Epigenetics of Huntington’s disease

Abstract

Although Huntington’s disease (HD) is rare, it deserves particular attention not only because of its devastating effects and inevitable progression as well as the familial ramifications, but also because of its potential utility as a model for other neurodegenerative diseases and psychiatric disorders. An autosomal dominant CAG trinucleotide repeat disorder, HD was first comprehensively phenotyped in an elegant study in 1872 by George Huntington, who clearly described the inheritance pattern and motor characteristics of the disease. The responsible gene locus was eventually found on chromosome 4 in a landmark paper in Cell in 1993. It is commonly accepted that 27–35 CAG repeats are ‘unstable’ and may produce disease in offspring, 36–39 repeats lead to later-onset disease and higher repeat lengths lead to inevitable disease with motor onset between the ages of 30–50 years. Several recent robust, large-scale prospective cohort studies have intensively studied the clinical and imaging biomarkers associated with disease progression in large cohorts over many years. As a result the genetics are well understood and the phenotype has been thoroughly investigated. However, the major challenge this field of research faces is in clarifying the intervening stages between genotype and phenotype, in the hope of developing disease-modifying drugs. This article reviews three papers that address significant gaps in our knowledge. Firstly, an article using a novel technique to identify biochemical pathways previously not known to be affected by mutant Huntingtin, secondly, a paper that robustly demonstrates respiratory chain enzyme dysfunction in vivo (and hence mitochondrial dysfunction in the disease), and finally, a paper that uses a large cohort to identify a putative novel phenotype associated with shorter CAG repeat lengths, challenging current assumptions about the repeat lengths necessary for disease development.

DOI: 10.1007/s00415-013-7158-x

Cite this paper

@article{Mclauchlan2013EpigeneticsOH, title={Epigenetics of Huntington’s disease}, author={D. Mclauchlan and Neil P. Robertson}, journal={Journal of Neurology}, year={2013}, volume={260}, pages={2938-2941} }