Genetic and Clinical Features in 24 Chinese Distal Hereditary Motor Neuropathy Families

Abstract

Background and Objectives: Distal hereditary motor neuropathy (dHMN) is a clinically and genetically heterogeneous group of inherited neuropathies. The objectives of this study were to report the clinical and genetic features of dHMN patients in a Chinese cohort.Aims and Methods: We performed clinical assessments and whole-exome sequencing in 24 dHMN families from Mainland China. We conducted a retrospective analysis of the data and investigated the frequency and clinical features of patients with a confirmed mutation.Results: Two novel heterozygous mutations in GARS, c.373G>C (p.E125Q) and c.1015G>A (p.G339R), were identified and corresponded to the typical dHMN-V phenotype. Together with families with WARS, SORD, SIGMAR1, and HSPB1 mutations, 29.2% of families (7/24) acquired a definite genetic diagnosis. One novel heterozygous variant of uncertain significance, c.1834G>A (p.G612S) in LRSAM1, was identified in a patient with mild dHMN phenotype.Conclusion: Our study expanded the mutation spectrum of GARS mutations and added evidence that GARS mutations are associated with both axonal Charcot-Marie-Tooth and dHMN phenotypes. Mutations in genes encoding aminoamide tRNA synthetase (ARS) might be a frequent cause of autosomal dominant-dHMN, and SORD mutation might account for a majority of autosomal recessive-dHMN cases. The relatively low genetic diagnosis yield indicated more causative dHMN genes need to be discovered.

Biallelic variants in the SORD gene are one of the most common causes of hereditary neuropathy among Czech patients

“…Five patients with biallelic SORD variants are presented; one is homozygous for the c.757del variant, and the remaining four patients, from two unrelated families, are compound heterozygous for c.757del and c.458C>A. Two sporadic cases homozygous for c.757del are described 23 . Patients presented with childhood disease onset and mild phenotype.…”

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.…”

Association of SORD mutation with autosomal recessive asymmetric distal hereditary motor neuropathy

“…Distal hereditary motor neuropathy (dHMN) is a clinically and genetically heterogeneous disorder affecting the muscles of distal limbs. Individuals with dHMN experience progressive weakness and atrophy of the muscles of the distal limbs [ 1 ]. In dHMN, generally, there is no involvement of sensory neurons, however, in some cases minimal involvement of sensory neurons is reported [ 2 ].…”

“…dHMN and Charcot-Mare-Tooth (CMT) diseases are clinically and genetically overlapping disorders and in some cases, they share the underlying genetic defects [ 4 , 5 ]. For instance, mutations in HSPB1 , IGHMBP2 , and DYNC1H1 cause both CMT and dHMN [ 1 , 6 – 15 ]. Moreover, mutations in the sorbitol dehydrogenase ( SORD ) gene have recently been associated with the autosomal recessive form of Charcot-Mare-Tooth disease type 2 (CMT2) and dHMN [ 1 , 8 , 16 , 17 ] .…”