Clinical and pathology characterization of small nerve fibers neuro(no)pathy in Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome.

Abstract

biallelic mutation/expansion of the gene RFC1 has been described in association with a spectrum of manifestation ranging from isolate sensory neuro(no)pathy to a complex presentation as Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS). Our aim was to define the frequency and characteristics of small fiber neuropathy (SFN) in RFC1-disease at different stages. RFC1-cases were screened for SFN using the Neuropathic Pain Symptom Inventory (NPSI) and Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaires. Clinical data were retrospectively collected. If available, lower limb skin biopsy samples were evaluated for somatic epidermal and autonomic subepidermal structures innervation and compared to healthy controls (HC). we enrolled 40 patients, median age at onset 54 years (IQR 49-61) and disease duration 10 years (IQR 6-16). Mild-to-moderate positive symptoms (median NPSI score 12.1/50, IQR 5.5-22.3) and relevant autonomic disturbances (median COMPASS-31 score 37.0/100, IQR 17.7-44.3) were frequently reported and showed scarce correlation with disease duration. A non-length-dependent impairment in nociception was evident on both clinical and paraclinical investigations. An extreme somatic denervation was observed in all patients at both proximal (fibers/mm RFC1-cases 0.0 vs HC 20.5, p < .0001) and distal sites (fibers/mm RFC1-cases 0.0 vs HC 13.1, p < .0001), instead only a slight decrease was observed in cholinergic and adrenergic innervation of autonomic structures. RFC1-disease is characterized by a severe and widespread somatic SFN. Skin denervation may potentially represent the earliest feature and drive towards the suspicion of this disorder.