Trinucleotide repeat (TNR) diseases are some of the latest disorders to be linked to epigenetic state. So Dr. Marguerite Evans-Galea and colleagues at the Murdoch Childrens Research Institute and The University of Melbourne, wrote up this review to act as a sort of cheat sheet for the mounting evidence of epigenetic mechanisms in TNR. This article also “highlights how the epigenetic profile can modulate disease outcome” as well as “the clinical potential of epigenetic biomarkers and therapies for TNR disease”.

Evans-Galea shares that “studies have established significant correlations between clinical features, expansion size, gene expression, the chromatin profile, and DNA methylation in regions surrounding the TNR. Multiple severe neuromuscular and neurodegenerative disorders are attributed to TNR expansions within simple DNA repeats. Although there is variation in clinical presentation, several TNR diseases affect multiple organs, demonstrate age-dependent progression and have a poor long-term prognosis.”

Based on this emerging evidence clinical research has begun to search for novel epigenetic targets and biomarkers. This effort has shown promise particularly in:

Huntington disease

Myotonic dystrophy

Friedreich ataxia

Fragile X syndrome

“Mounting data implicate epigenetic changes in TNR disease etiology, including age of onset, disease trajectory, and severity of phenotype. Understanding the link between the epigenetic profile and clinical outcome will provide novel insights into TNR disease pathobiology and may facilitate the development of much-needed tools in the clinic. The molecular mechanisms underlying TNR disease pathology are diverse, ranging from gene silencing through to the production of toxic RNA and protein. Although epigenetic profiles have yet to be characterized in many TNR diseases, it is clear that aberrant DNA methylation, histone modifications, and chromatin remodeling play a role. Many of these conditions have variable severity and penetrance, and how these different pathological mechanisms impact and interact with the TNR-associated epigenetic profile could significantly affect clinical outcome.”

Evans-Galea emphasizes that “therapies and biomarkers for TNR diseases are urgently needed. Epigenetic profiling in TNR disease can inform how genetic and epigenetic changes cooperate to impact clinical outcome, and biomarkers evaluated early in life could potentially predict the progression and trajectory of disease and provide tools for monitoring treatment intervention. Importantly, epigenetic profiling could also help us to better understand disease mechanism and possibly identify new therapeutic targets. Given the debilitating and sometimes fatal consequences of TNR disorders, understanding how an altered epigenetic profile impacts clinical outcome warrants further attention, and could provide key insights for developing novel epigenetic therapies and biomarkers.”

Learn more about TNRs and their mods at Trends in Molecular Medicine, Sept 2013.