Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by homozygous expansion of a GAA·TTC trinucleotide repeat within the first intron of the FXN gene, leading to reduced FXN transcription and decreased levels of frataxin protein. Recent advances in FRDA research have revealed the presence of several epigenetic modifications that are either directly or indirectly involved in this FXN gene silencing. Although epigenetic marks may be inherited from one generation to the next, modifications of DNA and histones can be reversed, indicating that they are suitable targets for epigenetic-based therapy. Unlike other trinucleotide repeat disorders, such as Huntington disease, the large expansions of GAA·TTC repeats in FRDA do not produce a change in the frataxin amino acid sequence, but they produce reduced levels of normal frataxin. Therefore, transcriptional reactivation of the FXN gene provides a good therapeutic option. The present paper will initially focus on the epigenetic changes seen in FRDA patients and their role in the silencing of FXN gene and will be concluded by considering the potential epigenetic therapies. 1. Introduction FRDA is a rare autosomal recessive neurodegenerative disorder that affects approximately 1-2 in 50,000 Caucasians [1]. In 96% of FRDA patients, the disease is caused by homozygous expansion of GAA·TTC repeats in intron 1 of the FXN gene [2]. Unaffected individuals have up to 40 GAA·TTC repeats, with a premutation range from 41 to 65 GAA repeats. The affected individuals contain 66 to 1700 GAA·TTC repeats [3], most commonly between 600 and 900 GAA·TTC repeats. In most cases, the GAA·TTC repeat number of the smaller allele is directly related to the age of onset and the severity of the disease. However, a small proportion of patients (approximately 4%) are compound heterozygous, having one allele with a GAA·TTC repeat expansion and the other allele with an inactivating (or loss-of-function) intragenic mutation, such as a point mutation [4, 5] or a deletion/duplication [6–9]. To date, no confirmed FRDA patients have been identified without at least one GAA·TTC repeat expansion. The exact mechanism underlying the GAA·TTC repeat expansion in FRDA is not fully understood, but evidence has been put forward for the involvement of abnormal DNA replication, transcription, or repair [10–12]. In FRDA patients, the expanded GAA·TTC repeats produce a marked reduction in the mitochondrial protein frataxin, ranging from 4% to 29% of normal levels [13]. However, asymptomatic carriers produce about 50% of
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