Alternative titles; symbols
SNOMEDCT: 720523006; ORPHA: 86812; DO: 0110297;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q34.13 | Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 | 609308 | Autosomal recessive | 3 | POMT1 | 607423 |
A number sign (#) is used with this entry because this form of limb-girdle muscular dystrophy-dystroglycanopathy (type C1; MDDGC1), also known as LGMDR11 and LGMD2K, is caused by homozygous or compound heterozygous mutation in the gene encoding protein O-mannosyltransferase (POMT1; 607423).
Mutation in the POMT1 gene can also cause a more severe congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A1; MDDGA1; 236670) and a congenital muscular dystrophy-dystroglycanopathy with impaired intellectual development (type B1; MDDGB1; 613155).
Limb-girdle muscular dystrophies resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239) represent the mildest end of the phenotypic spectrum of muscular dystrophies collectively known as dystroglycanopathies. The limb-girdle phenotype is characterized by onset of muscular weakness apparent after ambulation is achieved; impaired intellectual development and mild brain anomalies are variable (Balci et al., 2005; review by Godfrey et al., 2007). The most severe end of the phenotypic spectrum of dystroglycanopathies is represented by congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A; see MDDGA1, 236670), previously designated Walker-Warburg syndrome (WWS) or muscle-eye-brain disease (MEB), and the intermediate range of the spectrum is represented by congenital muscular dystrophy-dystroglycanopathy with or without impaired intellectual development (type B; see MDDGB1, 613155).
Genetic Heterogeneity of Limb-Girdle Muscular Dystrophy-Dystroglycanopathy (Type C)
Limb-girdle muscular dystrophy due to defective glycosylation of DAG1 is genetically heterogeneous. See also MDDGC2 (613158), caused by mutation in the POMT2 gene (607439); MDDGC3 (613157), caused by mutation in the POMGNT1 gene (606822); MDDGC4 (611588), caused by mutation in the FKTN gene (607440); MDDGC5 (607155), caused by mutation in the FKRP gene (606596); MDDGC7 (616052), caused by mutation in the ISPD gene (CRPPA; 614631); MDDGC8 (618135), caused by mutation in the POMGNT2 gene (614828); MDDGC9 (613818) caused by mutation in the DAG1 gene (128239); MDDGC12 (616094), caused by mutation in the POMK gene (615247); MDDGC14 (615352) caused by mutation in the GMPPB gene (615320); and MDDGC15 (612937), caused by mutation in the DPM3 gene (605951).
Dincer et al. (2003) reported 7 patients from 6 consanguineous Turkish families with autosomal recessive mental retardation and limb-girdle muscular dystrophy. An eighth British patient, who was not from a consanguineous family, had a similar phenotype. All patients acquired early motor milestones, excluding a congenital muscular dystrophy. Age at onset ranged from 1 to 6 years, with difficulty in walking and climbing stairs. Other features included slow progression, proximal muscle weakness, mild muscle hypertrophy, increased serum creatine kinase, microcephaly, and mental retardation (IQ range, 50 to 76). Brain imaging was normal in all cases, with no structural abnormalities or white matter changes. Skeletal muscle biopsy showed dystrophic changes, including mild fibrosis with many regenerating and few necrotic fibers, increased fiber size variability, and multiple central nuclei. Immunohistochemical staining showed severe hypoglycosylation of alpha-dystroglycan.
Lommel et al. (2010) reported a 10-year-old boy with LGMD2K resulting from compound heterozygous mutations in the POMT1 gene. He had delayed motor milestones and achieved walking at age 22 months. He also had secondary microcephaly and mental retardation with an IQ of 68. Brain MRI did not show structural changes. Other features included hypertrophy of the calf muscle, positive Gowers sign, limb-girdle weakness, and increased serum creatine kinase. Dermal fibroblasts from the patient showed decreased, but not absent, levels of POMT1 protein and 40% residual protein activity. This was increased compared to 6% residual protein activity and lack of protein detection in dermal fibroblasts from a patient with severe POMT1-related muscular dystrophy with brain and eye anomalies. Thus, the phenotypic severity was inversely correlated with residual O-mannosyltransferase activity of the POMT1 gene.
