Corticospinal conduction in RFC1-related disease: a transcranial magnetic stimulation study

Biallelic intronic expansions in RFC1 cause cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), which may present with hyperreflexia despite the coexistence of severe sensory neuropathy. The mechanism of this apparent corticospinal involvement remains unclear.

We assessed corticospinal tract integrity by transcranial magnetic stimulation (TMS) in 18 patients with genetically confirmed RFC1-related disease. Resting motor threshold (RMT), central motor conduction time (CMCT), and motor evoked potential/compound muscle action potential (MEP/CMAP) amplitude ratios were recorded bilaterally from the abductor pollicis brevis and abductor hallucis muscles. Clinical phenotype, neuroimaging, peripheral neurophysiology, and medication exposure were reviewed.

Among the 18 patients, 5 (28%) showed clinical hyperreflexia, 10 had full CANVAS, 4 had complex neuropathy phenotypes, and 4 had isolated sensory neuropathy. RMT, CMCT, and MEP/CMAP ratios did not differ significantly between patients with and without hyperreflexia. Neuroimaging did not reveal a structural central nervous system cause in the majority of cases.

Conventional TMS measures were within expected ranges and did not differ significantly according to hyperreflexia status. Hyperreflexia may occur in RFC1-related disease without detectable abnormalities in standard TMS metrics, although subtle corticospinal dysfunction cannot be excluded, particularly given the small sample size and the potential confounding effect of medication exposure.