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Título

Clinical and genotypical spectrum of hereditary motor neuropathies

Resumo

Introduction: The hereditary motor neuropathies (HMN), also known as distal spinal muscular atrophies, are genetically diverse group of diseases with predominantly distal lower motor neuron symptoms. More than twenty genes have been identified, with up to 60% of patients achieving a definite genetic diagnosis. Clinically, the HMN lie on a clinical spectrum alongside axonal Charcot-Marie-Tooth disease and hereditary spastic paraplegias. The HMN can be further divided into different clinical phenotypes, such as classical distal HMN, scapuloperoneal HMN (SPHMN) and spinal muscular atrophy with lower extremity predominance (SMALED). Objective: In this ongoing study, we describe the clinical and genotypical findings of patients with HMN in a tertiary healthcare service. Methods: We included 22 patients with clinical and electrophysiological diagnosis of HMN. We performed whole exome sequencing on 8 patients and a genetic panel for hereditary neuropathies on 7 patients, and 6 others await genetic testing. Clinical evaluation included phenotype and other neurological findings, such as pyramidal signs. Variant classification was in accordance with ACMG criteria. Results: Of the 22 patients, 15 were males and 7 were females. Classical distal HMN was the most common phenotype, with 17 patients. Of those, one patient presented with dHMN and myokymia, with an inconclusive genetic panel that included HINT1 gene. Another patient had a dHMN with upper limb predominance (Type V), split hands and lower limb pyramidal signs, with a variant of uncertain significance (VUS) in the GARS gene. Other genes associated with dHMN were VCP, SETX and HSPB1. Three patients presented with a SPHMN, with distal lower limb weakness and prominent scapular winging, two with a pathogenic variant on TRPV4 gene and another with pyramidal signs and a probable pathogenic variant on BICD2 gene. Two patients had a SMALED phenotype, with probable pathogenic variants in DYNC1H1 in one patient and BICD2 in another. Of the 15 patients with genetic analysis, 11 had a conclusive genetic diagnosis. Conclusions: There are few epidemiological studies on HMN, and to our knowledge, no systematic study has been conducted in Brazil. Interestingly, we found biallelic variants in VCP gene causing distal HMN, as well as a patient with SPSMA with a BICD2 variant, a gene normally associated with SMALED phenotype. Our study demonstrates the diverse clinical picture of the HMN.

Palavras Chave

Hereditary motor neuropathy; distal spinal muscular atrophy; Charcot-Marie-Tooth disease