An Unusual Mutation Type Explains the Nature of Late-Life Balance Problems

Idiopathic — the official medical term for “we don’t know what causes this” — is a label that often gets applied to late-onset ataxia, or balance problems in older adults. Fortunately, thanks to researchers at the University of Miami Miller School of Medicine and their colleagues in the UK, it is now known that some cases of late-onset ataxia, called CANVAS syndrome, are caused by a particular genetic mutation.

This mutation, a biallelic AAGGG expansion in RFC1, represents a major breakthrough: It is the first known common genetic cause of late-onset ataxia. The study, “Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia,” was published in the April 2019 issue of the prestigious journal Nature Genetics. Because of its scientific and clinical impact, the journal’s cover featured an artist’s design depicting a tear in the “CANVAS” of the genome in patients.

Of particular interest is the unusual nature of the mutation as an expansion of non-protein coding DNA region, in the past referred to as junk DNA. Such expansions are exceedingly difficult to measure, but are suspected to play a much bigger role in disease than is currently known. Examples of such DNA expansion disorders include amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease, and Huntington’s disease.

While balance problems may not be life-threatening on their own, late-onset ataxia is a major contributor to falls, which are the leading cause of fatal and non-fatal injuries for older Americans. More than 25 percent of U.S. adults aged 65 and older are injured in falls every year, accounting for three million emergency room visits. Balance problems often play a role in these falls.

UK researchers from the UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery collaborated closely with Stephan Züchner, M.D., professor and chair of the Miller School’s Dr. John T. Macdonald Foundation Department of Human Genetics. The study’s lead author, Andrea Cortese, M.D., from UCL, spent 2018 as a visiting scholar in the Department of Human Genetics and the Hussman Institute for Human Genomics.

Important parts of the research, which involved non-parametric linkage analysis, genome sequencing, and animal modeling, were conducted at the Miller School under the direction of Dr. Züchner, with assistance from Adriana P. Rebelo, Ph.D., and Ph.D. candidate Elena Buglo. The recessive genetic mutations they uncovered, which “may represent a frequent cause of late-onset ataxia in the general population,” are present at birth. It is estimated that about one in 5,000 people is affected.

Identifying a genetic cause of late-onset ataxia is the first step toward developing a screening test and possible treatments.

Tags: Adriana P. Rebelo, Elena Buglo, falls, late onset ataxia, Stephan Zuchner