Congenital muscular alpha-dystroglycanopathy and Walker-Warburg syndrome

Congenital muscular dystrophies are a heterogeneous group of inherited muscle diseases or myopathies that affect skeletal muscle development and function from birth or early childhood. In general, these diseases are caused by mutations in genes encoding proteins important for muscle structure and function.

The underlying pathogenic mechanism is common and is related to abnormal glycosylation of the α-dystroglycans. Alpha-dystroglycans are part of the junctions between muscle cells (called muscle fibers) and the extracellular matrix (the tissue between the muscle fibers). When glycosylation (addition of sugars) during the formation of alpha-dystroglycans is deficient, the bond between the muscle fibers and the surrounding matrix is lost and the muscle fiber degenerates, leading to an inflammatory process and the development of myopathy. This group of diseases, which affect the production of dystroglycans, are also known as dystroglycanopathies.

Walker-Warburg syndrome (WWS) is the most severe classic manifestation of dystroglycanopathy, but patients with less deleterious mutations may have less severe forms.

In WWS, symptoms are present at birth and include hypotonia, muscle weakness, developmental delay, mental retardation and, occasionally, seizures. Ocular abnormalities may be present and severe brain alterations such as lissencephaly, hydrocephalus, cerebellar hypoplasia and white matter myelination deficits occur. Patients usually do not survive beyond 3 years of age.

Treatment of patients with WWS focuses on relieving symptoms. If seizures occur, anticonvulsants are used. In some cases, neurosurgery is performed. Ocular involvement should be evaluated. Occasionally, supplemental nasogastric or gavage feeding is necessary.