Hidden genetic abnormality behind late-onset common cerebellar ataxia

Researchers at the University of Miami Miller School of Medicine, McGill University and other institutions have discovered that a well-hidden genetic variation in the FGF14 gene, called DNA tandem repeat expansion, causes a common form of early-onset cerebellar ataxia. late, a disorder that interferes with coordinated movement. Tandem repeat expansions are only found in 50 conditions, including Friedreich’s ataxia and Huntington’s disease, but researchers believe they could explain many other conditions.

The article, Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia, will be published online December 14 in the New England Journal of Medicine. These findings could lead to new diagnoses and therapies for patients suffering from late-onset ataxia.

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

Late-onset ataxia is highly concentrated in specific populations, including French Canadians. Co-lead author Bernard Brais, MDCM, M.Phil., Ph.D., Director of the Rare Neurological Diseases Group at McGill University in Montreal, treats many patients with this condition. His expertise in ataxia and related disorders and the patient and family research registry in Quebec were critical to the success of the study.

The expansion of late-onset ataxia was found in the FGF14 gene, which is associated with cell growth, tissue repair, and other tasks. While this gene is well-studied, no one has ever seen these repeat expansions, largely due to how RNA is processed in cells.

RNA can be separated into two categories: exons and introns. The exons code for proteins; introns contain noncoding RNA between exons. Because introns are detached from the coding RNA strand, it can be difficult to determine how intronic sequences, such as the FGF14 repeat expansions, affect protein production.

In the study, the Miami and Montreal teams sequenced entire genomes of French-Canadian, German, Australian and Indian families, applying a new and advanced computer algorithm to identify repeat expansions. Matt Danzi, Ph.D., associate scientist in Dr. Züchner’s lab and co-senior author of the paper, detected crucial abnormalities in the patients’ genomes. Co-lead author David Pellerin, MD, a McGill investigator, confirmed and characterized these unusual non-protein-coding repeat expansions in patients.

Dr. Züchner and his team have earned a wide reputation for solving genetic mysteries in rare neurological diseases. In this case, they had early access to advanced software tools and prepared unique databases of healthy controls, allowing them to increase the ability of short-read genomic sequencing to identify hidden intronic variations. Later, the Miami and Montreal teams used long read sequencing to confirm their findings. One of the next steps will be to understand how these expansions disrupt FGF14.

“As far as we can tell, these repeat expansions just make it harder for the gene to express itself at normal levels,” said Dr. Danzi. “Affected DNA and RNA become much larger than normal and interfere with normal RNA processing. The cells end up with much less protein than they need.”

These findings have already generated a flurry of activity around FGF14 and late-onset ataxia. Identifying the genetic factor of the condition will provide scientists and physicians with an essential tool to diagnose more patients. Current efforts have found more than 500 families with the variant, and follow-up studies may bring that number to more than a thousand. Repeat expansions in FGF14 may turn out to be the most common form of late-onset ataxia.

Furthermore, identifying abnormalities in a gene means that researchers can begin to develop new diagnostic tests, animal models, and eventually therapies to combat it. Treatments being developed for Friedreich’s ataxia can be used to treat patients with FGF14 expansions. Patients may also benefit from a drug called 4-aminopyridine, which is already used to treat other neurological conditions.