Researchers have identified a genetic defect as a common cause of late-onset ataxia meaning many patients can receive a definite diagnosis and treatment can be improved.
A DNA mutation known as a ‘repeat expansion’ to the RCF1 gene can account for 22% of cases of ataxia – a neurological disorder characterised by co-ordination, balance and speech difficulties – researchers led by UCL Queen Square Institute of Neurology (IoN) found. It is the first time in two decades that a particular genetic defect has explained more than 10% of cases of the disease.
Researchers also found the genetic defect can account for nearly all cases of CANVAS disease – a related disorder where patients have ataxia in combination with additional conditions.
Researchers said the finding will have direct and immediate implications for patients and families with ataxia worldwide.
Dr Andrea Cortese, of the UCL IoN and first author of the paper which was published in Nature Genetics, said: “As a result of our finding a larger number of patients will be able to receive a definite diagnosis, and hence better information about their prognosis and the management of their condition. A better understanding of the patient’s condition will also lead to more effective treatment.”
Dr Cortese added the study had been “an endless source of surprises. First, we found that familial CANVAS disease is caused by both a mutation and expansion of a repeated DNA unit, a type of genetic variant which is very uncommon in human diseases. Second, we found this defect is able to account not only for almost all cases of CANVAS but also for a significant number of ataxia cases. Third, we found that this genetic defect doesn’t clearly reduce the expression of the hosting RFC1 gene – which challenges the widely-accepted notion that gene defects present on both chromosomes affect how hosting genes are expressed.”
For the study, researchers combined traditional genetic investigations with next-generation sequencing techniques to identify the genetic defect.
Prof Mary Reilly, of the National Hospital for Neurology and Neurosurgery at UCLH (NHNN) and joint last author of the paper, said: “The identification of this genetic defect is of major interest not just because of its prevalence, but also because this finding highlights that late-onset disorders can be caused by a type of mutation called an autosomal recessive mutation, where a person needs two copies of the abnormal gene to cause the disease, usually inheriting one abnormal copy from each parent who are carriers but unaffected.”
Next steps in research in this area include understanding the exact ways in which the defect to the RCF1 gene leads to the development of ataxia and CANVAS.
The BRC-supported study received funding from The Medical Research Council and the Wellcome Trust as well as Ataxia UK, The MSA Trust, Brain Research UK, The Muscular Dystrophy Association and Muscular Dystrophy UK.
