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

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.

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Glycyl tRNA Synthetase (GARS) Gene Variant Causes Distal Hereditary Motor Neuropathy V

Case Reports in Pediatrics ◽

10.1155/2018/8516285 ◽

2018 ◽

Vol 2018 ◽

pp. 1-4 ◽

Cited By ~ 3

Author(s):

Peter Chung ◽

Hope Northrup ◽

Misbah Azmath ◽

Ricardo A. Mosquera ◽

Shade Moody ◽

...

Keyword(s):

Muscular Atrophy ◽

Trna Synthetase ◽

Motor Neuropathy ◽

Inherited Disorders ◽

Causative Gene ◽

Hereditary Motor ◽

Pathogenic Variants ◽

Neurogenic Muscular Atrophy ◽

Hereditary Motor Neuropathy ◽

Type V

Distal hereditary motor neuropathies (dHMN) are a rare heterogeneous group of inherited disorders specifically affecting the motor axons, leading to distal limb neurogenic muscular atrophy. The GARS gene has been identified as a causative gene responsible for clinical features of dHMN type V in families from different ethnic origins and backgrounds. We present the first cohort of family members of Nigerian descent with a novel heterozygous p.L272R variant on the GARS gene. We postulate that this variant is the cause of dHMN-V in this family, leading to variable phenotypical expressions that are earlier than reported in previous cases. The exact cause for the observed clinical heterogeneity within the family is unknown. One explanation is that there are modifier genes that affect the phenotype. These cases highlight the possibility of considering pathogenic variants in the GARS gene as a potential cause of early onset axonal polyneuropathy with atypical presentation.

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Alanyl-tRNA synthetase mutation in a family with dominant distal hereditary motor neuropathy

Neurology ◽

10.1212/wnl.0b013e3182574f8f ◽

2012 ◽

Vol 78 (21) ◽

pp. 1644-1649 ◽

Cited By ~ 38

Author(s):

Z. Zhao ◽

A. Hashiguchi ◽

J. Hu ◽

Y. Sakiyama ◽

Y. Okamoto ◽

...

Keyword(s):

Trna Synthetase ◽

Motor Neuropathy ◽

Hereditary Motor ◽

Hereditary Motor Neuropathy

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The G526R glycyl-tRNA synthetase gene mutation in distal hereditary motor neuropathy type V

Neurology ◽

10.1212/01.wnl.0000218304.02715.04 ◽

2006 ◽

Vol 66 (11) ◽

pp. 1721-1726 ◽

Cited By ~ 38

Author(s):

O. Dubourg ◽

H. Azzedine ◽

R. B. Yaou ◽

J. Pouget ◽

A. Barois ◽

...

Keyword(s):

Gene Mutation ◽

Trna Synthetase ◽

Motor Neuropathy ◽

Hereditary Motor ◽

Hereditary Motor Neuropathy ◽

Type V

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Distal hereditary motor neuropathy with vocal cord paresis: from difficulty in choral singing to a molecular genetic diagnosis

Practical Neurology ◽

10.1136/practneurol-2015-001307 ◽

2016 ◽

Vol 16 (3) ◽

pp. 247-251 ◽

Cited By ~ 5

Author(s):

Gillian Ingram ◽

Katy E S Barwick ◽

Louise Hartley ◽

Meriel McEntagart ◽

Andrew H Crosby ◽

...

Keyword(s):

Vocal Cord ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

Motor Neuropathy ◽

Choral Singing ◽

Hereditary Motor ◽

Vocal Cord Paresis ◽

Hereditary Motor Neuropathy ◽

Molecular Genetic Diagnosis

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Faculty Opinions recommendation of Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.2526956.9237054 ◽

2011 ◽

Author(s):

Davide Pareyson ◽

Chiara Marchesi

Keyword(s):

Motor Neuropathy ◽

Missense Mutations ◽

Transporter Gene ◽

Copper Transporter ◽

Hereditary Motor ◽

Hereditary Motor Neuropathy

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Biallelic SORD pathogenic variants cause Chinese patients with distal hereditary motor neuropathy

npj Genomic Medicine ◽

10.1038/s41525-020-00165-6 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Hai-Lin Dong ◽

Jia-Qi Li ◽

Gong-Lu Liu ◽

Hao Yu ◽

Zhi-Ying Wu

Keyword(s):

Ex Vivo ◽

Protein Solubility ◽

Chinese Patients ◽

Hereditary Neuropathy ◽

Motor Neuropathy ◽

Causative Gene ◽

Hereditary Motor ◽

Functional Studies ◽

Hereditary Motor Neuropathy

AbstractSorbitol dehydrogenase gene (SORD) has been identified as a novel causative gene of recessive forms of hereditary neuropathy, including Charcot–Marie–Tooth disease type 2 and distal hereditary motor neuropathy (dHMN). Our findings reveal two novel variants (c.404 A > G and c.908 + 1 G > C) and one known variant (c.757delG) within SORD in four Chinese dHMN families. Ex vivo cDNA polymerase chain reaction confirmed that c.908 + 1 G > C variant was associated with impaired splicing of the SORD transcript. In vitro cell functional studies showed that c.404 A > G variant resulted in aggregate formation of SORD and low protein solubility, confirming the pathogenicity of SORD variants. We have provided more evidence to establish SORD as a causative gene for dHMN.

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Distal hereditary motor neuropathy (DHMN): a new locus for an autosomal recessive form

Journal of the Peripheral Nervous System ◽

10.1111/j.1085-9489.2004.009209bi.x ◽

2004 ◽

Vol 9 (2) ◽

pp. 122-123 ◽

Cited By ~ 2

Author(s):

ML Mostacciuolo ◽

E Crestanello ◽

F Boaretto ◽

E Boscolo ◽

M Liguori ◽

...

Keyword(s):

Autosomal Recessive ◽

Motor Neuropathy ◽

Hereditary Motor ◽

Autosomal Recessive Form ◽

Recessive Form ◽

Hereditary Motor Neuropathy

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Characterising the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105650 ◽

2018 ◽

Vol 55 (12) ◽

pp. 814-823 ◽

Cited By ~ 8

Author(s):

Vincenzo Lupo ◽

Marina Frasquet ◽

Ana Sánchez-Monteagudo ◽

Ana Lara Pelayo-Negro ◽

Tania García-Sobrino ◽

...

Keyword(s):

Autosomal Recessive ◽

Late Onset ◽

Axonal Neuropathy ◽

Genetic Diagnosis ◽

Hereditary Neuropathy ◽

Motor Neuropathy ◽

Charcot Marie Tooth Disease ◽

Hereditary Motor Neuropathy ◽

Index Cases ◽

Mode Of Inheritance

BackgroundMutations in the metalloendopeptidase (MME) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in MME.MethodsWe screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes. In addition to the index case subjects, we also studied other clinically and/or genetically affected and unaffected family members.ResultsWe found 17 variants in MME in a total of 20 index cases, with biallelic MME mutations detected in 13 cases from nine families (three in homozygosis and six in compound heterozygosis) and heterozygous variants found in 11 families. All patients with biallelic variants had a similar phenotype, consistent with late-onset axonal neuropathy. Conversely, the phenotype of patients carrying heterozygous mutations was highly variable [CMT type 1 (CMT1), CMT2, dHMN and fALS] and mutations did not segregate with the disease.ConclusionMME mutations that segregate in an autosomal recessive pattern are associated with a late-onset CMT2 phenotype, yet we could not demonstrate that MME variants in heterozygosis cause neuropathy. Our data highlight the importance of establishing an accurate genetic diagnosis in patients carrying MME mutations, especially with a view to genetic counselling.

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