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.
The commonest HD CAG repeat length frequency, as you can see from this slide, is between 42 and 46.
Genetic anticipation occurs in Huntington's disease. And what this means is that there is younger onset in future generations. And this is illustrated in the following pedigree. And you can see inheriting through the paternal line results in younger onset in successive generations.
The age of onset in Huntington's disease is closely related to the CAG repeat length, particularly above 50 repeats.
You can see, in this slide, how the CAG can increase with paternal transmission. This is because of the somatic instability during spermatogenesis that I mentioned earlier through the male line. Through the female line, there is minimal change, as the CAG is much more stable in oocytes. You can see in this figure that the CAG is increasing with paternal transmission. And 95% of juvenile cases of Huntington's disease, where the onset is less than 20, are inherited through the paternal line.
Pathobiology of HD.
The HD mutation is in the first axon of a very large chain. It has 67 axons and encodes a protein of 350 kilodaltons. The protein has multiple different critical functions, and if it's knocked out embryologically in mice, it's embryologically lethal. Huntingtin is expressed in all tissues in the body.
Mutant huntingtin results in a number of deleterious cellular dysfunctions. The protein is produced as a full length. It probably undergoes proteolytic cleavage to produce a number of Huntington fragments. The actual proteolytic cleavage patterns and fragments of mutant huntingtin in humans has not been yet defined. But it is very clear that proteolytic cleavage occurs. These fragments cause a number of different cellular-mediated toxicities, including mitochondrial toxicity, vesicle transport dysfunction, excitotoxicity, aggregate formation, clathrin-mediated endocytosis dysfunction, impaired axonal transport. And also critically, it causes transcriptional dysregulation by presumed nuclear translocation of fragments.

Huntington’s disease and HD-like disorders

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