Alternative titles; symbols
SNOMEDCT: 717011006; ORPHA: 99938; DO: 0110164;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p14.3 | Charcot-Marie-Tooth disease, type 2D | 601472 | Autosomal dominant | 3 | GARS1 | 600287 |
A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 2D (CMT2D) is caused by heterozygous mutation in the GARS1 gene (600287), which encodes glycyl tRNA synthetase, on chromosome 7p14.
Autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794), or distal spinal muscular atrophy type VA (DSMAVA), is an allelic disorder with a similar phenotype.
For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A1 (118210).
Ionasescu et al. (1996) reported results of clinical, electrophysiologic, and genetic linkage studies on a large pedigree with autosomal dominant Charcot-Marie-Tooth axonal neuropathy type 2, which they designated CMT2D. The pedigree consisted of 38 members, 14 of which were affected. Onset of the disease was between 16 and 30 years of age with weakness of the hands. Affected members had severe weakness and atrophy of the hands and mild to moderate weakness of the feet. Deep tendon reflexes were absent in the upper extremities and decreased in the lower extremities. There was distal hypesthesia for touch, proprioception, and vibration sense. Variable pes cavus and hammertoes were present in all patients. Mild to moderate balance impairment was present in 5 patients with a positive Romberg sign. Gowers and Trendelenburg signs were present in 2 patients. Scoliosis was present in 4 patients. The disease had a mild progressive course in 12 patients. No nerve enlargement, no tremors, no paralysis of the vocal cord or diaphragm, and no abnormalities of cranial nerve function were detected. Motor nerve conduction velocities showed normal values with normal latencies. Electromyographs revealed signs of denervation with large motor unit potentials, fibrillation potentials, and positive sharp waves. Ionasescu et al. (1996) reported that the absence of palpably enlarged nerves distinguished this pedigree from cases of CMT1. The clinical picture in this pedigree was different from other axonal CMT2 types in that weakness and atrophy were more severe in the hands than in the feet, and that sensory impairment had the same prevalence as the motor involvement.
Sambuughin et al. (1998) reported a family in which autosomal dominant CMT2D and a form of distal spinal muscular atrophy (DSMAVA; 600794) segregated in the same kindred. All 17 affected members had bilateral weakness and wasting in thenar and first dorsal interossei muscles starting commonly with cold-induced cramps in the hands in their late teens. The mean age at onset was 18 years (range 12 to 36) and progression of illness was very slow. DSMAVA was diagnosed in 11 patients based on the presence of hand and peroneal muscle weakness and atrophy without sensory deficits. CMT2D was diagnosed in 6 other patients based on the presence of weakness and atrophy in the same muscle groups, hypoactive knee and ankle reflexes, stocking and glove distribution sensory loss, and reduced sensory nerve action potential amplitudes.
Yalcouye et al. (2019) reported 2 Malian sibs, aged 19 and 35 years, with CMT2D. Symptoms in both started at 12 years of age with upper extremity muscle weakness and progressed to involve the thenar and interosseous muscles and then the lower extremities. On examination, both sibs had distal muscle weakness and atrophy with sensory loss, which was more pronounced in the upper than the lower extremities. They both had decreased or absent reflexes and a steppage gait. The older sib had clawhands. Both sibs had recurrent seizures beginning at approximately 12 years of age, and an EEG showed slow frontal temporal waves in the older sib. Nerve conduction studies revealed no response in any nerves tested, including the left peroneal, sural, median and tibial nerves.
Ionasescu et al. (1996) reported evidence for linkage of the disorder to chromosome 7p14. A maximum lod score of 4.83 at theta = 0 was obtained with marker D7S435. The multipoint linkage map gave a peak lod score of 6.89 between markers D7S1808 and D7S435.
Lennon et al. (1997) confirmed linkage to chromosome 7 in 2 families with CMT2. They could demonstrate no clear clinical differences between the families linked to 1p (CMT2A) and those linked to chromosome 7 (CMT2D). In the full report by Pericak-Vance et al. (1997), the group reported that both admixture and multipoint linkage analysis provided conclusive evidence for additional heterogeneity within this clinical type in families in which linkage to both CMT2A and CMT2D were excluded.
Sambuughin et al. (1998) reported a family in which autosomal dominant CMT2D and DSMAVA segregated in the same kindred. Phenotypic differences in diagnosis were based primarily on greater sensory deficits in CMT2D. The disorder mapped to a refined region on chromosome 7p15, between markers D7S2496 and D7S1514. In addition, patients affected with either DSMAVA or CMT2D in the family reported by Sambuughin et al. (1998) carried identical haplotypes. Together, these findings suggested that defects in a single gene may be responsible for CMT2D and DSMAVA.
