ORPHA: 171439; DO: 0110935;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q22.31 | Nemaline myopathy 6, autosomal dominant | 609273 | Autosomal dominant | 3 | KBTBD13 | 613727 |
A number sign (#) is used with this entry because nemaline myopathy-6 (NEM6) is caused by heterozygous mutation in the KBTBD13 gene (613727) on chromosome 15q22.
For a discussion of genetic heterogeneity of nemaline myopathy, see 161800.
Nemaline myopathy-6 is an autosomal dominant skeletal muscle disorder characterized by childhood onset of slowly progressive proximal muscle weakness, exercise intolerance, and slow movements with stiff muscles. Patients are unable to run or correct themselves from falling over. Histopathologic changes seen on skeletal muscle biopsy include nemaline rods, cores devoid of oxidative enzyme activity, and predominance of hypertrophic type 1 fibers. There is no cardiac or respiratory involvement (summary by Sambuughin et al., 2010).
Gommans et al. (2002) reported a 5-generation Dutch family with autosomal dominant nemaline myopathy. The homogeneous clinical phenotype was characterized by normal early motor development followed by onset in childhood of difficulty running, climbing stairs, jumping, and lifting above the head, consistent with proximal muscle weakness. The most striking complaint was a feeling of muscle slowness or stiffness, and slow response times to falls. There was no involvement of respiratory or cardiac muscles. There was neck muscle weakness, but no facial weakness or dysphagia. Although there was mild disease progression with age, no patients were wheelchair-bound. Muscle imaging showed fatty infiltration that increased with age. Muscle biopsy showed type 1 fiber predominance, nemaline rods, loss of myofibrillar organization, and some core-like structures. Linkage analysis excluded the TPM3 (191030), ACTA1 (102610), NEB (161650), and TPM2 (190990) genes.
Olive et al. (2010) reported a Spanish family in which 4 members had a phenotype similar to that reported by Gommans et al. (2002). After a normal neonatal period and normal motor milestones, affected individuals presented at age 4 to 5 years with slowly progressive proximal muscle weakness in the arms and legs manifest as gait abnormality and difficulties performing sports; they were unable to run or jump, but could walk long distances. All individuals also had distal muscle weakness in the upper and lower limbs, and hypotrophy of the forearm muscles. A particular feature was slowness of movements that appeared as bradykinetic slow-motion behavior and clumsiness. Three of 4 patients remained ambulant into adulthood. Creatine kinase was normal, and EMG studies showed myopathic pattern. There was no cardiac or respiratory involvement or peripheral neuropathy. Muscle biopsy showed marked variation in fiber size, internal nuclei, and aggregates of abnormal fine, granular, or rod-shaped structures in the cytoplasm or in subsarcolemmal regions, as well as core-like areas devoid of oxidative enzyme activity. There was predominance and hypertrophy of type 1 fibers.
Nemaline myopathy-6 is transmitted in an autosomal dominant pattern (Olive et al., 2010).
By genomewide linkage analysis of the affected Dutch family reported by Gommans et al. (2002), Gommans et al. (2003) identified a candidate disease region on chromosome 15q. By combining the results with linkage data from another affected Dutch family, Gommans et al. (2003) defined a 12-cM interval between markers D15S155 and D15S125 (maximum 2-point lod score of 10.65). Haplotype analysis excluded a common ancestor. Sequence analysis excluded mutations in the TPM1 gene (191010), which maps to this region.
By linkage analysis of a Spanish family with nemaline myopathy, Olive et al. (2010) found linkage (lod score of 2.077) to the 15q21-q23 NEM6 locus identified by Gommans et al. (2003).
In affected members of 4 unrelated families with nemaline myopathy-6 (Gommans et al., 2002; Olive et al., 2010), Sambuughin et al. (2010) identified heterozygous missense mutations in the KBTBD13 gene (613727.0001 and 613727.0002). Another patient with sporadic disease carried a third heterozygous missense mutation (613727.0003).
Gommans, I. M. P., Davis, M., Saar, K., Lammens, M., Mastaglia, F., Lamont, P., van Duijnhoven, G., ter Laak, H. J., Reis, A., Vogels, O. J. M., Laing, N., van Engelen, B. G. M., Kremer, H. A locus on chromosome 15q for a dominantly inherited nemaline myopathy with core-like lesions. Brain 126: 1545-1551, 2003. Note: Erratum: Brain 126: 2115 only, 2003. [PubMed: 12805120] [Full Text: https://doi.org/10.1093/brain/awg162]
Gommans, I. M. P., van Engelen, B. G. M., ter Laak, H. J., Brunner, H. G., Kremer, H., Lammens, M., Vogels, O. J. M. A new phenotype of autosomal dominant nemaline myopathy. Neuromusc. Disord. 12: 13-18, 2002. [PubMed: 11731279] [Full Text: https://doi.org/10.1016/s0960-8966(01)00231-0]
Olive, M., Goldfarb, L. G., Lee, H. S., Odgerel, Z., Blokhin, A., Gonzalez-Mera, L., Moreno, D., Laing, N. G., Sambuughin, N. Nemaline myopathy type 6: clinical and myopathological features. Muscle Nerve 42: 901-907, 2010. [PubMed: 21104864] [Full Text: https://doi.org/10.1002/mus.21788]
Sambuughin, N., Yau, K. S., Olive, M., Duff, R. M., Bayarsaikhan, M., Lu, S., Gonzalez-Mera, L., Sivadorai, P., Nowak, K. J., Ravenscroft, G., Mastaglia, F. L., North, K. N., and 9 others. Dominant mutations in KBTBD13, a member of the BTB/Kelch family, cause nemaline myopathy with cores. Am. J. Hum. Genet. 87: 842-847, 2010. Note: Erratum: Am. J. Hum. Genet. 88: 122 only, 2011. [PubMed: 21109227] [Full Text: https://doi.org/10.1016/j.ajhg.2010.10.020]