To describe the clinical course in the case of a Guamanian man with pathogenic biallelic RFC1 gene ACAGG expansions associated with early motoneuron involvement.

CANVAS was first described as a late-onset slowly progressive cerebellar ataxia with sensory neuronopathy and vestibular areflexia. Biallelic intronic AAGGG pentanucleotide repeat expansions in RFC1 were identified as causative of the syndrome by Cortese et al. in 2019. Since its initial description, the RFC1-associated disease spectrum has broadened and biallelic ACAGG repeat motif expansions have been associated with a distinct phenotype including motor neuronopathy in Asian and Pacific Islander cohorts.

Retrospective chart review.

At age 44, our proband developed asymmetric foot drop, painful abdominal muscle cramping, upper limb action tremor and described chronic dry cough, precipitated by dry and spicy foods. At age 50, he displayed tongue and upper limb fasciculations, mild asymmetric distal weakness, non-length dependent reduction of lower limb pallesthesia and diffuse hyporeflexia. His CK levels were consistently elevated, ranging from 4-15x upper limit of normal. MRI showed thoracic cord atrophy. SBMA genetic testing, exome and mitochondrial genome sequencing were unrevealing. His older brother was similarly affected with chronic cough, abdominal muscle cramps, limping and high CK and two of his sisters had chronic cough.

By age 54, his distal weakness and gait imbalance had progressed, and he displayed left lateral gaze-evoked nystagmus with right vestibular hyporeflexia on head-impulse testing. He had mild upper limb dysmetria, diffuse fasciculations and a positive Romberg sign. ExpansionHunter Denovo (EHDn) testing revealed ACAGG repeat expansions of the RFC1 gene, estimated at 40-60 and 51-81 repeats. His affected brother was found to harbor the same expansions. Standard PCR and repeat-primed PCR testing confirmed pathogenic expansions.

This case report offers further evidence of a distinct CANVAS phenotype associated with ACAGG RFC1 expansions characterized by early motoneuron involvement.