Common genetic cause of late-onset ataxia revealed

By Elissa Wolfson, The Science Advisory Board assistant editor

December 16, 2022 -- A Quebec-led international collaboration has discovered a previously unknown common genetic cause of late-onset cerebellar ataxia. The study, published December 14 in the New England Journal of Medicine, may potentially improve diagnosis and open new treatment avenues for thousands of people with this debilitating neurodegenerative condition worldwide.

Late-onset cerebellar ataxias (LOCA) are a heterogenous group of neurodegenerative diseases that manifest in adulthood. Ataxia usually progresses slowly and affects walking, speech, and hand coordination. These unsteadiness and coordination problems become permanent at around 59 years of age. Ataxia is most often transmitted from an affected parent, although it can appear in families with no previous history. Up to three in 100,000 people worldwide develop this condition.

The researchers studied 66 Quebec patients from different families who had late-onset ataxia for which no underlying genetic cause had been found. Using advanced genetic technologies, the team found that 40 (61%) of these patients carried the same novel disease-causing variant in the gene FGF14, making it Quebec's most common genetic cause of late-onset ataxia. They also found that a small stretch of repetitive DNA underwent a large size increase in patients, a phenomenon known as repeat expansion.

International collaborators reported that 10% to 18% of LOCA patients in independent cohorts also carried the same FGF14 error, confirming that a repeat expansion in FGF14 is one of the most common genetic causes of late-onset ataxia described to date. The team also studied brains from deceased patients and patient-derived neurons and found that the error causes decreased expression of the gene and its protein.

The FGF14 repeated mutation sequence raises interest since it is identical to the one causing Friedreich's ataxia in the FXN gene, the most common cause of autosomal recessive ataxia worldwide. Because of this similarity, it is possible that some new treatments under development for Friedreich's ataxia may also be used to treat patients with an expansion in FGF14.

This study also suggests that patients may benefit from a drug called aminopyridine that is already marketed for other neurological conditions. Since some patients with an expansion in FGF14 have responded well to this treatment, researchers are optimistic about its benefits.

"This opens the door to a clinical trial of this drug in these patients," McGill University co-author Dr. Bernard Brais said in a statement. "It also makes genetic testing possible so people and families can arrive at the end of their long diagnostic journey."

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