). Early symptoms and signs include weight loss, incoordination and involuntary movements followed by depression, anxiety, irritability, and eventually profound dementia. Patients look very much like the "Westphal" variant of HD, a phenotype dominated by parkinsonism and dystonia; chorea is less prominent. MRI showed prominent striatal atrophy with flattening of the head of the caudate, moderate cortical atrophy, and preserved brainstem and cerebellar volumes. An autopsy of one patient revealed severe atrophy of the head of the caudate and putamen, severe neuronal degeneration in the striatum with a dorsal-to-ventral gradient, and occasional intranuclear inclusions.
Genetic testing for CAG-repeat expansions in the IT-15 gene (HD) were negative, and Margolis et al also excluded linkage to a locus near chromosome 20p previously linked in another HD-look-alike family. Using a new technique for detecting CAG repeat expansions, Margolis et al demonstrated a CAG-repeat expansion in affected family members of approximately 50-60 triplet repeats. Linkage studies to identify the abnormal gene in this pedigree are ongoing.
Commentary
This is an interesting and important paper. Despite a decade of investigation, several critical questions remain unanswered regarding the underlying mechanism of cell loss in HD. Polyglutamine expansion within a protein (IT-15 or the target protein abnormal in Margolis et al’s pedigree) leads to a gain of function, causing aggregation of the protein within the neuron. Is the protein aggregate directly toxic to neurons, or are the neuronal inclusions an end-stage feature of the cascade? The discovery of the genes responsible for phenocopies of HD will help define the intracellular pathways responsible for the characteristic selective neuronal loss within the striatum, and will also likely suggest new targets for therapeutic approaches to interfere with these pathways. —Steven Frucht, MD. Dr. Frucht, Assistant Professor of Neurology, Movement Disorders Division, Columbia-Presbyterian Medical Center, is Assistant Editor of Neurology Alert.
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