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16 - Huntington's disease

Published online by Cambridge University Press:  12 October 2009

Jean Paul G. Vonsattel
Affiliation:
New York Brain Bank, The Taub Institute, Columbia University, New York, USA
Maxim Lianski
Affiliation:
New York Brain Bank, The Taub Institute, Columbia University, New York, USA
Margaret M. Esiri
Affiliation:
University of Oxford
Virginia M. -Y. Lee
Affiliation:
University of Pennsylvania School of Medicine
John Q. Trojanowski
Affiliation:
University of Pennsylvania School of Medicine
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Summary

Huntington's disease (HD) is an autosomal dominant illness, usually with mid-life onset, of psychiatric, cognitive and motor symptoms. Death occurs 12–15 years from the time of symptomatic onset (Folstein, 1989; Harper et al., 1991). The HD mutation consists of an unstable expansion of CAG (trinucleotide) repeats within the coding region of the gene ‘IT15’ (for ‘Interesting transcript’ referred to as HD-IT15 CAG repeats). This gene, on chromosome 4 (4p63), encodes the 350 kDa protein huntingtin of unknown function (Group et al., 1993). An expanded polyglutamine residue (polyQ) distinguishes the mutated huntingtin (with about 37 to 250 polyQ) from the wild type (with 8 to about 34–36 polyQ) (Nance et al., 1999; Rubinsztein et al., 1996). The disease occurs when the critical threshold of about 37 polyQ is exceeded. This phenomenon is observed in a group of inherited, neurodegenerative diseases caused by polyQ extension, which is increasingly referred to as polyglutaminopathies (Paulson, 1999). The pathogenicity of the mutant huntingtin is unknown. The mutant huntingtin retains some functions of the wild type huntingtin since individuals homozygous for the HD gene produce only mutant huntingtin and are clinically indistinguishable from heterozygous patients (Wexler et al., 1987; Myers et al., 1989). The mutant huntingtin is present in all organs, yet the brunt of the changes of HD identified so far occurs in the brain (Sathasivam et al., 1999). The degeneration involves initially the striatum (neuronal loss, gliosis) and cortex, and eventually may appear throughout the brain as a constellation of the toxic effect of the mutation and the ensuing secondary changes.

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Publisher: Cambridge University Press
Print publication year: 2004

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