Alternative titles; symbols
SNOMEDCT: 783166000; ORPHA: 399096; DO: 0070201;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p14.3 | Miyoshi muscular dystrophy 3 | 613319 | Autosomal recessive | 3 | ANO5 | 608662 |
A number sign (#) is used with this entry because Miyoshi muscular dystrophy-3 (MMD3) is caused by homozygous or compound heterozygous mutation in the ANO5 gene (608662) on chromosome 11p14.
Limb-girdle muscular dystrophy-2L (LGMD2L; 611307) is also caused by mutation in the ANO5 gene.
For a general phenotypic description and a discussion of genetic heterogeneity of Miyoshi muscular dystrophy, see MMD1 (254130).
Linssen et al. (1998) reported a Dutch family with Miyoshi myopathy not caused by dysferlin mutations (DYSF; 603009) and not linked to the MMD2 locus (613318) on chromosome 10. Age at onset ranged from 39 to 51 years, and the presenting symptom was inability to stand on tiptoe due to asymmetric distal muscle weakness of the lower limbs.
Jaiswal et al. (2007) reported 2 Finnish brothers with Miyoshi myopathy. The 41-year-old proband reported discomfort of the calf muscles since age 20 years. In his late twenties, he had difficulty running, and was unable to run after age 30. He remained ambulatory with a waddling gait. Physical examination showed mild weakness of the calf muscles, hypertrophy of the extensor digitorum brevis muscles, weakness of the proximal lower limb muscles, and increased serum creatine kinase. MRI showed fatty infiltration of affected muscles. His 46-year-old brother was clinically asymptomatic, but he had increased serum creatine kinase and showed fatty infiltration of the distal lower limb muscles on MRI.
Among 16 male patients, most of Finnish origin, with recessive ANO5 mutations, Penttila et al. (2012) found that only 3 had distal lower limb weakness consistent with Miyoshi myopathy. One patient had proximal and distal lower limb weakness. The rest of the patients had proximal muscle weakness more consistent with the LGMD2L phenotype. There were no particular genotype/phenotype correlations.
Clinical Variability
Penttila et al. (2012) observed that female patients with ANO5 mutations had consistently milder phenotypes than males with similar mutations. In a cohort of 25 mutation carriers, including 9 females and 16 males, most of Finnish origin, none of the females had clinically detectable muscle weakness despite increased serum creatine kinase and myopathic findings in muscle biopsy samples. They also had less severe fatty degenerative changes on MRI and less severely increased serum creatine kinase compared to males. Females presented with myalgia, exercise intolerance, calf hypertrophy, or isolated hyperCKemia. These gender differences were evident even among sibs in the same family, and there were no particular genotype/phenotype correlations.
By genomewide linkage analysis of 2 families with Miyoshi myopathy reported by Linssen et al. (1998) and Jaiswal et al. (2007), Bolduc et al. (2010) found linkage to a new locus, termed MMD3, on chromosome 11p14.3-cen between rs722490 and rs509244, with a cumulative lod score greater than 2.5. This locus overlapped with the LGMD2L candidate region.
The transmission pattern of MMD3 in the families reported by Bolduc et al. (2010) was consistent with autosomal recessive inheritance.
In affected members of a Dutch family with MMD3 (Linssen et al., 1998), Bolduc et al. (2010) identified a homozygous mutation in the ANO5 gene (191dupA; 608662.0004). Two Finnish brothers with Miyoshi myopathy (Jaiswal et al., 2007) were found to be homozygous for another mutation in the ANO5 gene (R758C; 608662.0006). The 191dupA mutation was also observed in compound heterozygous state in a family with LGMD2L (611307), confirming that the 2 disorders are allelic. Electron microscopy of a patient's muscle biopsy showed disruption of the sarcolemmal membrane, and Bolduc et al. (2010) postulated a defect in membrane repair.
Jaiswal et al. (2007) found that fibroblasts derived from 2 Finnish brothers with Miyoshi muscular dystrophy-3 exhibited membrane repair defects in vitro. However, the cells showed normal calcium-triggered exocytosis of lysosomes, which is believed to be a mechanism for membrane wound repair, indicating that another mechanism must be involved.
Bolduc, V., Marlow, G., Boycott, K. M., Saleki, K., Inoue, H., Kroon, J., Itakura, M., Robitaille, Y., Parent, L., Baas, F., Mizuta, K., Kamata, N., Richard, I., Linssen, W. H. J. P., Mahjneh, I., de Visser, M., Bashir, R., Brais, B. Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies. Am. J. Hum. Genet. 86: 213-221, 2010. [PubMed: 20096397] [Full Text: https://doi.org/10.1016/j.ajhg.2009.12.013]
Jaiswal, J. K., Marlow, G., Summerill, G., Mahjneh, I., Mueller, S., Hill, M., Miyake, K., Haase, H., Anderson, L. V. B., Richard, I., Kiuru-Enari, S., McNeil, P. L., Simon, S. M., Bashir, R. Patients with a non-dysferlin Miyoshi myopathy have a novel membrane repair defect. Traffic 8: 77-88, 2007. [PubMed: 17132147] [Full Text: https://doi.org/10.1111/j.1600-0854.2006.00505.x]
Linssen, W. H. J. P., de Visser, M., Notermans, N. C., Vreyling, J. P., Van Doorn, P. A., Wokke, J. H. J., Baas, F., Bolhuis, P. A. Genetic heterogeneity in Miyoshi-type distal muscular dystrophy. Neuromusc. Disord. 8: 317-320, 1998. [PubMed: 9673985] [Full Text: https://doi.org/10.1016/s0960-8966(98)00020-0]
Penttila, S., Palmio, J., Suominen, T., Raheem, O., Evila, A., Muelas Gomez, N., Tasca, G., Waddell, L. B., Clarke, N. F., Barboi, A., Hackman, P., Udd, B. Eight new mutations and the expanding phenotype variability in muscular dystrophy caused by ANO5. Neurology 78: 897-903, 2012. Note: Erratum: Neurology 80: 226 only, 2013. [PubMed: 22402862] [Full Text: https://doi.org/10.1212/WNL.0b013e31824c4682]