Alternative titles; symbols
SNOMEDCT: 1197152005; ORPHA: 139536; DO: 0111203;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p14.3 | Neuronopathy, distal hereditary motor, autosomal dominant 5 | 600794 | Autosomal dominant | 3 | GARS1 | 600287 |
A number sign (#) is used with this entry because of evidence that autosomal dominant distal hereditary motor neuronopathy-5 (HMND5) is caused by heterozygous mutation in the GARS gene (600287) on chromosome 7p14.
Heterozygous mutation in the GARS1 gene can also cause Charcot-Marie-Tooth disease type 2D (CMT2D; 601472), which has some overlapping features.
Autosomal dominant distal hereditary motor neuronopathy-5 (HMND5), also known as distal hereditary motor neuronopathy type VA (dHMN5A or HMN5A), is a neuromuscular disorder characterized by onset of distal muscle weakness and atrophy predominantly affecting the upper limbs in the first few decades of life. The disorder is slowly progressive, and most patients eventually have lower limb involvement with foot deformities. Although sensory impairment is uncommon, some patients show this feature, illustrating the phenotypic overlap with CMT2D. Rare patients may have pyramidal signs or hyperreflexia (summary by Christodoulou et al., 1995 and Dubourg et al., 2006).
For a discussion of genetic heterogeneity of autosomal dominant distal HMN, see HMND1 (182960).
Meadows and Marsden (1969) reported 3 sibs with a form of distal muscular atrophy confined largely to the upper extremities. All had weakness of the hands since early childhood, manifest by difficulty writing. The condition worsened significantly much later in life, in the sixth and seventh decades. Hand weakness and atrophy were apparent in all, and 2 sibs had lower limb weakness with hyporeflexia/areflexia; the remaining sib had hyporeflexia/areflexia without lower limb weakness. EMG and muscle biopsy confirmed a neurogenic disorder. The mode of inheritance was unclear.
Christodoulou et al. (1995) identified a large 5-generation Bulgarian family from Burgass with an autosomal dominant distal spinal muscular atrophy (dSMA) with upper limb predominance. Afflicted members had weakness and wasting which was more prominent in the upper limbs and more selectively involved the thenar muscles and the first dorsal interossei. They had clinical information on 114 family members, of whom 30 were affected. The disease commenced with hand involvement at a mean age of 17 years (median 16 years). In 40% of patients, symptoms subsequently developed in their feet within about 2 years. In 1 branch of the family, mild pyramidal features and, rarely, up-going plantar responses were observed. There were no sensory symptoms or signs except for slightly reduced vibratory sense in the feet in 10% of the patients. Progression of the disease was very slow, with patients still ambulant at the age of 64. Electrophysiologic investigations showed reduced or, in severely wasted muscles, unobtainable compound motor action potentials. Motor conduction velocities and distal latencies were normal, except in severely wasted muscles, where the former were reduced. Christodoulou et al. (1995) concluded that the family fell into the type V category of distal spinal muscular atrophy according to Harding (1993), who proposed a classification into 7 types of distal SMA according to their clinical and genetic features. The family was similar to the one reported by Lander et al. (1976), but differed in that weakness and wasting were more severe in the thenar muscles and first dorsal interossei.
Sambuughin et al. (1998) reported a family in which autosomal dominant CMT2D and distal spinal muscular atrophy type V 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. DSMAV 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.
Antonellis et al. (2003) reported an Algerian Sephardic Jewish family with autosomal dominant DSMAV. A father and daughter had bilateral hand amyotrophy and weakness, particularly in the thenar and dorsal interosseus muscles. Motor and sensory nerve conduction velocities were normal.
Forrester et al. (2020) reported 7 unrelated probands (patients 1, 3-8) with peripheral neuropathy associated with heterozygous missense variants in the GARS1 gene that were identified through next-generation sequencing. Common features included distal muscle weakness and atrophy of the upper and lower limbs, often with pes cavus, hammertoes, or tight Achilles tendon. Patient 5 was an 11-year-old boy with frequent falls, hyporeflexia, pes cavus, and weakness and atrophy of the hand muscles. His father and paternal grandmother were similarly affected, and there was a family history of the disorder on the paternal side, although the severity was variable. Patient 8, who was 52 years old, was the only one to report sensory deficits with numbness of the hands and foot drop, suggestive of CMT2D. The authors noted the phenotypic variability both within families with the same mutation and between patients with different mutations.
The transmission pattern of HMN5A in the family reported by Christodoulou et al. (1995) was consistent with autosomal dominant inheritance.
In 3 French families with the disorder, Dubourg et al. (2006) observed autosomal dominant inheritance with incomplete penetrance.
Linkage studies in the Bulgarian family reported by Christodoulou et al. (1995) excluded the SMA locus (253300) on chromosome 5. Using more than 140 microsatellite polymorphic markers for a genome screen, Christodoulou et al. (1995) found a maximum lod score of 5.99 at theta = 0.007 for locus D7S795 located on 7p. Sambuughin et al. (1998) mapped the disorder in their family to a region on 7p15 between markers D7S2496 and D7S1514.
