Neuropathology of Friedreich ataxia and its links to metabolic pathways

Frataxin is an evolutionarily conserved mitochondrial protein essential for energy metabolism. Biallelic GAA repeat expansions in the FXN gene reduce frataxin expression, causing Friedreich's ataxia. Frataxin deficiency impairs key mitochondrial metabolic enzymes, leading to widespread mitochondrial dysfunction with disrupted glucose and fatty acid oxidation. Although systemic mitochondrial dysfunction affects multiple organ systems, neurological deficits are the only feature uniformly observed in all FRDA patients. This review highlights recent insights into the neuropathology of FRDA, emphasizing the detailed developmental timing of neuroanatomical changes. It also focuses on selective mitochondrial metabolic pathways, including fatty acid metabolism, ceramide synthesis, and ketogenesis, which may underlie neuron-specific vulnerability and serve as potential targets for pharmacological or dietary intervention. The possibility of non-traditional interventions based on metabolic features of FRDA offers hope for ameliorating the severity of FRDA.