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The incidence is estimated at 1-2/100,000 live births. Walker-Warburg Syndrome (WWS) has a worldwide distribution.

Patients present with global developmental delay, intellectual disability, generalized severe hypotonia, muscle weakness, seizures, and various eye defects which include microphthalmia, microcornea, lens defects, cataract, shallow anterior chamber, atrophy of the optic nerve, coloboma, glaucoma or buphthalmos. Brain MRI shows type II cobblestone lissencephaly in all cases, and may also show hydrocephalus, encephalocele, severe brainstem, and cerebellar hypoplasia with possible Dandy-Walker malformation. The corpus callosum is absent in some patients. White matter abnormalities can also be observed. Other urogenital or facial dysmorphic features can be found in rare patients.

This disease caused by abnormal O-glycosylation of alpha-dystroglycan leading to brain abnormalities and congenital muscular dystrophy. At least 14 genes have been implicated in the etiology of WWS, and others are yet unknown. The most common mutations are found in Protein O-Mannosyltransferase 1 and 2 (POMT1 and POMT) genes, FKTN, and FKRP genes. LARGE and POMGNT1 genes from the alpha-dystroglycan glycosylation pathway were also linked to this disease. A mutation in the COL4A1 gene not directly related to posttranslational modification of dystroglycan has also been identified in some WWS patients without associated muscle involvement.

Diagnosis is based on ultrasonography and fetal MRI for ocular and brain abnormalities. Laboratory investigations usually show elevated creatine kinase and myopathic/dystrophic muscle pathology with altered alpha-dystroglycan expression.

Differential diagnoses include other types of congenital muscular dystrophies and myopathies with type II lissencephaly. Trisomy 13, 18 and many congenital syndromes with malformations of the brain also have similar clinical manifestations. Some in utero infections can also be associated with hydrocephaly, intrauterine growth restriction, and cataract.

Antenatal diagnosis is possible in families with known mutations. Prenatal ultrasound after 22-25 weeks of gestational age (WGA) and fetal MRI at 30 WGA may be helpful for diagnosis in families where the molecular defect is unknown.

Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.

No specific treatment is available. Management is only supportive and preventive. Surgery is required in some patients for the treatment of hydrocephalus or encephalocele.

WWS is the most severe form of congenital muscular dystrophy. It is generally lethal in the first few months of life with most children dying before the age of three years.