• Marguerite V Evans-Galea, Nissa Carrodus, Simone M Rowley, Louise A Corben, Geneieve Tai, Richard Saffery, John C Galati, Nicholas C Wong, Jeffrey M Craig, David R Lynch, Sean R Regner, Alicia F D Brocht, Susan L Perlman, Khalaf O Bushara, Christopher M Gomez, George R Wilmot, Lingli Li, Elizabeth Varley, Martin B Delatycki, and Joseph P Sarsero.
• Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia. marguerite.galea@mcri.edu.au
• Ann. Neurol. 2012 Apr 1; 71 (4): 487-97.

ObjectiveFriedreich ataxia (FA) is the most common ataxia and results from an expanded GAA repeat in the first intron of FXN. This leads to epigenetic modifications and reduced frataxin. We investigated the relationships between genetic, epigenetic, and clinical parameters in a large case-control study of FA.MethodsClinical data and samples were obtained from individuals with FA during annual visits to our dedicated FA clinic. GAA expansions were evaluated by polymerase chain reaction (PCR) and restriction endonuclease digest. DNA methylation was measured using bisulfite-based EpiTYPER MassARRAY (Sequenom, San Diego, CA). FXN expression was determined using real-time reverse transcriptase PCR. Significant correlations between the different parameters were examined using the nonparametric Spearman rank correlation coefficient, as well as univariate and multivariate regression modeling.ResultsCharacteristic DNA methylation was identified upstream and downstream of the expansion, and validated in an independent FA cohort. Univariate and multivariate analyses showed significant inverse correlations between upstream methylation and FXN expression, and variation in downstream methylation and age of onset. FXN expression also inversely correlated with the Friedreich Ataxia Rating Scale score, an indicator of disease severity.InterpretationThese novel findings provide compelling evidence for the link between the GAA expansion, the DNA methylation profile, FXN expression, and clinical outcome in FA. Epigenetic profiling of FXN could be used to gain greater insight into disease onset and progression, but also as a biomarker to learn more about specific treatment responses and pharmacological mechanism(s). This work also highlights the potential for developing therapies aimed at increasing frataxin levels to treat this debilitating disease.Copyright © 2011 American Neurological Association.

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