Ellsworth et al. (1999) performed a more detailed linkage analysis of the original CMT2D family (Ionasescu et al., 1996) based on new knowledge of the physical locations of various genetic markers. The region containing the CMT2D gene, as defined by the original family, was found to overlap with those defined by Christodoulou et al. (1995) and Sambuughin et al. (1998) with CMT2 and/or distal SMA manifestations. Ellsworth et al. (1999) determined that the most likely location of the CMT2D gene is between markers D7S2496 and D7S632. They suggested that defects in a single gene account for the disease in all of the families.
The transmission pattern of CMT2D in the families reported by Ionasescu et al. (1996) and Pericak-Vance et al. (1997) was consistent with autosomal dominant inheritance.
In families with CMT2 reported by Ionasescu et al. (1996) and Pericak-Vance et al. (1997), Antonellis et al. (2003) identified a mutation in the GARS gene (600287.0001).
Abe and Hayasaka (2009) identified a heterozygous mutation in the GARS gene (600287.0006) in a Japanese patient with CMT2D. No mutations in the GARS gene were found in 109 additional Japanese patients with axonal CMT, suggesting that GARS mutations are a rare cause of the disorder in this population.
In 2 Malian sibs with CMT2D, Yalcouye et al. (2019) identified a heterozygous mutation in the GARS1 gene (S265Y; 600287.0012) by next-generation sequencing of a panel of 50 genes associated with CMT. The patients' mother also had the mutation but was asymptomatic, suggesting incomplete penetrance.
Reviews
Irobi et al. (2004) reviewed the molecular genetics of the distal motor neuropathies.
Using positional cloning, Seburn et al. (2006) found that a mutagenesis-induced dominant mouse model Nmf249 was caused by an in-frame indel mutation at pro278 in the Gars gene. Affected mice had a sensorimotor polyneuropathy with overt neuromuscular dysfunction by 3 weeks of age, smaller size, and shortened life spans compared to wildtype mice. Mutant mice showed neurodegenerative changes at the neuromuscular junction, with more severe changes at distal muscles. Nerve conduction velocities were severely decreased, and peripheral nerves showed reduced axonal diameters and loss of large-diameter axons, but no evidence of demyelination. Homozygous mutant mice were embryonic lethal. The affected pro278 residue is near the catalytic domain-2 of the protein, but the mutation did not affect Gars mRNA levels, and the recombinant mutant enzyme showed normal kinetics and activity. The findings were not consistent with either loss of function (haploinsufficiency) or a dominant-negative loss-of-function effect, but Seburn et al. (2006) postulated aberrant pathogenic function of the mutant protein.
Spaulding et al. (2021) found impaired protein translation in motor neurons of mice with a dominant mutation in Gars (Gars C201R/+ or Gars P278KY/+). Gene expression studies in the spinal cord motor neurons from the mutant mice demonstrated upregulated genes involved in the integrated stress response. The mutant mice were bred with Gcn2 (609280) homozygous knockout mice, which prevented the progression of neuropathy. Mutant Gars mice were also treated with a Gcn2 inhibitor, and some improvement in motor performance and sciatic nerve conduction velocity was seen. Spaulding et al. (2021) concluded that mutations in GARS cause neuropathy by activating the integrated stress response in a subset of neurons and that inhibiting GCN2 could be a therapeutic strategy.
Zuko et al. (2021) overexpressed tRNA Gly-GCC in mice with a heterozygous C201R mutation in the Gars gene. The overexpression of tRNA Gly-GCC prevented peripheral neuropathy in the mutant mice without affecting Gars mRNA and GlyRS protein levels. This provided evidence that the mutant Gars sequesters tRNA Gly and depletes it for translation.
