Friedreich’s ataxia - A Comprehensive Look

Friedreich’s ataxia is a rare, progressive, autosomal recessive neurodegenerative, multisystem disorder caused by a homozygous GAA repeat expansion in the frataxin gene, resulting in a deficiency of the mitochondrial protein frataxin. This core pathology impairs iron–sulfur cluster biosynthesis and mitochondrial adenosine triphosphate production, leading to mitochondrial dysfunction and increased oxidative stress. While characterized by ataxia, Friedreich’s ataxia is multisystemic, including cardiomyopathy, which represents the major determinant of reduced survival. Omaveloxolone, approved by the United States Food and Drug Administration and recommended by the Committee for Medicinal Products for Human Use of the European Medicine Agency, is the first available treatment for eligible patients, acting as a potent activator of the Nuclear factor erythroid 2-related factor 2 pathway. Clinical evaluation demonstrated a statistically significant improvement in neurological function, as measured by Friedreich Ataxia Rating Scale scores (combining Friedreich Ataxia Rating Scale and modified Friedreich Ataxia Rating Scale), and analysis also showed that drugs augmenting mitochondrial function significantly improved Left ventricular mass index. A common adverse event is the elevation of alanine aminotransferase and aspartate aminotransferase concentrations, which are generally transient, reversible, and mostly occur within the first 12 weeks of treatment and are likely related to Nuclear factor erythroid 2-related factor 2-mediated metabolic adaptations rather than drug-induced liver injury. Due to the limitations of existing outcome measures in tracking slow disease progression, future randomized controlled trials should run for at least 24 months and employ a multifaceted biomarker toolbox, such as combining Friedreich Ataxia Rating Scale scores and Left ventricular mass index assessment, to accurately capture treatment effects across different aspects of the disease.