Clinical characteristics: The phenotypic spectrum associated with biallelic RFC1 AAGGG repeat expansion encompasses a range including (1) typical cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS); (2) cerebellar, sensory, and vestibular impairment; (3) more limited phenotypes involving predominantly or exclusively one of the systems involved in balance control; (4) autonomic dysfunction; and (5) cough. Onset begins after age 35 years. In a retrospective study of 100 affected individuals after ten years of disease duration, two thirds had clinical features of CANVAS; 16 had a complex sensory ataxia with cerebellar or vestibular involvement; and 15 had a sensory neuropathy as the only clinically detectable manifestation.
Diagnosis/testing: The diagnosis of RFC1 CANVAS / spectrum disorder is established in a proband with suggestive findings and biallelic intronic AAGGG pentanucleotide expansions in RFC1 identified by molecular genetic testing that is targeted to detect these expansions. Note that pathogenic RFC1 AAGGG repeat expansions cannot be detected by sequence-based multigene panels or exome sequencing. However, they can be suspected by genome sequencing.
Management: Treatment of manifestations: The goals of treatment are to maximize function and reduce complications. Depending on the clinical manifestations, each affected individual should be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists, physical therapists, physiatrists, and (depending on individual needs) speech therapists, respiratory therapists, nutritionists, and gastroenterologists.
Surveillance: Routine follow up by multidisciplinary specialists to assess: progression of neurologic findings; mobility, self-help skills; need for alternative communication methods; and aspiration risk and feeding methods.
Agents/circumstances to avoid: Medications of known toxicity for peripheral nerves (e.g., neurotoxic chemotherapy agents, pyridoxine), the cerebellum (e.g., phenytoin), or the vestibular system (e.g., aminoglycosides); chronic alcohol consumption.
Genetic counseling: RFC1 CANVAS / spectrum disorder is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an RFC1 AAGGG repeat expansion, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once biallelic RFC1 AAGGG repeat expansions have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
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