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Huntington disease (HD, OMIM #143100) is a dominantly inherited neurodegenerative disorder due to a CAG repeat expansion in the HTT gene, encoding a polyglutamine tract in the N-terminal part of the huntingtin protein. Most cases are inherited from an affected parent, but in about 10% of cases the condition appears to be de novo.1 De novo or sporadic cases are usually due to CAG repeat expansion of intermediate alleles. Intermediate alleles have 27–35 CAG repeats, and the higher the number of repeats, the higher the risk for expansion into disease range, usually upon paternal transmission.2 In most cases, the change in repeat size is minor, and gradual increases into the disease range over several generations is the basis of new genetic mutations and stable disease prevalence. So far, the largest single-step expansions reported were from 27 to 383 and from 35 to 582 CAG repeats. It has recently been shown that intermediate alleles and disease alleles share the same haplotypes, which is expected if intermediate alleles are the main source of new mutation cases. The high-risk haplotypes are called A1 and A2, and are both prevalent among Caucasians but rare in other ethnic groups.4
Acknowledgments
Acknowledgment: The authors thank Dr. Harald Hovdal, the referring clinician, and the patient and her family for their interest in resolving this case.
Footnotes
Study funding: No targeted funding reported.
Author contributions: Gunnar Houge: writing of manuscript, clinical work, interpretation of data. Ove Bruland: acquisition and analysis of data. Inga Bjørnevoll: acquisition of data, clinical contact. Michael R. Hayden: supervision of part of study. Alicia Semaka: acquisition and interpretation of data, revision of manuscript.
Disclosures: G. Houge, O. Bruland, and I. Bjørnevoll report no disclosures. M. Hayden is a Killam University Professor; holds a Canada Research Chair in Human Genetics and Molecular Medicine; and is supported by the Canadian Institutes of Health Research (CIHR). A. Semaka is supported by the Canadian Institutes of Health Research (CIHR) and is funded by a Doctoral Award from the CIHR and a Senior Trainee Award from the Michael Smith Foundation for Health Research. Go to Neurology.org for full disclosures.
- Received February 12, 2013.
- Accepted in final form May 10, 2013.
- © 2013 American Academy of Neurology
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