Recent developments in Friedreich's ataxia: a state-of-the-art review

Friedreich's Ataxia (FRDA) is a progressive disorder, which is autosomal recessive. It is one of the most common inherited ataxias in Europe, the Middle East, South Asia and North Africa. It is a life limiting condition, the time of onset until death is on average 36 years. A lack of certainty about specific phenotypic changes, has meant that, until recently, there have been no medications licensed for use in FRDA. Over the last 5 years, the development of omaveloxolone has stimulated increasing research into the mechanistic understanding of FRDA. We have conducted a critical review of all the studies published between 1999 and December 2024. The free text search terms were ((Friedreich's Ataxia) OR (FRDA) OR (FRDA) OR (inherited ataxias)) AND ((recent developments) OR (new developments) OR (new treatments) OR (phenotype)). We identified common themes, for example cellular phenotypical changes, such as mitochondrial and iron dysregulation and common medications that have been trialled. We have analysed the relevant, available studies (n = 139), highlighting the underlying reasons for any reported discrepancies. The papers in this review demonstrate what we know about the frataxin deficiency, which causes mitochondrial dysfunction and iron dysregulation. We also discuss what is not known and how these gaps in knowledge can affect the development of new therapeutic approaches. We investigate the cellular phenotypical changes in FRDA that are either established or hypothesized in the current literature, review the medications that have been tested and their trial outcomes, and consider potential future approaches that could guide the development of new therapies for FRDA.