News : 2019 : April

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” (balance problems in older adults).

Fortunately, thanks to researchers at the University of Miami and their colleagues in the UK, we now know 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 was published in the prestigious journal Nature Genetics and, because of its scientific and clinical impact, the journal featured an artist design highlighting the finding. The image depicts 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 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 currently known. Examples of such DNA expansion disorders include Lou Gehrig disease or Huntington disorder.

While balance problems may not be life threatening on their own, late-onset ataxia is a major contributor to falls. Falls are the leading cause of fatal and non-fatal injuries for older Americans, accounting for 3 million emergency room visits annually. In a given year, more than 25% of U.S. adults aged 65 and older will fall, and balance problems often play a role.

UK researchers from the UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery closely collaborated with University of Miami’s Dr. Stephan Züchner, Chair and Professor in the Dr. John T. Macdonald Foundation Department of Human Genetics. The lead author of this study, Dr. Andrea Cortese from UCL spent 12 months in 2018 at the Hussman Institute and the Department of Human Genetics as a visiting scholar. Important parts of the research, which involved non-parametric linkage analysis, genome sequencing and animal modeling, were conducted at UM under the director of Dr. Züchner, with assistance from Elena Buglo and Dr. Adriana Rebelo.

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 1 in 5,000 people are affected.

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

Journal article:

Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yan YW, Humphrey J, Jaunmuktane Z, Sivakumar P, Polke J, Ilyas M, Tribollet E, Tomaselli PJ, Devigili G, Callegari I, Versino M, Salpietro V, Efthymiou S, Kaski D, Wood NW, Andrade NS, Buglo E, Rebelo A, Rossor AM, Bronstein A, Fratta P, Marques WJ, Züchner S, Reilly MM, Houlden H. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet. 2019 Apr;51(4):649-658. doi: 10.1038/s41588-019-0372-4. Epub 2019 Mar 29. PubMed PMID: 30926972.