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.

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.

Symptoms

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.

Disease management

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.

Genes analyzed

FKRP FKTN POMGNT1 POMT1 POMT2

Bibliography

Beltran-Valero de Bernabé D, Voit T, Longman C, et al. Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome. J Med Genet. 2004 May;41(5):e61.

Hu P, Yuan L, Deng H. Molecular genetics of the POMT1-related muscular dystrophy-dystroglycanopathies. Mutat Res Rev Mutat Res. 2018 Oct-Dec;778:45-50.

Mercuri E, Messina S, Bruno C, et al. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology. 2009 May 26;72(21):1802-9. doi: 10.1212/01.wnl.0000346518.68110.60. Epub 2009 Mar 18. Erratum in: Neurology. 2019 Aug 20;93(8):371.

Erratum in: Neurology. 2019 Aug 20;93(8):371.

Østergaard ST, Johnson K, Stojkovic T, et al. Limb girdle muscular dystrophy due to mutations in POMT2. J Neurol Neurosurg Psychiatry. 2018 May;89(5):506-512.

Wallace SE, Conta JH, Winder TL, et al. A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype associated with POMT1 nonsense mutations. Neuromuscul Disord. 2014 Apr;24(4):312-20.

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