A novel mutation in the GARS gene in a Malian family with Charcot‐Marie‐Tooth disease

Abstract

Background Charcot‐Marie‐Tooth (CMT) disease is a very heterogeneous neurological condition with more than 90 reported genetic entities. It is the most common inherited peripheral neuropathy; however, cases are rarely reported in sub‐Saharan Africa. In addition, only few families, mostly of Caucasian ancestry, have been reported to have Charcot‐Marie‐Tooth disease type 2D (CMT2D) mutations. To date no case of CMT2D was reported in Africa. We present here a consanguineous family with CMT phenotype in which a novel mutation in the GARS (glycyl‐tRNA synthetase) gene was identified. Methods Patients were examined thoroughly and nerve conduction studies (NCS) were performed. DNA from the proband was used for CMT gene panel testing (including 50 genes, PMP22 duplication and mtDNA ). Putative mutations were verified in all available family members to check for segregation. Results Two individuals, a male and a female, were found to be affected. Symptoms started in their teenage years with muscle weakness and atrophy in hands. Later, distal involvement of the lower limbs was noticed. Patients complained of minor sensory impairment. NCS showed no response in the upper as well as the lower limbs. Genetic testing surprisingly identified a novel heterozygous missense mutation c.794C>A (p.Ser265Tyr) in the GARS gene associated with CMT2D. This variant segregated with the disease in the family and was also seen in the mother who presented no symptoms. Conclusion This is the first report of a genetically confirmed CMT2D case in Africa, expanding its genetic epidemiology. Increasing access to genetic testing may reveal more novel CMT variants or genes in the African population that could be relevant to other populations and further our understanding of their mechanism.

Screening for GARS Variants in A Cohort of Chinese Patients With Inherited Peripheral Neuropathy

“…NCS of the Patient 1 and Patient 2 showed distinctively lower CMAP in median nerve than in ulnar nerve, and this imbalance involvement argued against a primary length-dependent distal axonopathy and was more in favor of a motor neuronopathy [9]. Sensory loss was the characteristic of CMT2D, and in other studies, sensory nerve action potential amplitude was decreased or diminished in CMT2D patients [6,12]. However, we did not think normal sensory nerve conduction study could deny the diagnosis of CMT2D for Patient 1, for sensory nerve degeneration in CMT2D could involve small-size and middle-size bers, sparing large myelinated bers [9,16], and sural nerve biopsy showed unclear laminar structure in myelin sheath, axonal degeneration and necrosis of peripheral nerve myelin sheath and axon.…”

“…In 2003, Antonellis et al con rmed that GARS gene was the pathogenic gene of CMT2D/HMN5A for the rst time [11]. Up to now, only 20 mutations of GARS gene have been reported to be associated with CMT2D/HMN5A [5,12,13]. Classic phenotype of CMT2D/HMN5A is weakness and atrophy of upper extremities, especially the thenar eminence and the rst dorsal interosseous muscle groups.…”

“…Considering anti-Hu antibody combined with nervous system lesion had a strong connection with tumor especially small cell lung cancer [19,21,22], and in some cases neurological symptoms presented ahead of tumor diagnosis [19], consecutive follow-up for Patient 4 was necessary. Asymptomatic carriers with pathogenic variation were found in different studies [12,23], so we cannot exclude the possibility that descendants of Patient 4 may show symptoms later. But based on current evidence, we should not tell the Patient 4's family this possibility that may increase unnecessary psychological burden.…”

“…Coexistence of CMT2D and HMN5A phenotypes caused by same mutation remained unknown etiology. Recently, the GARS c.794C > A (p.S265Y) mutation was reported in a Malian family with CMT2D [12], and c.373G > A (p.E125K) was associated to an infant patient with failure to thrive and severe muscle weakness [18]. These two amino acid sites might be critical to GARS.…”

Mutation Analysis of GARS and Genotype-Phenotype Correlation in CMT2D/HMN5A in Chinese Patients

“…In 2003, Antonellis et al con rmed that GARS gene was the pathogenic gene of CMT2D/HMN5A for the rst time [11]. Up to now, only 20 variants of GARS gene have been reported to be associated with CMT2D/HMN5A [5,12,13]. Classic phenotype of CMT2D/HMN5A is weakness and atrophy of upper extremities, especially the thenar eminence and the rst dorsal interosseous muscle groups.…”