Distal hereditary motor neuropathies: Mutation spectrum and genotype–phenotype correlation

Abstract

Background and purpose Distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of disorders characterized by degeneration of the motor component of peripheral nerves. Currently, only 15% to 32.5% of patients with dHMN are characterized genetically. Additionally, the prevalence of these genetic disorders is not well known. Recently, biallelic mutations in the sorbitol dehydrogenase gene (SORD) have been identified as a cause of dHMN, with an estimated frequency in undiagnosed cases of up to 10%. Methods In the present study, we included 163 patients belonging to 108 different families who were diagnosed with a dHMN and who underwent a thorough genetic screening that included next‐generation sequencing and subsequent Sanger sequencing of SORD. Results Most probands were sporadic cases (62.3%), and the most frequent age of onset of symptoms was 2 to 10 years (28.8%). A genetic diagnosis was achieved in 37/108 (34.2%) families and 78/163 (47.8%) of all patients. The most frequent cause of distal hereditary motor neuropathies were mutations in HSPB1 (10.4%), GARS1 (9.8%), BICD2 (8.0%), and DNAJB2 (6.7%) genes. In addition, 3.1% of patients were found to be carriers of biallelic mutations in SORD. Mutations in another seven genes were also identified, although they were much less frequent. Eight new pathogenic mutations were detected, and 17 patients without a definite genetic diagnosis carried variants of uncertain significance. The calculated minimum prevalence of dHMN was 2.3 per 100,000 individuals. Conclusions This study confirms the genetic heterogeneity of dHMN and that biallelic SORD mutations are a cause of dHMN in different populations.

Human HspB1, HspB3, HspB5 and HspB8: Shaping these Disease Factors during Vertebrate Evolution

“…All four sHSP genes harboring such mutations were historically subject to strong purifying selection. These facts and observations offer an explanation for both the high proportion of dominant mutations among neuromuscular disease-associated sHSP mutations, and also for the relatively high proportion of sHSP mutations (6.3% and 10.4%; Echaniz-Laguna et al 2017;Frasquet et al 2021;respectively) among all mutations in patients with inherited peripheral neuropathies.…”

Spinal Muscular Atrophy Type IIIb Complicated by Moyamoya Syndrome: A Case Report and Literature Review

“…Different from the SMA, Kennedy's disease is an Xlinked recessive genetic disorder, usually occurs in middle-aged and elderly men, the main clinical features are male breast development, bulbar muscle involvement and jaw tremor (Breza and Koutsis, 2019). And the distal hereditary motor neuropathy is a length dependent motor nerve damage, mainly involving the distal muscles of the limbs leading to weakness and atrophy, can be presented as "crane leg sign, " "hammer finger" (Frasquet et al, 2021), this is highly inconsistent with the patient's proximal muscle involvement. Therefore, Kennedy's disease and distal hereditary motor neuropathy can be ruled out.…”

Les neuropathies héréditaires associées au gène SORD

“…Plus rarement, la neuropathie était classée comme CMT intermédiaire (10 % des cas rapportés) [3]. Cinq publications récentes ont depuis affiné le tableau clinique des patients atteints de CMT2 ou de NMH et porteurs de variants bialléliques du gène SORD [4][5][6][7][8]. Les premiers symptômes apparaissent entre la deuxième et la troisième décennie et se caractérisent par un déficit moteur des membres inférieurs longueur-dépendant.…”

“…Pour ce variant, la fréquence des porteurs dans la population générale est estimée à 3/1 000 [3]. SORD est devenu un des gènes les plus fréquemment mutés dans les CMT2, après celui codant la mitofusine-2, MFN2 [8], mais aussi dans les NMH, après HSPB1 [4][5][6]. Treize autres variants du gène SORD ont été décrits, entraînant souvent une altération de l'épissage et/ou une perte de fonction de la protéine SORD.…”