Bello et al. (2012) reported 2 unrelated patients with LGMD2K who developed cardiomyopathy. One presented at age 3 years with increased serum creatine kinase. Muscle biopsy at age 5 years showed mild myopathic changes. His psychomotor development was normal. At age 12 years, routine echocardiography showed diffuse left ventricular wall hypokinesia. He presented at the age of 17 years with shortness of breath and easy fatigability, and cardiac work-up showed left ventricular hypertrophy, left ventricular dilation, systolic dysfunction, and right ventricular dilation. Neurologic examination showed calf and thigh hypertrophy, relative wasting of the scapulohumeral girdle, and mild symmetrical weakness of the proximal muscles. Brain MRI was normal, but the patient showed some executive dysfunction; his IQ was 82. The second patient was a 34-year-old man who presented at age 33 with muscle weakness of the lower limbs and myalgias in the shoulder girdle. Serum creatine kinase was increased, and muscle biopsy showed a severe myopathy with type I fiber predominance, central nuclei, and cores. Neurologic examination showed calf hypertrophy and normal cognition. Echocardiography showed biventricular dilatation, consistent with cardiomyopathy. Muscle biopsy in both patients showed reduced DAG glycosylation. Bello et al. (2012) reported another patient with congenital muscular dystrophy (MDDGB1; 613155) due to POMT1 mutations who also developed cardiomyopathy, suggesting that cardiac involvement can be added to the phenotypic spectrum of POMT1 mutations.
In 5 Turkish patients, born of consanguineous parents, with limb-girdle muscular dystrophy and mental retardation, some of whom were described by Dincer et al. (2003), Balci et al. (2005) identified a homozygous mutation in the POMT1 gene (A200P; 607423.0005). Haplotype analysis indicated that it was a common founder mutation. Balci et al. (2005) noted that the phenotype associated with the A200P mutation was significantly milder than that found in other patients with POMT1 mutations.
In 2 unrelated patients with LGMD2K who also developed cardiomyopathy, Bello et al. (2012) identified compound heterozygous mutations in the POMT1 gene (see, e.g., 607423.0019 and 607423.0020).
Balci, B., Uyanik, G., Dincer, P., Gross, C., Willer, T., Talim, B., Haliloglu, G., Kale, G., Hehr, U., Winkler, J., Topaloglu, H. An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene. Neuromusc. Disord. 15: 271-275, 2005. [PubMed: 15792865] [Full Text: https://doi.org/10.1016/j.nmd.2005.01.013]
Bello, L., Melacini, P., Pezzani, R., D'Amico, A., Piva, L., Leonardi, E., Torella, A., Soraru, G., Palmieri, A., Smaniotto, G., Gavassini, B. F., Vianello, A., Nigro, V., Bertini, E., Angelini, C., Tosatto, S. C. E., Pegoraro, E. Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy. Europ. J. Hum. Genet. 20: 1234-1239, 2012. [PubMed: 22549409] [Full Text: https://doi.org/10.1038/ejhg.2012.71]
Dincer, P., Balci, B., Yuva, Y., Talim, B., Brockington, M., Dincel, D., Torelli, S., Brown, S., Kale, G., Haliloglu, G., Gerceker, F. O., Atalay, R. C., Yakicier, C., Longman, C., Muntoni, F., Topaloglu, H. A novel form of recessive limb girdle muscular dystrophy with mental retardation and abnormal expression of alpha-dystroglycan. Neuromusc. Disord. 13: 771-778, 2003. [PubMed: 14678799] [Full Text: https://doi.org/10.1016/s0960-8966(03)00161-5]
Godfrey, C., Clement, E., Mein, R., Brockington, M., Smith, J., Talim, B., Straub, V., Robb, S., Quinlivan, R., Feng, L., Jimenez-Mallebrera, C., Mercuri, E., and 10 others. Refining genotype-phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain 130: 2725-2735, 2007. [PubMed: 17878207] [Full Text: https://doi.org/10.1093/brain/awm212]
Lommel, M., Cirak, S., Willer, T., Hermann, R., Uyanik, G., van Bokhoven, H., Korner, C., Voit, T., Baric, I., Hehr, U., Strahl, S. Correlation of enzyme activity and clinical phenotype in POMT1 associated dystroglycanopathies. Neurology 74: 157-164, 2010. [PubMed: 20065251] [Full Text: https://doi.org/10.1212/WNL.0b013e3181c919d6]