Spinocerebellar Ataxia Type 7: A Neurodegenerative Disorder with Peripheral Neuropathy

Abstract

Background: Autosomal dominant spinocerebellar ataxias (SCA) are a group of inherited neurodegenerative disorders that typically show peripheral neuropathy. SCA7 is one of the rarest forms of SCA (<1/100,000 individuals). However, the disease shows a prevalence of ∼800/100,000 inhabitants in certain regions of Mexico. This low global prevalence may explain, at least in part, the isolated anecdotal and limited clinical data regarding peripheral neuropathy in SCA7 patients. Aim: To assess sensory and motor peripheral nerve action potentials in an SCA7 patients group and in healthy volunteers, and subsequently correlate the electrophysiological findings with clinical and genetic features. Materials and Methods: We enrolled in our study, 13 symptomatic SCA7 patients with a confirmed molecular and clinical diagnosis, and 19 healthy volunteers as the control group. Nerve conduction studies were carried out using standard electromyography recording methods. The sensory and motor latency, amplitude and conduction velocity were recorded in both experimental groups and analyzed using the Student's t-test. Results: SCA7 patients showed a significant prolongation of sensory nerve conduction latencies, as well as a decrease in sensory amplitudes. Decreases in motor amplitudes and peroneal conduction velocity were also observed. Finally, we found an association between CAG repeats and the severity of cerebellar and non-cerebellar symptoms with electrophysiological signs of demyelinization. Discussion: Our results reveal the existence of a critical sensorimotor peripheral neuropathy in SCA7 patients. Moreover, we show that using sensitive electrophysiological tools to evaluate nerve conduction can improve the diagnosis and design of therapeutic options based on pharmacological and rehabilitative strategies. Conclusion: These findings demonstrate that SCA7 is a disease that globally affects the peripheral nervous system.

SCA7 mice recapitulate CNS, PNS and retina pathologies and show a transcriptional signature of Purkinje cell dysfunction prevailing in SCA1 and SCA2 mice.

“…The sensory component might also be affected as non-myelinated bers also show alterations. SCA7 140Q/5Q mice ndings parallel recent studies of SCA7 patients, who showed abnormal motor and sensory nerve conductions (12), and complement previous neuropathological evidence of degenerating signs in the dorsal root and anterior horn of patients' spinal cord (5,7). Like SCA7, other polyQ SCA patients are affected by peripheral neuropathy symptoms and peripheral nerve pathology was reported in other polyQ SCA model (59,60).…”

“…Brain imaging reveals the prominent atrophy of the cerebellum's grey and white matters and the pons, a correlation between cerebellar volume decrease and motor impairment, and more prominent degeneration in lobule IX and X of cerebellum compared to other structures (1,3,5,(7)(8)(9)(10)(11). Neurophysiological studies suggest the existence of a critical sensorimotor peripheral neuropathy (5,12,13). Visual impairment is mainly due to severe loss of cone and rod photoreceptors (5,14).…”

Molecular Targets and Therapeutic Strategies in Spinocerebellar Ataxia Type 7

“…However, as for many neurodegenerative disorders, the accuracy of clinical assessment has limitation due to variation in the age of onset and disease progression. The recent study on a large cohort of 50 patients originating from a founder mutation in Mexico has allowed the specific clinical characterization of adult-onset patients (> 18 years) and early-onset patients (≤ 18 years) and the new observation of frontal-executive deficits and sensory-motor peripheral neuropathy in SCA7 [35,40]. It is noteworthy that infantile forms are much more severe and cause multisystem disorder including failure to thrive, hypotonia, myoclonic seizures, and non-central nervous systems dysfunctions like congestive heart failure, patent ductus arteriosus, atrial septum defect, renal failure, hepatomegaly, muscle atrophy, capillary leak syndrome, and hemangioma [30,33,[41][42][43][44][45][46].…”

The Molecular Basis of Spinocerebellar Ataxia Type 7

“…Particularly in Veracruz, where its prevalence is estimated to be as high as 1/125. High SCA7 prevalence has also been reported in several other parts of the world ( La Spada, 1993 ; Johansson et al, 1998 ; Jonasson et al, 2000 ; Zaheer and Fee, 2014 ; Faruq et al, 2015 ; Salas-Vargas et al, 2015 ).…”