| #608840 | ||||||||||||
| MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION), TYPE B, 6; MDDGB6 | ||||||||||||
| Alternative titles; symbols | ||||||||||||
| MUSCULAR DYSTROPHY, CONGENITAL, LARGE-RELATED MUSCULAR DYSTROPHY, CONGENITAL, TYPE 1D; MDC1D | ||||||||||||
| Phenotype Gene Relationships | ||||||||||||
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| Phenotypic Series | ||||||||||||
| Clinical Synopsis | ||||||||||||
| TEXT | ||||||||||||
| A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with mental retardation (type B6; MDDGB6), previously designated CMD1D, is caused by homozygous or compound heterozygous mutation in the LARGE gene (603590) on chromosome 22q12. Mutation in the LARGE gene can also cause a severe congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A6; MDDGA6; 613154). | ||||||||||||
| Description | ||||||||||||
| MDDGB6 is an autosomal recessive congenital muscular dystrophy with mental retardation and structural brain abnormalities (Longman et al., 2003). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan, collectively known as 'dystroglycanopathies' (Mercuri et al., 2009). For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155). | ||||||||||||
| Clinical Features | ||||||||||||
| Longman et al. (2003) identified 1 patient with LARGE-related congenital muscular dystrophy among 36 patients with congenital muscular dystrophy and either mental retardation, structural brain changes, or abnormal alpha-dystroglycan immunolabeling. The affected 17-year-old girl presented with congenital muscular dystrophy, profound mental retardation, and white matter changes and subtle structural abnormalities on brain MRI. Her skeletal muscle biopsy showed reduced immunolabeling of alpha-dystroglycan. Immunoblotting with an antibody to a glycosylated epitope demonstrated a reduced molecular weight form of alpha-dystroglycan that retained some laminin-binding activity. The authors designated the form of CMD caused by mutation in the LARGE gene as 'MDC1D.' Clement et al. (2008) identified 1 patient with LARGE-related congenital muscular dystrophy among a large study of 27 patients with a dystroglycanopathy. The patient was a 14-year-old individual with mental retardation, nystagmus, abnormal electroretinogram, and increased serum creatine kinase. Brain MRI showed periventricular and temporal white matter changes, posterior concavity of the brainstem, hypoplastic pons, and frontoparietal pachygyria. Clarke et al. (2011) reported 2 sisters, born of consanguineous Lebanese parents, with congenital muscular dystrophy associated with mental retardation and brain anomalies. Both showed delayed psychomotor development in infancy, although 1 sister was more severely affected than the other. The more severely affected sister could climb stairs with difficulty at age 8 years, but could not run, whereas the less severely affected sister walked independently at age 2 years. The first sister had a myopathic face with an open mouth, mild tongue hypertrophy, muscle hypertrophy of the calves, thighs, and shoulder girdle, and predominantly lower limb weakness with positive Gowers sign and waddling gait. She had mild Achilles tendon contractures and mild myopia and strabismus, but no other eye anomalies. Brain MRI of both girls showed marked cerebellar atrophy, dilated ventricles, and white matter abnormalities; 1 had cerebellar cysts and pachygyria of the frontal lobes. Serum creatine kinase was increased, and there was reduced alpha-dystroglycan staining in patient fibroblasts. | ||||||||||||
| Molecular Genetics | ||||||||||||
| In a patient with LARGE-related congenital muscular dystrophy, Longman et al. (2003) identified compound heterozygosity for 2 mutations in the LARGE gene (603590.0001-603590.0002). In a patient with LARGE-related congenital muscular dystrophy, Clement et al. (2008) identified compound heterozygous mutations in the LARGE gene (603590.0001 and 603590.0007). In 2 sisters with LARGE-related congenital muscular dystrophy, Clarke et al. (2011) identified a homozygous insertion/deletion in the LARGE gene (603590.0008). Each unaffected parent was heterozygous for the mutant allele. | ||||||||||||
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