Alternative titles; symbols
SNOMEDCT: 726616006; ICD10CM: G71.035; ORPHA: 206549; DO: 0110284;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p14.3 | Muscular dystrophy, limb-girdle, autosomal recessive 12 | 611307 | Autosomal recessive | 3 | ANO5 | 608662 |
A number sign (#) is used with this entry because of evidence that autosomal recessive limb-girdle muscular dystrophy-12 (LGMDR12) is caused by homozygous or compound heterozygous mutation in the ANO5 gene (608662) on chromosome 11p14.
Miyoshi muscular dystrophy-3 (MMD3; 613319) is also caused by mutation in the ANO5 gene.
For a general phenotypic description and a discussion of genetic heterogeneity of LGMD, see LGMDR1 (253600).
At the 229th ENMC international workshop, Straub et al. (2018) reviewed, reclassified, and/or renamed forms of LGMD. The proposed naming formula was 'LGMD, inheritance (R or D), order of discovery (number), affected protein.' Under this formula, LGMD2L was renamed LGMDR12.
Jarry et al. (2007) reported 14 French Canadian patients from 8 different families with limb-girdle muscular dystrophy with quadriceps atrophy. Age at onset ranged from 11 to 50 years. The majority of patients reported muscle pain. Although the severity of the phenotype was variable, all affected individuals had prominent weakness and atrophy of the quadriceps femoris muscles, often with asymmetric involvement. Serum creatine kinase was normal or significantly increased. EMG studies showed myopathic changes, and muscle biopsies showed dystrophic changes with increased connective tissue and fiber splitting. Two patients with more advanced disease showed neurogenic changes on EMG. MRI studies on 4 patients showed atrophy of the biceps brachii and quadriceps femoris muscles with fatty infiltration. Four patients were wheelchair-bound after an average disease duration of 12 years. Less common findings included facial weakness in 2 patients and calf hypertrophy in 4. Inheritance was consistent with autosomal recessive. Because of the prominent involvement of the quadriceps muscle, molecular and linkage analysis specifically excluded IBM2 (see 605820) and LGMD2H (LGMDR8; 254110). Jarry et al. (2007) referred to Boddie and Stewart-Wynne (1974), who concluded that so-called 'quadriceps myopathy' is not a distinct disease entity but rather a clinical syndrome with heterogeneous pathologic bases.
Penttila et al. (2012) reported 16 male patients, mostly of Finnish descent, with muscular disease due to recessive mutations in the ANO5 gene. Most patients (7) had proximal lower limb weakness, 4 had proximal upper and lower limb weakness, and 1 had proximal upper limb weakness only. Three had distal lower limb weakness, consistent with Miyoshi myopathy-3, and 1 had proximal and distal lower limb weakness. Of the 12 male patients with LGMD2L, the mean age at onset was in the thirties and the disorder was slowly progressive. There was no cardiac, bulbar, or respiratory involvement, and all remained ambulatory, some of them using a cane in their seventies. Serum creatine kinase was increased, and muscle biopsies showed nonspecific dystrophic changes. MRI showed fatty degenerative changes in the gastrocnemius medialis, adductor magnus, hamstring, and vastus muscles of the quadriceps. There were no genotype/phenotype correlations. Female mutation carriers had a much less severe phenotype, more consistent with a mild form of MMD3.
By genomewide linkage analysis of 8 French Canadian families with autosomal recessive limb-girdle muscular dystrophy with prominent quadriceps involvement, Jarry et al. (2007) identified a candidate region, termed LGMD2L, on chromosome 11p13-p12 (maximum multipoint lod score of 3.81 at marker D11S1360 in 6 of 8 families). Fine mapping and haplotype analysis delineated a 3.3-cM region between markers D11S935 and D11S4966 (cumulative lod score of 4.56 for all 8 families). Some families showed shared haplotypes, suggesting a common mutation. Sequencing analysis excluded mutations in the TRAF6 gene (602355).
In affected members of 2 unrelated French Canadian families with LGMD2L, Bolduc et al. (2010) identified a homozygous mutation in the ANO5 (608662.0003), resulting in a frameshift and premature termination. Haplotype analysis suggested a founder effect. One of the families was known to be consanguineous and had been reported by Jarry et al. (2007); however, the other 7 families reported by Jarry et al. (2007) did not have ANO5 mutations. Affected members of a third unrelated French Canadian family with LGMD2L were found to be compound heterozygous for 2 different mutations in the ANO5 gene (608662.0004-608662.0005). 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.
Boddie, H. G., Stewart-Wynne, E. G. Quadriceps myopathy--entity or syndrome? Arch. Neurol. 31: 60-62, 1974. [PubMed: 4834543] [Full Text: https://doi.org/10.1001/archneur.1974.00490370086015]
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]
Jarry, J., Rioux, M. F., Bolduc, V., Robitaille, Y., Khoury, V., Thiffault, I., Tetreault, M., Loisel, L., Bouchard, J. P., Brais, B. A novel autosomal recessive limb-girdle muscular dystrophy with quadriceps atrophy maps to 11p13-p12. Brain 130: 368-380, 2007. [PubMed: 17008331] [Full Text: https://doi.org/10.1093/brain/awl270]
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]
Straub, V., Murphy, A., Udd, B. 229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017. Neuromusc. Disord. 28: 702-710, 2018. [PubMed: 30055862] [Full Text: https://doi.org/10.1016/j.nmd.2018.05.007]