Alternative titles; symbols
ORPHA: 588, 899; DO: 0111236;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p34.1 | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 3 | 253280 | Autosomal recessive | 3 | POMGNT1 | 606822 |
A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A3; MDDGA3), previously designated Walker-Warburg syndrome (WWS) or muscle-eye-brain disease (MEB), is caused by homozygous or compound heterozygous mutation in the POMGNT1 gene (606822) on chromosome 1p34. POMGNT1 encodes protein O-mannose beta-1,2-N-acetylglucosaminyltransferase.
Mutation in the POMGNT1 gene can also cause a less severe congenital muscular dystrophy-dystroglycanopathy with impaired intellectual development (type B3; MDDGB3; 613151) and a limb-girdle muscular dystrophy-dystroglycanopathy (type C3; MDDGC3; 613157).
Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. It represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of DAG1 (128239), collectively known as 'dystroglycanopathies' (summary by Godfrey et al., 2007).
For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670).
Historically, the most severe forms of the dystroglycanopathies were described as Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB); these designations have been retained here when used in the literature.
Early Descriptions of Muscle-Eye-Brain Disease
In Finland, Raitta et al. (1978) observed an apparently new disorder comprising congenital muscular dystrophy with high serum creatine phosphokinase, severe congenital myopia, congenital glaucoma, pallor of the optic discs, retinal hypoplasia, mental retardation, hydrocephalus, abnormal EEG, and myoclonic jerks. Santavuori and Leisti (1980) identified 14 affected persons in 11 sibships in Finland. The characteristics are severe early-onset muscle weakness, mental retardation, and pathologic eye findings, usually consisting of congenital myopia. Santavuori et al. (1989) reported a large series of cases.
In 6 patients from 4 Dutch families, Leyten et al. (1992) found the combination of congenital muscular dystrophy and involvement of the central nervous system and eyes. The progression of the disorder was rapid in 5 of the 6 patients. The patients included 2 sisters and a brother and sister; in a sibship with 1 case, the parents were related.
Muscle-eye-brain disease has phenotypic similarities with the Walker-Warburg syndrome, another congenital muscular dystrophy caused by hypoglycosylation of alpha-dystroglycan (DAG1). Santavuori et al. (1990) argued for the distinctness of MEB disease and pointed to the consistent involvement of muscle and the longer survival in MEB disease. Dobyns et al. (1990) further discussed the possible relationship between the 2 conditions.
Cormand et al. (2001) reported 14 patients from 11 families who were classified as having MEB based on survival past 3 years of age, cobblestone complex on MRI with mild or moderate cerebellar/vermis hypoplasia, normal or thin corpus callosum, and characteristic eye abnormalities. Seven patients and 8 fetuses from 8 families were classified as having Walker-Warburg syndrome by a more severe presentation, including hydrocephalus, severe cobblestone complex, encephalocele, absent corpus callosum, and eye abnormalities.
POMGNT1-Related Muscle-Eye-Brain Disease
Vervoort et al. (2004) reported a non-Finnish family in which 2 sibs had POMGNT1-related MEB confirmed by genetic analysis. Both sibs had congenital hypotonia, early-onset glaucoma, and psychomotor retardation. Common features included hydrocephalus, hypotonia, glaucoma, high myopia, optic nerve hypoplasia, elevated serum creatine kinase, and abnormal facies characterized by everted lower lip, short nasal bridge, mild micrognathia, and midface hypoplasia. One sib appeared more severely affected; she required a ventriculoperitoneal shunt, developed epilepsy at 5 months of age, and showed more severe cognitive and motor delays compared to her affected brother.
Biancheri et al. (2006) reported an Italian patient who had brain and muscle abnormalities consistent with MEB disease but no ocular abnormalities. The authors identified homozygosity for a POMGNT1 mutation (606822.0008) in this patient. She had onset of symptoms at age 22 months; at age 30 years, she had severe mental retardation and seizures but was able to walk without muscle weakness. Brain MRI showed cortical dysplasia and hypoplasia of the brainstem. The authors commented on the unusual phenotype in this patient.
