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

Objectives: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome results from variations in and is mostly caused by intronic biallelic pathogenic expansions (RE-). 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- intronic expansion underwent a comprehensive clinical and neurophysiologic assessment and were screened for additional exonic variations.

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