Abe, A., Hayasaka, K. The GARS gene is rarely mutated in Japanese patients with Charcot-Marie-Tooth neuropathy. J. Hum. Genet. 54: 310-312, 2009. [PubMed: 19329989] [Full Text: https://doi.org/10.1038/jhg.2009.25]
Antonellis, A., Ellsworth, R. E., Sambuughin, N., Puls, I., Abel, A., Lee-Lin, S.-Q., Jordanova, A., Kremensky, I., Christodoulou, K., Middleton, L. T., Sivakumar, K., Ionasescu, V., Funalot, B., Vance, J. M., Goldfarb, L. G., Fischbeck, K. H., Green, E. D. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am. J. Hum. Genet. 72: 1293-1299, 2003. [PubMed: 12690580] [Full Text: https://doi.org/10.1086/375039]
Christodoulou, K., Kyriakides, T., Hristova, A. H., Georgiou, D.-M., Kalaydjieva, L., Yshpekova, B., Ivanova, T., Weber, J. L., Middleton, L. T. Mapping of a distal form of spinal muscular atrophy with upper limb predominance to chromosome 7p. Hum. Molec. Genet. 4: 1629-1632, 1995. [PubMed: 8541851] [Full Text: https://doi.org/10.1093/hmg/4.9.1629]
Ellsworth, R. E., Ionasescu, V., Searby, C., Sheffield, V. C., Braden, V. V., Kucaba, T. A., McPherson, J. D., Marra, M. A., Green, E. D. The CMT2D locus: refined genetic position and construction of a bacterial clone-based physical map. Genome Res. 9: 568-574, 1999. [PubMed: 10400924]
Ionasescu, V., Searby, C., Sheffield, V. C., Roklina, T., Nishimura, D., Ionasescu, R. Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D). Hum. Molec. Genet. 5: 1373-1375, 1996. [PubMed: 8872480] [Full Text: https://doi.org/10.1093/hmg/5.9.1373]
Irobi, J., De Jonghe, P., Timmerman, V. Molecular genetics of distal hereditary motor neuropathies. Hum. Molec. Genet. 13: R195-R202, 2004. [PubMed: 15358725] [Full Text: https://doi.org/10.1093/hmg/ddh226]
Lennon, F., Pericak-Vance, M. A., Speer, M. C., West, S. G., Menold, M. M., Stajich, J. M., Wolpert, C. M., Slotterbeck, B. D., Saito, M., Tim, R. W., Rozear, M. P., Middleton, L. T., Tsuji, S., Vance, J. M. CMT2 mapping progress: confirmation of a second locus and evidence for additional genetic heterogeneity. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A282 only, 1997.
Pericak-Vance, M. A., Speer, M. C., Lennon, F., West, S. G., Menold, M. M., Stajich, J. M., Wolpert, C. M., Slotterbeck, B. D., Saito, M., Tim, R. W., Rozear, M. P., Middleton, L. T., Tsuji, S., Vance, J. M. Confirmation of a second locus for CMT2 and evidence for additional genetic heterogeneity. Neurogenetics 1: 89-93, 1997. [PubMed: 10732809] [Full Text: https://doi.org/10.1007/s100480050013]
Sambuughin, N., Sivakumar, K., Selenge, B., Lee, H. S., Friedlich, D., Baasanjav, D., Dalakas, M. C., Goldfarb, L. G. Autosomal dominant distal spinal muscular atrophy type V (dSMA-V) and Charcot-Marie-Tooth disease type 2D (CMT2D) segregate within a single large kindred and map to a refined region on chromosome 7p15. J. Neurol. Sci. 161: 23-28, 1998. [PubMed: 9879677] [Full Text: https://doi.org/10.1016/s0022-510x(98)00264-0]
Seburn, K. L., Nangle, L. A., Cox, G. A., Schimmel, P., Burgess, R. W. An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model. Neuron 51: 715-726, 2006. [PubMed: 16982418] [Full Text: https://doi.org/10.1016/j.neuron.2006.08.027]
Spaulding, E. L., Hines, T. J., Bais, P., Tadenev, A. L. D., Schneider, R., Jewett, D., Pattavina, B., Pratt, S. L., Morelli, K. H., Stum, M. G., Hill, D. P., Gobet, C., and 11 others. The integrated stress response contributes to tRNA synthetase-associated peripheral neuropathy. Science 373: 1156-1161, 2021. [PubMed: 34516839] [Full Text: https://doi.org/10.1126/science.abb3414]
Yalcouye, A., Diallo, S. H., Coulibaly, T., Cisse, L., Diallo, S., Samassekou, O., Diarra, S., Coulibaly, D., Keita, M., Guinto, C. O., Fischbeck, K., Landoure, G., The H3Africa Consortium. A novel mutation in the GARS gene in a Malian family with Charcot-Marie-Tooth disease. Molec. Genet. Genomic Med. 7: e782, 2019. Note: Electronic Article. [PubMed: 31173493] [Full Text: https://doi.org/10.1002/mgg3.782]
Zuko, A., Mallik, M., Thompson, R., Spaulding, E. L., Wienand, A. R., Been, M., Tadenev, A. L. D., van Bakel, N., Sijlmans, C., Santos, L. A., Bussmann, J., Catinozzi, M., Das, S., Kulshrestha, D., Burgess, R. W., Ignatova, Z., Storkebaum, E. tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase. Science 373: 1161-1166, 2021. [PubMed: 34516840] [Full Text: https://doi.org/10.1126/science.abb3356]