Early Peripheral Nerve Involvement at the Time of Coughing in Patients With RFC1 Intronic Expansion.

Objectives: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome results from variations in RFC1 and is mostly caused by intronic biallelic pathogenic expansions (RE-RFC1). Refractory chronic cough (RCC) is frequently observed for years to decades preceding ataxia onset. Whether peripheral nerves are involved in the presymptomatic phase characterized by RCC is uncertain.

Methods: Here, patients previously screened for RCC and identified as having at least one RE-RFC1 intronic expansion underwent a comprehensive clinical and neurophysiologic assessment and were screened for additional exonic variations.

Results: Fourteen patients with RCC and RE-RFC1 were investigated. Seven patients presented with biallelic RE-RFC1 (Bi-RE-RFC1) while 7 presented with monoallelic RE-RFC1 (Mono-RE-RFC1). In patients with Mono-RE-RFC1, no additional exonic variation was identified, and clinical examinations were normal. Most of the patients with Bi-RE-RFC1 presented with subtle neurologic impairment, mainly exhibiting decreased lower limb vibration sense (85.7%). Nerve conduction studies revealed that all patients with Bi-RE-RFC1 exhibited lower sensory sum scores than patients with Mono-RE-RFC1 (median 20.2 µV vs 84.9 µV, p = 0.0012). In addition, the radial-to-sural sensory ratios were null or inverted (>0.5) in all patients but one with Bi-RE-RFC1, which is consistent with sensory neuronopathy.

Discussion: Patients with Bi-RE-RFC1 already exhibit widespread sensory neuron involvement at the time of apparently isolated RCC.