Huntington’s disease and HD-like disorders

Published on July 1, 2014   23 min

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Other Talks in the Series: The Genetic Basis of Neurological Disorders

"Huntington's Disease and HD-like Disorders." Sarah Tabrizi, professor of neurology at the Institute of Neurology, University College London.
Genetic causes of chorea: HD and HD-like disorders. HD-like disorders can be called HD phenocopies. They're all characterized by variable presentation of chorea, dystonia, and parkinsonism, cognitive impairment, and psychiatric disturbance.
The CAG repeat diseases comprise Huntington's disease, DRPLA, SBMA, and SCA1, 2, 3, 6, 7 and 17. They're sometimes called the PolyQ disorders.
Huntington's disease.
This was first described by George Huntington in 1872. It is the commonest genetic cause of chorea. It is dominantly inherited. And the mean age of onset is about 40. About 8% of new cases have no family history.
Huntington's disease is caused by a CAG repeat expansion in the Huntington gene encoding the Huntington protein. It was cloned in 1993 by a large collaborative research group.
HD genetics are interesting. And there is a CAG repeat threshold. Normal individuals have less than 29 CAG repeats. And this is not pathogenic, and it's not unstable. Between 29 and 35, it's an intermediate repeat range. It's not pathogenic to that individual, but it may expand into disease range in future generations and appear like a new mutation. This is because of paternal meiotic instability during spermatogenesis where CAG repeat expansions can occur during spermatogenesis due to meiotic instability. This means that in future generations, the expansion can be pathogenic. There is a reduced penetrance range of 36 to 39 CAG repeats, which can be pathogenic and has a risk of HD of between 25% at 36 repeats and 90% at 39 repeats. However, if you have 40 or more CAG repeats, that is fully pathogenic and fully penetrant and always causes Huntington's disease.

Huntington’s disease and HD-like disorders

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