NEJM: a common genetic cause of late-onset ataxia

A new study published Dec.
14, 2022, in the New England Journal of Medicine, identifies a previously unknown genetic cause of late-onset cerebellar ataxia, a finding that will improve diagnosis and open new avenues
of treatment for this progressive disease.

Tardive cerebellar ataxia (LOCA) is a group of heterogeneous neurodegenerative disorders that present unstable
in adulthood.
Worldwide, 1 to 3 out of every 100,000 people will develop late-onset ataxia
.
Until recently, most people with late-onset ataxia did not get a genetic diagnosis
.

An international team led by Dr.
Bernard Brais, a neurologist and researcher at McGill University, and Dr.
Stephan Züchner of the Miller School of Medicine at the University of Miami, in collaboration with neurologists from the University of Montreal and the University of Sherbrooke, studied a group of 66 Quebec patients from different families who had tardive ataxia, the underlying genetic cause of which has not yet been found
。 Using state-of-the-art genetic techniques, the team found that 40 (61%) patients carried the same novel pathogenic body in the FGF14 gene, making it the most common genetic cause
of late-onset ataxia in Quebec.
They found that in patients, the length of a small segment of duplicate DNA increased dramatically, a phenomenon known as repetitive dilation
.

To confirm their initial findings, the team contacted international collaborators
in Tübingen, Germany, Perth, Australia, London, England, and Bangalore, India.
They found that in these separate cohorts, 10-18% of LOCA patients also carried the same FGF14 error
.
These results confirm that repeated amplification of FGF14 is one of the most common genetic causes of
late-onset ataxia described to date.

In addition to gene discovery, the team also looked at brains from deceased patients and neurons from patients, finding that errors lead to reduced
expression of genes and their proteins.

People with FGF14-associated late-onset ataxia usually begin to develop instability (ataxia)
in their 50s.
The disorder may begin with short-term ataxia
due to exercise and alcohol intake.
Coordination problems become permanent on average around age 59
.
The disease usually progresses slowly and affects walking, speaking, and hand coordination
.
Over time, it usually requires a walker
.
This condition is most often transmitted by affected parents, although it can appear in
families with no previous history of ataxia.

The mutated FGF14 GAA repeat is of great interest because it is the same gene in the FXN gene that causes Friedrich's ataxia, which is the most common cause
of autosomal recessive ataxia worldwide.
Because of this similarity, some new treatments for Friedrich ataxia under development may be used to treat patients
with FGF14 amplification.

The study also suggests that patients may benefit from a drug called aminopyridine, which is already being used to treat other neurological disorders
.
This is particularly promising because some patients with FGF14 amplification respond well
to this treatment.

"This opens the door for this drug to be tested in these patients for clinical trials," Dr.
Braces said
.
"This is great news
for patients in Canada and around the world.
It also makes genetic testing possible so people and families can end their long diagnostic journey
.
”

The study, published in the New England Journal of Medicine on December 14, 2022, was supported by many national institutions, including the National Institutes of Health, the Monaco Foundation Group, and the Montreal General Hospital Foundation
.