Alternative titles; symbols
SNOMEDCT: 766764008; ORPHA: 139557; DO: 0111196;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq21.1 | Neuronopathy, distal hereditary motor, X-linked | 300489 | X-linked recessive | 3 | ATP7A | 300011 |
A number sign (#) is used with this entry because X-linked distal hereditary motor neuronopathy (HMNX) is caused by mutation in the copper transport gene ATP7A (300011) on Xq21.
For a discussion of genetic heterogeneity of distal hereditary motor neuronopathy, see HMND1 (182960).
Takata et al. (2004) reported a white Brazilian family in which 17 males were affected with a distal form of spinal muscular atrophy affecting both the upper and lower limbs. The disorder was transmitted in an X-linked recessive pattern of inheritance. In 6 of 9 patients who were examined, age at onset ranged from 1 to 10 years, and the first detected symptom was foot deformity (pes cavus or pes varus); gait instability was reported in 2 other individuals. Subsequently, distal lower limb weakness and atrophy were observed, and finally, the hands were affected. Despite the large clinical variability, the disease progression was very slow and independent gait was maintained even late in life. There was no cognitive, pyramidal, or sensory impairment. EMG showed chronic denervation, muscle biopsy showed a neurogenic pattern, and sural nerve biopsy was normal.
Kennerson et al. (2009) reported a 3-generation family with X-linked distal motor neuropathy. Age at onset ranged from 10 to 30 years and was characterized by distal motor weakness particularly of the lower limbs that resulted in gait abnormalities and atrophy of lower limb muscles. There was either little or no sensory involvement in affected individuals. Obligate female heterozygotes were unaffected.
In the family reported by Takata et al. (2004), linkage analysis identified a disease locus in a 4.3-cM region between markers DXS8046 and DXS990 at chromosome Xq13.1-q21 (maximum 2-point lod score of 5.74 at marker DXS986).
By linkage analysis of a family with X-linked distal motor neuropathy, Kennerson et al. (2009) refined the DSMAX locus to a 1.44-cM (14.2-Mb) interval on chromosome Xq13.1-q21 between DXS8046 and DXS8114. Sequence analysis excluded mutation in the GJB1 gene (304040) on Xq13, and high-resolution melt analysis excluded mutations in the coding region of 9 additional candidate genes. Kennerson et al. (2009) postulated that the disorder in this family was allelic to that reported by Takata et al. (2004) despite the earlier age of onset in the latter family.
In affected members of 2 families previously reported by Takata et al. (2004) and Kennerson et al. (2009), Kennerson et al. (2010) identified 2 different mutations in the ATP7A gene: T994I (300011.0015) and P1386S (300011.0016), respectively. In vitro functional expression assays indicated that the mutations resulted in impaired copper transport into the secretory pathway for incorporation into nascent proproteins, perhaps due to reduced conformational flexibility. Kennerson et al. (2010) suggested that the late onset of distal muscular atrophy implies that these mutations produced attenuated effects that required years to provoke pathologic consequences. Motor neurons may be particularly sensitive to perturbations in copper homeostasis or copper deficiency, which may impair normal axonal growth and synaptogenesis.
Kennerson, M. L., Nicholson, G. A., Kaler, S. G., Kowalski, B., Mercer, J. F. B., Tang, J., Llanos, R. M., Chu, S., Takata, R. I., Speck-Martins, C. E., Baets, J., Almeida-Souza, L., and 10 others. Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. Am. J. Hum. Genet. 86: 343-352, 2010. [PubMed: 20170900] [Full Text: https://doi.org/10.1016/j.ajhg.2010.01.027]
Kennerson, M., Nicholson, G., Kowalski, B., Krajewski, K., El-Khechen, D., Feely, S., Chu, S., Shy, M., Garbern, J. X-linked distal hereditary motor neuropathy maps to the DSMAX locus on chromosome Xq13.1-q21. Neurology 72: 246-252, 2009. [PubMed: 19153371] [Full Text: https://doi.org/10.1212/01.wnl.0000339483.86094.a5]
Takata, R. I., Speck Martins, C. E., Passosbueno, M. R., Abe, K. T., Nishimura, A. L., Morvalina Da Silva, M. D., Monteiro, A., Jr., Lima, M. I., Kok, F., Zatz, M. A new locus for recessive distal spinal muscular atrophy at Xq13.1-q21. J. Med. Genet. 41: 224-229, 2004. [PubMed: 14985388] [Full Text: https://doi.org/10.1136/jmg.2003.013201]