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Huntington's disease: How intermediate are intermediate repeat lengths?§

Authors

  • Ferdinando Squitieri MD, PhD,

    Corresponding author
    1. Neurogenetics and Rare Diseases Centre, IRCCS Neuromed, Pozzilli, Italy
    • Center for Neurogenetics and Rare Diseases, IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Italy

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  • Joseph Jankovic MD

    1. Department of Neurology, Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas, USA
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  • Funding agencies: This work was supported by funds from the Italian government to Associazione Italiana Corea di Huntington-Neuromed and to IRCCS Neuromed and by Telethon (project no. GGP12218; to F.S.).

  • Relevant conflicts of interest/financial disclosures: F.S. is a member of the Euro HD-Network. F.S. and J.J. are members of the Huntington Study Group.

  • §

    Full financial disclosures and author roles may be found in the online version of this article.

Abstract

Background: Huntington's disease (HD) is a devastating heredoneurodegenerative disorder associated with a wide variety of neurological and psychiatric symptoms caused by an expanded CAG repeat in the HTT gene. The expansion mutation in HTT is dominantly transmitted and codes for a protein named huntingtin (htt).

Hypothesis: One hypothesis, according to a multistep mechanism, is that the intergenerational transmission of the normal repeat size causes small, progressive CAG stretch elongations in the general population from one generation to another, until a critical pathological CAG repeat threshold is reached. Mutations may originate in the offspring from paternally transmitted CAG repeats, falling within an intermediate alleles (IA) range of 27 to 35 in repeat length.

Conclusions: There has been emerging evidence that some individuals with IAs might develop an HD phenotype. This presents a challenge for genetic counseling, because these individuals are often reassured that they are “disease free.” However, there are many unanswered questions related to the role of IAs in the development of the HD phenotype and in the pathogenesis of HD. © 2012 Movement Disorder Society © 2012 Movement Disorder Society

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