Neuropathology of Friedreich ataxia and its links to metabolic pathways

Mercado-Ayón E, Lazaropoulos MP, Mercado-Ayón Y, Lynch DR. Neuropathology of Friedreich ataxia and its links to metabolic pathways. Neurodegener Dis Manag. 2025 Dec 25:1-12. doi: 10.1080/17582024.2025.2607957. Epub ahead of print. PMID: 41447358. 

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.

Unrecognized high prevalence of expanded composite repeats in Friedreich ataxia

Devore MC, Lam C, Wiley G, Park CC, Lynch DR, Bidichandani SI. Unrecognized high prevalence of expanded composite repeats in Friedreich ataxia. Hum Mol Genet. 2025 Dec 23:ddaf190. doi: 10.1093/hmg/ddaf190. Epub ahead of print. PMID: 41432640. 

In a prospective series of 112 unrelated patients, we found that approximately 20% of people with Friedreich ataxia have at least one such expanded composite allele. Other minor sequence interruptions in the expanded GAA repeat were detected in a further 10% of patients. Most expanded composite alleles revealed by longread genome sequencing are not detectable by standard PCR-based testing, and have therefore remained hidden despite their relatively high prevalence. This results in erroneous genotyping of patients and heterozygous carriers.