Muscular Dystrophy-Dystroglycanopathy (Congenital With Mental Retardation), Type B, 1

A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with mental retardation (type B1; MDDGB1) is caused by homozygous or compound heterozygous mutation in the POMT1 gene (607423), which encodes protein O-mannosyltransferase, on chromosome 9q34.

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 less severe limb-girdle muscular dystrophy-dystroglycanopathy (type C1; MDDGC1; 609308).

Description

Congenital muscular dystrophies resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239) are characterized by early onset of muscle weakness, usually before ambulation is achieved; mental retardation and mild brain anomalies are variable (Balci et al., 2005; Godfrey et al., 2007). Congenital muscular dystrophy-dystroglycanopathies with or without mental retardation (type B) represent the intermediate range of the spectrum of dystroglycanopathies. They are less severe than 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 more severe than limb-girdle muscular dystrophy-dystroglycanopathy (type C; see MDDGC1, 609308).

Genetic Heterogeneity of Congenital Muscular Dystrophy-Dystroglycanopathy with or without Mental Retardation (Type B)

Congenital muscular dystrophy with mental retardation due to defective glycosylation of DAG1 is genetically heterogeneous. See also MDDGB2 (613156), caused by mutation in the POMT2 gene (607439); MDDGB3 (613151), caused by mutation in the POMGNT1 gene (606822); MDDGB4 (613152), caused by mutation in the FKTN gene (607440); MDDGB5 (616612), caused by mutation in the FKRP gene (606596); MDDGB6 (608840), caused by mutation in the LARGE gene (603590); and MDDGB14 (615351), caused by mutation in the GMPPB gene (615320).

Clinical Features

Villanova et al. (2000) reported 4 Italian patients from 3 families affected with an autosomal recessive form of congenital muscular dystrophy. One of the patients was previously reported by De Stefano et al. (1996). The phenotype was similar in all cases, and was characterized by hypotonia at birth, joint contractures associated with severe psychomotor retardation, inability to walk, striking enlargement of the calf and quadriceps muscles, absent speech, and mental retardation. Cranial MRI showed enlargement of the cisterna magna and cerebellar hypoplasia, without evidence of neuronal migration defects. Muscle biopsy showed changes consistent with muscular dystrophy and also showed a mild to moderate reduction of laminin alpha-2 (LAMA2; 156225) and overexpression of laminin alpha-5 (LAMA5; 601033). Linkage analysis in the family with 2 affected members excluded linkage to LAMA2 on chromosome 6q22, MEB (MDDGA3; 253280) on 1p34, and FCMD (MDDGA4; 253800) on 9q31. Villanova et al. (2000) noted that 2 sibs with partial merosin-deficient congenital muscular dystrophy from a consanguineous Turkish family reported by Topaloglu et al. (1998) may have had the same disorder.

Van Reeuwijk et al. (2006) reviewed 3 patients reported by Villanova et al. (2000) and reported 2 additional unrelated patients with POMT1-related congenital muscular dystrophy. All 5 patients had a milder form of Walker-Warburg syndrome, with less severe structural brain abnormalities and absence of severe eye abnormalities, except for myopia in some cases. Van Reeuwijk et al. (2006) suggested that 1 or both POMT1 transcripts in these patients conferred residual enzyme activity. The findings extended the phenotypic spectrum associated with POMT1 mutations.

D'Amico et al. (2006) reported 3 unrelated children with severe motor impairment, leg hypertrophy, microcephaly, and mental retardation. Onset occurred at birth, 2 months, and 6 months, respectively. As infants, all had hypotonia and grossly delayed motor milestones. Other features included facial weakness with tendency to keep the mouth open, mild macroglossia, lower limb stiffness and hypertrophy, contractures, and increased serum creatine kinase. Skeletal muscle biopsies showed dystrophic changes and defects of DAG1. None had brain or ocular malformations, and all had normal brain MRI. Bello et al. (2012) reported follow-up of 1 of the patients reported by D'Amico et al. (2006), who carried compound heterozygous mutations in the POMT1 gene (607423.0013 and 607423.0014). He had hypotonia, delayed motor development without the ability to walk, severe mental retardation, and autistic features. Other features included diffuse muscle wasting, scoliosis, and microcephaly. Muscle biopsy showed a severe reduction of DAG glycosylation. At age 17 years, he developed acute respiratory distress, and cardiac evaluation showed moderate left ventricular dysfunction consistent with cardiomyopathy. Bello et al. (2012) reported 2 additional patients with limb-girdle muscular dystrophy (MDDGC1; 609308) and POMT1 mutations who also developed cardiomyopathy, suggesting that cardiac involvement can be added to the phenotypic spectrum of POMT1 mutations.

Mercuri et al. (2009) reported 10 patients with POMT1-related congenital muscular dystrophy. Nine patients had microcephaly, mental retardation, increased serum creatine kinase, and decreased or absent glycosylated alpha-dystroglycan. Most only achieved sitting. Six patients had normal brain imaging, whereas the other 4 had cerebellar dysplasia, periventricular white matter changes, and thin corpus callosum. One had retinal dystrophy and another had myopia. The tenth patient had only congenital cataracts and no mental retardation; the authors noted that this was the first patient ever reported with POMT1 mutations and normal cognition.

Pathogenesis

In cultured muscle cells from 1 of the affected patients reported by Villanova et al. (2000), Lattanzi et al. (2000) found that the differentiation rate and stability of the patient's cells were comparable to normal control cells. However, although the patient's myoblasts showed the expected 80-kD merosin subunit, the mature myotube culture showed a shifted 60-kD band, suggesting that damage in the disorder occurs at the extracellular matrix, which may alter muscle cell attachment to the basal lamina. Matrix metalloproteinase (MMP) zymography showed increased gelatinolytic activity with an increased amount of MMP1 (120353) in the patient's cell culture, suggesting altered regulation of a metabolic pathway involved in muscle cell involvement with the basal lamina.

Molecular Genetics

In 3 patients from 2 families reported by Villanova et al. (2000), van Reeuwijk et al. (2006) identified compound heterozygous mutations in the POMT1 gene (607423.0006-607423.0009).

In 3 unrelated patients with a severe form of congenital muscular dystrophy, D'Amico et al. (2006) identified compound heterozygous mutations in the POMT1 gene (607423.0010-607423.0014). None had structural brain abnormalities.