Ellsworth et al. (1999) performed a more detailed linkage analysis of the region on 7p and found overlap between the areas defined by Christodoulou et al. (1995) and Sambuughin et al. (1998) and the area defined by Ionasescu et al. (1996) in a CMT2D family. 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.
Irobi et al. (2004) reviewed the molecular genetics of the distal motor neuropathies.
In affected members of the families with DSMAV reported by Christodoulou et al. (1995) and Antonellis et al. (2003) and the family with both DSMAV and CMT2D reported by Sambuughin et al. (1998), Antonellis et al. (2003) identified heterozygous missense mutations in the GARS gene (600287.0002-600287.0004) that segregated with the disorder in the families.
Dubourg et al. (2006) identified a heterozygous missense mutation in the GARS gene (G526R; 600287.0004) in 12 affected members from 3 French families of Sephardic Jewish origin with HMN type V. Four mutation carriers were clinically asymptomatic, suggesting incomplete penetrance. Most presented with distal upper limb involvement between the second and fourth decades; none had sensory involvement. Haplotype analysis suggested a founder effect.
In a patient (patient 1) and his mother with HMN5A, Boczonadi et al. (2018) identified a heterozygous missense mutation in the GARS1 gene (H216R; 600287.0008). The mutation was identified through sequencing of a gene panel. Patient fibroblasts did not show a defect in mitochondrial translation, but detailed studies on induced neuronal progenitor cells derived from patient fibroblasts showed decreased levels of mitochondrial respiratory chain complexes, impaired mitochondrial respiration and metabolism, defects in calcium flux dynamics, and increased autophagic vacuoles. These findings were consistent with tissue-specific effects of the mutation; the authors postulated a dominant gain-of-function mechanism. The patients had onset of upper limb-predominant distal neuropathy in their early twenties.
In 7 unrelated patients with DMHN5A, Forrester et al. (2020) identified heterozygous missense variants in the GARS1 gene (see, e.g., H472R; 600287.0013). The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in affected family members of 6 probands, whereas it occurred de novo in 1 patient. Although functional studies of the variants were not performed, 3 (H216R, G327R, and H472R) were classified as pathogenic or likely pathogenic, and 3 were considered to be of uncertain pathogenic significance (R27P, K510Q, and M555V), according to ACMG criteria.
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]
Boczonadi, V., Meyer, K., Gonczarowska-Jorge, H., Griffin, H., Roos, A., Bartsakoulia, M., Bansagi, B., Ricci, G., Palinkas, F., Zahedi, R. P., Bruni, F., Kaspar, B., Lochmuller, H., Boycott, K. M., Muller, J. S., Horvath, R. Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons. Hum. Molec. Genet. 27: 2187-2204, 2018. [PubMed: 29648643] [Full Text: https://doi.org/10.1093/hmg/ddy127]
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]
Dubourg, O., Azzedine, H., Ben Yaou, R., Pouget, J., Barois, A., Meininger, V., Bouteiller, D., Ruberg, M., Brice, A., LeGuern, E. The G526R glycyl-tRNA synthetase gene mutation in distal hereditary motor neuropathy type V. Neurology 66: 1721-1726, 2006. Note: Erratum: Neurology, 67: 727 only, 2006. [PubMed: 16769947] [Full Text: https://doi.org/10.1212/01.wnl.0000218304.02715.04]
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]
Forrester, N., Rattihalli, R., Horvath, R., Maggi, L., Manzur, A., Fuller, G., Gutowski, N., Rankin, J., Dick, D., Buxton, C., Greenslade, M., Majumdar, A. Clinical and genetic features in a series of eight unrelated patients with neuropathy due to glycyl-tRNA synthetase (GARS) variants. J. Neuromusc. Dis. 7: 137-143, 2020. [PubMed: 31985473] [Full Text: https://doi.org/10.3233/JND-200472]
Harding, A. E. Inherited neuronal atrophy and degeneration predominantly of lower motor neurons. In: Dyck, P. J.; Thomas, P. K. (eds.): Peripheral Neuropathy. Vol. 2. (3rd ed.) Philadelphia: W. B. Saunders (pub.) 1993. Pp. 1051-1064.
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]
Lander, C. M., Eadie, M. J., Tyrer, J. H. Hereditary motor peripheral neuropathy predominantly affecting the arms. J. Neurol. Sci. 28: 389-394, 1976. [PubMed: 180264] [Full Text: https://doi.org/10.1016/0022-510x(76)90032-0]
Meadows, J. C., Marsden, C. D. A distal form of chronic spinal muscular atrophy. Neurology 19: 53-58, 1969. [PubMed: 5813127] [Full Text: https://doi.org/10.1212/wnl.19.1.53]
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]
Sobue, I., Saito, N., Iida, M., Ando, K. Juvenile type of distal and segmental muscular atrophy of upper extremities. Ann. Neurol. 3: 429-432, 1978. [PubMed: 727722] [Full Text: https://doi.org/10.1002/ana.410030512]