Congenital muscular alpha-dystroglycanopathy and Walker-Warburg syndrome

The systroglycanopathies are a group of clinically heterogeneous disorders associated with central nervous system disorders and, less frequently, with ocular pathology. They are caused by 8 genes encoding for glycosyltransferase enzymes or other accessory proteins.

Dystroglycan diseases are associated with mutations in different genes that cause a defective post-translational modification of alpha-dystroglycan. Both are genetically and phenotypically heterogeneous. In the current nomenclature, these phenotypes are known as the "MDDG" series and include mild to severe forms of congenital muscular dystrophy and mild forms of muscular dystrophy of the shoulder girdle.

Dystroglicanopathies are characterized by a variety of brain development abnormalities, which can be identified on magnetic resonance imaging, and include lissencephaly, cerebellar cysts, pontine hypoplasia and posterior concavity of the brainstem.

Congenital muscular dystrophy-dystroglicanopathy with cerebral and ocular abnormalities (type A or MDDGA) includes the most serious phenotypes, known as Walker-Warburg syndrome and Fukuyama congenital muscular dystrophy, and a milder phenotype called muscle-eye-brain disease.

Congenital muscular dystrophy-dystroglicanopathy with or without mental retardation (type B or MDDGB) is also genetically heterogeneous. Type B phenotypes are less severe than type A but more severe than type C (muscular dystrophy-dystroflucanopathy of the shoulder girdle).

Within the types A or MDDGA we can distinguish:

1- Fukuyama congenital muscular dystrophy: one of the most common autosomal recessive disorders in Japan (0.7 to 1.2 per 10,000 births). It is characterized by hypotonia, generalized weakness, severe developmental delay, seizures, microcephaly and elevated CK levels.

The electroencephalogram is abnormal in this disorder and shows epileptiform activity. Cortical dysgenesis is detected by computed tomography or brain magnetic resonance. The specific lesions are pachygyria and polymicrogyria in the temporal and occipital regions. Transient hyperintensities of T2 appear in the white matter and hypoplasia of the bump and cerebellar cysts can occur. Ocular involvement is limited to simple myopia without structural changes.

The locus for the Fukuyama congenital muscular dystrophy gene (MDDGA4) (FKTN gene) is located on chromosome 9q31-33. The respective protein, fukutin, is secreted out of the cell and can be a component of the extracellular membrane that strengthens muscle membranes. Pathological studies of the brain have suggested that fukutin is a component of the basement membrane. FKTN mutations have also been associated with severe dilated cardiomyopathy together with a mild form of muscular dystrophy of the waist and extremities. In addition, mutations of the FKTN gene have been identified in children with a LGMD phenotype and normal intelligence and brain structure called muscular dystrophy-dystroglycan disease (girdle-member) type C4 (MDDGC4).

2- Walker-Warburg syndrome: type of CMD associated with ocular dysplasia, hydrocephalus and brain malformations. Eye abnormalities include cataracts, optic nerve hypoplasia, corneal opacity and retinal dysplasia or detachment. The serum CK concentration is mild to moderately elevated in this disorder and the electrodiagnostic findings are myopathic. Brain MRI shows hypodense white matter, cerebellum and hypoplastic bulge, ventricular dilation (with or without hydrocephalus) and abnormal cortical development known as type II lissencephaly. Other malformations include the Dandy-Walker cyst, sometimes associated with posterior encephaloceles. The median survival is only four months.

The Walker-Warburg phenotype is associated with mutations in the POMT1, POMT2, FKTN, FKRP, POMGNT1, LARGE, ISPD, GTDC2 and DAG1 genes. These mutations cause a defective glycosylation of the alpha-dystroglycan complex. In current terminology, WWS associated with POMT1 mutations is designated as muscular dystroflucanocanopathy (congenital with brain and eye abnormalities) type A1 (MDDGA1). Other mutations in the POMT1 gene are related to a milder phenotype of congenital muscular dystrophy with microcephaly and mental retardation, but without the ocular manifestations or structural cerebral malformations of WWS. In addition, POMT1 and POMT2 genetic mutations have been identified in children with subtypes of autosomal recessive muscular dystrophy of the waist and extremities (MDDGC1 and MDDGC2).

3- Muscle-eye-brain disease (MEB): it has a milder phenotype than WWS. The disorder is especially common in Finland.

Patients with MEB usually have hypotonia, severe progressive myopia since childhood and developmental delay. Pale retina, low or flat electroretinogram and visual failure related to retinal degeneration develop with advanced age. Seizures are common and cognitive impairment is often severe. At the age of five approximately, the motor ability of patients decreases and they start to suffer from contractures and spsticity.

Laboratory findings in MEB disease include an elevated serum CK level. An electromyography can show myopathic signs and the electroencephalogram is always abnormal. MRI shows lissencephaly, although it is less severe than in WWS; The brainstem in                meb disease is characteristically flat. Ventriculomegaly and hypodensities of the white matter can also be observed. Visual evoked potentials are delayed and giant (> 50 µv) in most patients.

Muscle biopsy usually shows dystrophic changes, although these may be minimal. Immunohistochemistry shows normal dystrophin and other dystrophin-associated proteins, except for deficient alpha-dystroglycan.

The clinical phenotype of MEB can be caused by genetic mutations of POMGNT1, FKRP, POMT2, POMT1, FKTN and LARGE. In current terminology, POMGNT1-related muscle-eye-brain disease is designated as muscular dystrophilic-dystroflucanopathy (congenital with brain and eye abnormalities) type A3 (MDDGA3).

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