Alternative titles; symbols
ORPHA: 370959, 370968; DO: 0112380;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q24.3 | Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 2 | 613156 | Autosomal recessive | 3 | POMT2 | 607439 |
A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with impaired intellectual development (type B2, MDDGB2) is caused by homozygous or compound heterozygous mutation in the POMT2 gene (607439) on chromosome 14q24.3. POMT2 encodes an integral membrane protein of the endoplasmic reticulum (ER) that shares significant sequence similarity with a family of protein O-mannosyltransferases of S. cerevisiae.
Mutation in the POMT2 gene can also cause a congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A2, MDDGA2; 613150) and a limb-girdle muscular dystrophy-dystroglycanopathy (type C2, MDDGC2; 613158).
MDDGB2 is an autosomal recessive congenital muscular dystrophy associated with impaired intellectual development and mild structural brain abnormalities (Yanagisawa et al., 2007). It is part of a group of similar disorders, collectively known as 'dystroglycanopathies,' resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239) (Godfrey et al., 2007).
For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).
Yanagisawa et al. (2007) reported 4 patients with POMT2-related congenital muscular dystrophy. At birth, each presented with hypotonia, microcephaly, and delayed psychomotor development associated with severe mental retardation. They had severe diffuse muscle weakness in the face, trunk, and girdle muscles, tongue and calf muscle hypertrophy, diffuse joint contractures, and decreased or absent deep tendon reflexes. Three had a severe spinal deformity with marked fixed hyperextension of cervical, dorsal, and lumbar regions. One patient died of respiratory failure at age 24 years; the other 3 were alive at ages 6, 14, and 27 years, respectively. There was also some phenotypic variability: only 1 patient gained the ability to sit unaided at age 1 year. The patient was able to walk without support at age 2.5 years, but lost ambulation at age 10 years. Although all patients could understand simple orders, only 1 could speak about 20 words. Two patients had bilateral hip dislocation. Only 1 had significant ophthalmologic findings with pigmentary retinopathy, and 1 patient had cardiac involvement with nonprogressive left ventricular hypertrophy. Brain MRI showed moderate or mild cortical atrophy in all patients, with variable features of ventriculomegaly, hypoplasia of the corpus callosum, and periventricular white matter abnormalities. All had moderate or mild cerebellar vermis hypoplasia without brainstem involvement. Serum creatine kinase levels were markedly elevated, and electromyogram (EMG) showed myopathic changes. Muscle biopsies showed dystrophic changes and severely decreased glycosylation of alpha-dystroglycan.
Godfrey et al. (2007) reported 2 sibs with POMT2-related congenital muscular dystrophy and low IQ. Although clinical details were limited, both patients had infantile onset of symptoms as well as increased serum creatine kinase. One achieved walking, the other sitting. One had contractures, muscle hypertrophy, and microcephaly. The other had hypoplastic cerebellum, micropenis, and cryptorchidism.
Mercuri et al. (2009) reported 6 Italian patients with POMT2-related congenital muscular dystrophy. Three had cerebellar hypoplasia, including 1 with flat pons and ventricular dilatation and another with flat pons. The other 3 patients had normal brain MRI, although 1 had mild white matter changes. All had increased serum creatine kinase, decreased alpha-dystroglycan, and mental retardation; most had microcephaly. Eye findings were limited to myopia and strabismus.
Yanagisawa et al. (2009) reported a 4-year-old French boy with MDDGB2. He had mental retardation, microcephaly, increased serum creatine kinase, and congenital hypotonia, but could sit unsupported. He had no cerebral dysplasia, brainstem, cerebellar, or ocular abnormalities, but imaging showed some white matter abnormalities in the parietal-occipital region. Genetic analysis identified compound heterozygous mutations in the POMT2 gene (607439.0004 and 607439.0017).
Martinez et al. (2014) reported 3 brothers, aged 21, 19, and 17 years, with MDDGB2 due to a homozygous missense mutation in the POMT2 gene (Y666C; 607439.0004). In addition to the classic features of muscular dystrophy, intellectual impairment, and microcephaly, all 3 patients had distinct and progressive cardiac anomalies, including significant dilatation of the aortic root, depressed left ventricular systolic function, and/or left ventricular wall motion abnormalities. Martinez et al. (2014) suggested that patients with this disorder have longitudinal cardiac surveillance imaging.
In 4 unrelated patients with congenital muscular dystrophy and severe mental retardation, Yanagisawa et al. (2007) identified homozygous or compound heterozygous mutations in the POMT2 gene (607439.0004-607439.0006).
In 2 sibs with congenital muscular dystrophy and low IQ, Godfrey et al. (2007) identified a homozygous mutation in the POMT2 gene (Y666C; 607439.0004).
In a large study of 81 Italian patients with a dystroglycanopathy, Mercuri et al. (2009) found that 6 with congenital muscular dystrophy had mutations in the POMT2 gene (see, e.g., 607439.0014-607439.0016).
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]
Martinez, H. R., Craigen, W. J., Ummat, M., Adesina, A. M., Lotze, T. E., Jefferies, J. L. Novel cardiovascular findings in association with a POMT2 mutation: three siblings with alpha-dystroglycanopathy. Europ. J. Hum. Genet. 22: 486-491, 2014. [PubMed: 24002165] [Full Text: https://doi.org/10.1038/ejhg.2013.165]
Mercuri, E., Messina, S., Bruno, C., Mora, M., Pegoraro, E., Comi, G. P., D'Amico, A., Aiello, C., Biancheri, R., Berardinelli, A., Boffi, P., Cassandrini, D., and 23 others. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology 72: 1802-1809, 2009. Note: Erratum: Neurology 93: 371 only, 2019. [PubMed: 19299310] [Full Text: https://doi.org/10.1212/01.wnl.0000346518.68110.60]
Yanagisawa, A., Bouchet, C., Quijano-Roy, S., Vuillaumier-Barrot, S., Clarke, N., Odent, S., Rodriguez, D., Romero, N. B., Osawa, M., Endo, T., Lia, T. A., Seta, N., Guicheney, P. POMT2 intragenic deletions and splicing abnormalities causing congenital muscular dystrophy with mental retardation. Europ. J. Med. Genet. 52: 201-206, 2009. [PubMed: 19138766] [Full Text: https://doi.org/10.1016/j.ejmg.2008.12.004]
Yanagisawa, A., Bouchet, C., Van den Bergh, P. Y. K., Cuisset, J.-M., Viollet, L., Leturcq, F., Romero, N. B., Quijano-Roy, S., Fardeau, M., Seta, N., Guicheney, P. New POMT2 mutations causing congenital muscular dystrophy: identification of a founder mutation. Neurology 69: 1254-1260, 2007. [PubMed: 17634419] [Full Text: https://doi.org/10.1212/01.wnl.0000268489.60809.c4]