150 years of Friedreich Ataxia: from its discovery to therapy

In 1863, Nikolaus Friedreich (1825-1882), a German pathologist from Heidelberg, described a new spinal disease for the first time (Friedreich 1863a,b,c). However, it was only in 1876 that he had articulated the hereditary nature of the disorder (Koeppen 2013). It took a staggering 120 years to discover the genetic defect underlying Friedreich Ataxia (FRDA) (Campuzano et al. 1996). The identification of mutations in the gene encoding frataxin (FXN) initiated the rapid growth of a scientific field in which FRDA became a model disorder. Frataxin has been found to locate to mitochondria, control mitochondrial iron homoeostasis and, if deficient, lead to oxidative stress. Genetically, it is a recessively inherited disorder caused by an expansion mutation of GAA repeats in the first intron within the FXN gene, leading to a largely reduced expression of the frataxin protein. The discovery that frataxin expression can be modulated by epigenetic mechanisms has opened new research avenues and treatment strategies. Large networks have been established in Europe (European Friedreich Ataxia Consortium of Translational Studies, EFACTS), America (Collaborative Clinical Research Network, CCRN), and Australia to study cohorts of FRDA patients. The development of sensitive clinical scales and biomarkers to detect disease progression and effects of therapeutical interventions is of uttermost importance. In this issue, researchers, many of whom participate in the ‘European Friedreich Ataxia Consortium of Translational Studies (EFACTS)’, summarize the current status of FRDA research. Pierre Vankan (Vankan 2013) reports that the FRDA prevalence in Europe shows a southwest to northeast gradient, with a high prevalence of around 1 : 20 000 in northern Spain, southern and central France, and Ireland, and a low prevalence of 1 : 250 000 in Scandinavia, eastern Germany, Austria, and Russia. This observed distribution coincides with the gradient of the chromosomal R1b marker within Western Europe. Although FRDA and the R1b marker are not genetically linked, they may have co-existed in a hypothetical founder population. Because of this correlation, Pierre Vankan hypothesizes that the FRDA distribution in Europe is derived from Palaeolithic migrations out of the Franco-Cantabrian ice age refuge (Vankan 2013). The majority of FRDA cases are caused by an expansion mutation of (GAA)n trinucleotide repeats within the first intron of the FXN gene which encodes the mitochondrial protein frataxin. This leads to a silencing of the FXN gene, the subsequent lower generation of frataxin protein causing the clinical phenotype of FRDA (Cnop et al. 2013; Parkinson et al. 2013a; Weidemann et al. 2013). To explain the silencing of FXN in FRDA, two models have been proposed. The first model implicates a transcriptional blockage created by the expanded (GAA)n repeats, which induce sticky triplex DNA structures. The second model implicates heterochromatin effects caused by expanded repeats. Over the recent years it has become clear that the Frataxin gene is heterochromatinized and is a target of epigenetic regulation (Yandim et al. 2013). However, a role of triplex DNA in triggering heterochromatinization is possible, reconciling the two models. From these data two lines of research on the pathophysiology of FRDA and potential therapeutic opportunities have evolved. The first line of research studies the physiological function of frataxin, the consequences of its loss and therapeutic strategies to complement frataxin in patients. The second line of research investigates the epigenetic