Clement et al. (2008) found that 6 of 7 unrelated patients with MEB due to POMGNT1 mutations had changes consistent with MEB on brain MRI, including ventricular dilatation, cerebellar hypoplasia/dysplasia, brainstem abnormalities, and pontine hypoplasia. Cortical abnormalities included polymicrogyria, pachygyria, and cobblestone cortex. All 6 patients also had cerebellar cysts, and 3 had a pontine cleft. The seventh patient had cerebellar cysts and pontine hypoplasia, but no signs of cortical dysplasia by age 16 years. The study was part of a larger study of 27 patients with various genetic forms of muscular dystrophy due to defective dystroglycan glycosylation.
POMGNT1-Related Walker-Warburg Syndrome
Godfrey et al. (2007) identified 1 patient with POMGNT1-related WWS among a larger study of 92 probands with muscular dystrophy and evidence of a dystroglycanopathy. Although clinical details were limited, the patient had neonatal onset and low IQ, never achieved sitting, and exhibited increased serum creatine kinase. Brain MRI showed cerebellar hypoplasia, cerebellar cysts, white matter abnormalities, hydrocephalus, and lissencephaly. As part of the larger study, Godfrey et al. (2007) defined WWS as prenatal or neonatal absence of motor development and severe structural brain abnormalities, including complete agyria or severe lissencephaly, marked hydrocephalus, severe cerebellar involvement, and complete or partial absence of the corpus callosum. Common eye abnormalities included congenital cataracts, microphthalmia, and buphthalmos. Death usually occurred before 1 year of age.
Mercuri et al. (2009) identified 1 patient with POMGNT1-related WWS among a larger study of 81 Italian patients with muscular dystrophy and evidence of a dystroglycanopathy. Although clinical details were limited, the patient had severely impaired motor development, microcephaly, mental retardation, 25-fold increased serum creatine kinase, seizures, myopia, and retinal dysplasia. The patient could sit with support. Brain MRI findings were consistent with WWS, as defined by severe lissencephaly, hydrocephalus, and cerebellar and corpus callosum involvement.
The transmission pattern of MDDGA3 in the families reported by Yoshida et al. (2001) was consistent with autosomal recessive inheritance.
Cormand et al. (1999) reported assignment of the MEB gene to chromosome 1p34-p32 by linkage analysis and homozygosity mapping in 8 families with 12 affected individuals. Seven of the families were Finnish and one Turkish. After a genomewide search for linkage in 4 affected sib pairs pinpointed the assignment to 1p, the MEB locus was more precisely assigned to a 9-cM interval flanked by markers D1S200 proximally and D1S211 distally. Multipoint linkage analysis gave a maximum lod score of 6.17 at D1S2677.
Yoshida et al. (2001) demonstrated that loss-of-function mutations in the POMGNT1 gene (606822.0001-606822.0006) are responsible for MEB.
In 2 sibs with MEB disease, Vervoort et al. (2004) identified compound heterozygosity for 2 mutations in the POMGNT1 gene (606822.0007-606822.0008).
Taniguchi et al. (2003) identified 7 disease-causing mutations in the POMGNT1 gene among 6 non-Finnish Caucasian, Japanese, and Korean patients with suspected MEB, severe FCMD (MDDGA4; 253800), or Walker-Warburg syndrome. Mutations were dispersed throughout the entire POMGNT1 gene. A slight correlation was observed between the location of the mutation and clinical severity in the brain: patients with mutations near the 5-prime terminus of the POMGNT1 coding region showed relatively severe brain symptoms such as hydrocephalus, whereas patients with mutations near the 3-prime terminus had milder phenotypes. The authors suggested that MEB may exist in populations outside of Finland, and that the clinical spectrum of MEB may be broader than recognized theretofore.
