Friedreich ataxia: what can we learn from non-GAA repeat mutations?

Lynch DR, Shen M, Wilson RB. Friedreich ataxia: what can we learn from non-GAA repeat mutations? Neurodegener Dis Manag. 2025 Jan 15:1-10. doi: 10.1080/17582024.2025.2452147. Epub ahead of print. PMID: 39810561. 

 Compound heterozygote patients with one expanded GAA allele and a non-GAA repeat mutation can have subtle differences in phenotype from typical FRDA, including, in patients with selected missense mutations, both more severe features and less severe features in the same patient. In this review, we propose explanations for such phenotypes based on the potential for activities of frataxin other than enhancement of iron-sulfur cluster synthesis, as well as crucial future experiments for fully understanding the role of frataxin in cells.

Altered Intracerebellar Functional Connectivity in Friedreich's Ataxia: A Graph-Theory Functional MRI Study

Tranfa M, Costabile T, Pontillo G, Scaravilli A, Pane C, Brunetti A, Saccà F, Cocozza S. Altered Intracerebellar Functional Connectivity in Friedreich's Ataxia: A Graph-Theory Functional MRI Study. Cerebellum. 2025 Jan 14;24(2):30. doi: 10.1007/s12311-025-01785-3. PMID: 39808241; PMCID: PMC11732920. 

Graph analysis revealed regional intra-cerebellar FC changes in FRDA, marked by reduced functional centrality in cerebellar regions of the vermis and responsible for executive functions. These changes correlated with cognitive alterations, highlighting the role of the cerebellar cortex in the cognitive impairment observed in FRDA. In conclusion, our observations confirm that the cerebellum is involved in the pathophysiology of FRDA not only from a structural, but also from a functional standpoint, and suggests that integrating information from different parcellations could provide complementary knowledge and help us in decoding the exact relationship between FC alterations and cognitive changes in FRDA.