Illustration of a human head and neck showing a cut-through to the brain on the left hand side on a background picture of fluorescent neurons and with a DNA helix to the right hand side to represent genetic brain and neurological disorders such as the movement disorder ataxia.
Credit: KATERYNA KON/SCIENCE PHOTO LIBRARY/Getty Images

Research led by McGill University in Montreal has identified a tandem repeat expansion mutation that appears to cause late-onset cerebellar ataxia, a condition that results in problems with coordinated movement in older adults.

The mutation is in the fibroblast growth factor-14 gene (FGF14), but is well hidden inside an intronic, non-coding part of the gene and so has not been identified before, despite the gene being relatively well studied.

“This form of ataxia strikes people relatively late in life, and there are virtually no treatments,” said Stephan Züchner, co-director of the John P. Hussman Institute for Human Genomics, Chief Genomics Officer for the Miller School of Medicine and co-senior investigator on the study. “But now, we know the disease is caused by a single gene, and that should lead to great therapeutic progress.”

Tandem repeat expansion mutations are known to cause other neurological diseases such as Friedreich’s ataxia and Huntington’s disease. So far about 50 conditions are known to be caused by tandem repeat expansions, but experts believe many more conditions could be caused by this type of mutation. Previously these genetic variants were hard to detect, but new technology is now allowing more repeat expansion mutations to be discovered.

In this study, which is published in NEJM, the researchers sequenced the genomes of six French Canadian people from three families who had inherited late-onset cerebellar ataxia. They were able to identify a pathogenic repeat expansion common to all six patients.

For validation purposes, the team also tested patients from two case-control cohorts in Canada (66 patients, 209 controls) and Germany (228 patients, 199 controls) for the mutation, as well as 20 Australian and 31 Indian patients with late-onset cerebellar ataxia.

The results in the validation cohorts showed that 61%, 18%, 15%, and 10% of Canadian, German, Australian, and Indian patients, respectively, had the same FGF14 expansion mutation. Overall, 128 patients with late-onset cerebellar ataxia with the same mutation were identified by the study investigators.

One of the next steps Züchner and colleagues want to take is to find out more about how the mutation they discovered causes disease.

“As best we can tell, these repetitive expansions just make it difficult for the gene to be expressed at normal levels,” said Matt Danzi, associate scientist in Züchner’s lab and co-primary author on the paper, in a press statement. “The affected DNA and RNA gets much larger than usual and interferes with normal RNA processing. Cells end up with a lot less of the protein than they need.”

This kind of ataxia currently has no real treatments available, but the researchers now hope that the genetic information they have uncovered will make it easier to target with new therapies. Since the paper was submitted, many more individuals with the FGF14 variant have been identified, which could also help with developing new treatments and diagnostics for the condition. It is also possible there may be therapies already approved or in development that could be repurposed for late-onset cerebellar ataxia patients with this mutation.

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