In 1 patient with WWS, Godfrey et al. (2007) identified a homozygous truncating mutation in the POMGNT1 gene (W475X; 606822.0012).
In 1 patient with WWS, Mercuri et al. (2009) identified a homozygous truncating mutation in the POMGNT1 gene (R63X; 606822.0009). The same mutation had been reported in a patient with MEB disease (Taniguchi et al., 2003).
Diesen et al. (2004) identified a splice site mutation in intron 17 of the POMGNT1 gene (606822.0002) as a founder mutation in the Finnish population; it was present in 18 of 19 Finnish MEB patients. Phenotypic variability was observed among the 18 homozygous Finnish patients, suggesting that other factors contribute to the pathogenesis of the disorder.
Michele et al. (2002) demonstrated in both MEB disease and FCMD patients that alpha-dystroglycan is expressed at the muscle membrane, but similar hypoglycosylation in the diseases directly abolishes binding activity of dystroglycan for the ligands laminin (see 150240), neurexin (see 600565), and agrin (103320). Michele et al. (2002) showed that this posttranslational biochemical and functional disruption of alpha-dystroglycan is recapitulated in the muscle and central nervous system of mutant myodystrophy (myd) mice, which have a mutation in the LARGE gene (603590). Michele et al. (2002) demonstrated that myd mice have abnormal neuronal migration in the cerebral cortex, cerebellum, and hippocampus, and show disruption of the basal lamina. In addition, myd mice reveal that dystroglycan targets proteins to functional sites in brain through its interactions with extracellular matrix proteins. Michele et al. (2002) suggested that at least 3 mammalian genes function within a convergent posttranslational processing pathway during the biosynthesis of dystroglycan and that abnormal dystroglycan-ligand interactions underlie the pathogenic mechanism of muscular dystrophy with brain abnormalities.
Biancheri, R., Bertini, E., Falace, A., Pedemonte, M., Rossi, A., D'Amico, A., Scapolan, S., Bergamino, L., Petrini, S., Cassandrini, D., Broda, P., Manfredi, M., Zara, F., Santorelli, F. M., Minetti, C., Bruno, C. POMGnT1 mutations in congenital muscular dystrophy: genotype-phenotype correlation and expanded clinical spectrum. Arch. Neurol. 63: 1491-1495, 2006. [PubMed: 17030669] [Full Text: https://doi.org/10.1001/archneur.63.10.1491]
Clement, E., Mercuri, E., Godfrey, C., Smith, J., Robb, S., Kinali, M., Straub, V., Bushby, K., Manzur, A., Talim, B., Cowan, F., Quinlivan, R., and 10 others. Brain involvement in muscular dystrophies with defective dystroglycan glycosylation. Ann. Neurol. 64: 573-582, 2008. [PubMed: 19067344] [Full Text: https://doi.org/10.1002/ana.21482]
Cormand, B., Avela, K., Pihko, H., Santavuori, P., Talim, B., Topaloglu, H., de la Chapelle, A., Lehesjoki, A.-E. Assignment of the muscle-eye-brain disease gene to 1p32-p34 by linkage analysis and homozygosity mapping. Am. J. Hum. Genet. 64: 126-135, 1999. [PubMed: 9915951] [Full Text: https://doi.org/10.1086/302206]
Cormand, B., Pihko, H., Bayes, M., Valanne, L., Santavuori, P., Talim, B., Gershoni-Baruch, R., Ahmad, A., van Bokhoven, H., Brunner, H. G., Voit, T., Topaloglu, H., Dobyns, W. B., Lehesjoki, A.-E. Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease. Neurology 56: 1059-1069, 2001. [PubMed: 11320179] [Full Text: https://doi.org/10.1212/wnl.56.8.1059]
Diesen, C., Saarinen, A., Pihko, H., Rosenlew, C., Cormand, B., Dobyns, W. B., Dieguez, J., Valanne, L., Joensuu, T., Lehesjoki, A.-E. POMGnT1 mutation and phenotypic spectrum in muscle-eye-brain disease. J. Med. Genet. 41: e115, 2004. Note: Electronic Article. [PubMed: 15466003] [Full Text: https://doi.org/10.1136/jmg.2004.020701]
Dobyns, W. B., Pagon, R. A., Curry, C. J. R., Greenberg, F. Response to Santavuori et al. regarding Walker-Warburg syndrome and muscle-eye-brain disease. (Letter) Am. J. Med. Genet. 36: 373-374, 1990.
