Mutation in RFC1 gene is likely to be common cause of late-onset ataxia – Ataxia

Mutation in RFC1 gene is likely to be common cause of late-onset ataxia

Mutation in RFC1 gene is likely to be common cause of late-onset ataxia

Many people with late onset cerebellar ataxia do not get a specific diagnosis since and their ataxia is classed as ‘idiopathic’. Late onset ataxia can involve a combination of cerebellar (relating to the part of the brain that regulates movement), proprioceptive (relating to the position and movement of the body) and vestibular impairment (relating to the parts of the brain that control balance and eye movements). In such cases it is referred to as CANVAS, an acronym which stands for cerebellar ataxia (CA), neuropathy (N) and vestibular areflexia (VA) syndrome (S). CANVAS is slowly progressive and is commonly characterised by imbalance, sensory neuronopathy (damage to the sensory nerves), bilateral vestibulopathy (damage to the balance portions of both inner ears) and chronic cough, and is considered a distinct condition.

CANVAS and late-onset ataxia usually occur sporadically, but sometimes occur in siblings, suggesting the possibility of recessive transmission (where two copies of a faulty gene must be present in order for the disorder to develop). In such cases parents are carriers but do not have the condition themselves. In recent attempts to establish the underlying genetic defect responsible for familial CANVAS researchers have discovered that expansion in both copies of the gene which codes for a protein called RFC1 is responsible. This protein is responsible for DNA replication and repair. The study, led by UCL Queen Square Institute of Neurology (IoN), was undertaken in 29 individuals (23 affected by CANVAS and 6 unaffected) from 11 families. Most of the families consisted of affected siblings and in none was there evidence that the condition had been passed directly from parent to child.

The carrier frequency of this mutation in healthy controls was found to be 0.7%. This is similar to the carrier frequency of the GAA expansion in the frataxin gene which causes the most common recessive ataxia, Friedreich’s ataxia. By screening additional sporadic cases of late onset ataxia, the researchers confirmed the presence of the mutation in 22% of them, and higher percentages if sensory neuronopathy and/or bilateral areflexia coexisted. This, researchers say, suggests that the mutation represents a frequent and under recognized cause of late-onset ataxia. This should have major implications for diagnosis and management of ataxia patients.

Dr Andrea Cortese, the first author of the study, said: “So far, the search for a cause of progressive imbalance in adult and elderly patients has been difficult and often unsuccessful. Our study has shown that a significant proportion of these cases is explained by a common genetic defect.”

View the press release on the UCL website here or view the paper abstract here.

Posted on 25/04/2019


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