Recent genetic research involving French Canadian families has shed light on the molecular diagnosis of late-onset cerebellar ataxias (LOCAs), pinpointing a GAA repeat expansion in the FGF14 gene, which is linked to fibroblast growth factor 14. This genetic anomaly, when exceeding 250 repeats, correlates strongly with LOCA, as evidenced by case-control studies in French Canadian and German populations that confirmed its significant association with the disease. These findings are further supported by genetic testing in Australian and Indian patients with LOCA, which indicated varying prevalence rates.

The presence of the FGF14 (GAA)≥250 expansion was found in 128 patients across various cohorts, and further investigations into postmortem cerebellum tissues and iPSC-derived motor neurons from these patients showed reduced levels of FGF14 RNA and protein. This underlines the detrimental effect of the GAA repeat expansion on gene expression and protein function, highlighting its potential as a critical genetic marker for LOCA diagnosis and pointing towards opportunities for developing targeted therapies based on these genetic insights.

Reference: Pellerin D, Danzi MC, Wilke C. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. N Engl J Med. 2023 Jan 12;388(2):128-141. doi: 10.1056/NEJMoa2207406. Epub 2022 Dec 14. PMID: 36516086; PMCID: PMC10042577.