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]
Leyten, Q. H., Gabreels, F. J. M., Renier, W. O., Renkawek, K., ter Laak, H. J., Mullaart, R. A. Congenital muscular dystrophy with eye and brain malformations in six Dutch patients. Neuropediatrics 23: 316-320, 1992. [PubMed: 1491751] [Full Text: https://doi.org/10.1055/s-2008-1071365]
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. 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]
Michele, D. E., Barresi, R., Kanagawa, M., Saito, F., Cohn, R. D., Satz, J. S., Dollar, J., Nishino, I., Kelley, R. I., Somer, H., Straub, V., Mathews, K. D., Moore, S. A., Campbell, K. P. Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 418: 417-422, 2002. [PubMed: 12140558] [Full Text: https://doi.org/10.1038/nature00837]
Raitta, C., Santavuori, P., Lamminen, M., Leisti, J. Ophthalmological findings in a new syndrome with muscle, eye and brain involvement. Acta Ophthal. 56: 465-472, 1978. [PubMed: 581135] [Full Text: https://doi.org/10.1111/j.1755-3768.1978.tb05700.x]
Santavuori, P., Leisti, J. Muscle, eye and brain disease (MEB). In: Eriksson, A. W.; Forsius, H. R.; Nevanlinna, H. R.; Workman, P. L.; Norio, R. K. (eds.): Population Structure and Genetic Disorders. New York: Academic Press (pub.) 1980. Pp. 647-651.
Santavuori, P., Pihko, H., Sainio, K., Lappi, M., Somer, H., Haltia, M., Raitta, C., Ketonen, L., Leisti, J. Muscle-eye-brain disease and Walker-Warburg syndrome. (Letter) Am. J. Med. Genet. 36: 371-372, 1990. [PubMed: 2363444] [Full Text: https://doi.org/10.1002/ajmg.1320360334]
Santavuori, P., Somer, H., Sainio, K., Rapola, J., Kruus, S., Nikitin, T., Ketonen, L., Leisti, J. Muscle-eye-brain disease (MEB). Brain Dev. 11: 147-153, 1989. [PubMed: 2751061] [Full Text: https://doi.org/10.1016/s0387-7604(89)80088-9]
Taniguchi, K., Kobayashi, K., Saito, K., Yamanouchi, H., Ohnuma, A., Hayashi, Y. K., Manya, H., Jin, D. K., Lee, M., Parano, E., Falsaperla, R., Pavone, P., and 9 others. Worldwide distribution and broader clinical spectrum of muscle-eye-brain disease. Hum. Molec. Genet. 12: 527-534, 2003. [PubMed: 12588800] [Full Text: https://doi.org/10.1093/hmg/ddg043]
Vervoort, V. S., Holden, K. R., Ukadike, K. C., Collins, J. S., Saul, R. A., Srivastava, A. K. POMGnT1 gene alterations in a family with neurological abnormalities. Ann. Neurol. 56: 143-148, 2004. [PubMed: 15236414] [Full Text: https://doi.org/10.1002/ana.20172]
Yoshida, A., Kobayashi, K., Manya, H., Taniguchi, K., Kano, H., Mizuno, M., Inazu, T., Mitsuhashi, H., Takahashi, S., Takeuchi, M., Herrmann, R., Straub, V., Talim, B., Voit, T., Topaloglu, H., Toda, T., Endo, T. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev. Cell 1: 717-724, 2001. [PubMed: 11709191] [Full Text: https://doi.org/10.1016/s1534-5807(01)00070-3]