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Walker-Warburg syndrome

Synonym(s) HARD syndrome
Hydrocephalus-agyria-retinal dysplasia syndrome
Prevalence 1-9 / 1 000 000
Inheritance Autosomal recessive
Age of onset Infancy
  • Q04.3
  • D058494
MedDRA -


Disease definition

Walker-Warburg Syndrome (WWS) is a rare form of congenital muscular dystrophy associated with brain and eye abnormalities.


The prevalence is estimated at 1/60,500. WWS has a worldwide distribution.

Clinical description

Patients present at birth with generalized severe hypotonia, muscle weakness, absent or very poor psychomotor development, eye involvement and seizures. Brain MRI shows type II cobblestone lissencephaly, hydrocephalus (see these terms), severe brainstem and cerebellar hypoplasia (Dandy-Walker malformation is possible, see this term). White matter abnormalities are also observed.


This disease is due to abnormal O-glycosylation of alpha-dystroglycan, which leads, in addition to the brain abnormalities, to congenital muscular dystrophy. WWS represents the most severe phenotype of the so called dystroglycanopathies (see this term). Several genes have been implicated in the etiology of WWS, and others are as yet unknown. Most mutations were found in the Protein O-Mannosyltransferase 1 and 2 (POMT1 and POMT) genes. Other genes in the alpha-dystroglycan glycosylation pathway were found mutated in WWS cases (FKTN, LARGE, FKRP and POMGNT1). A mutation in the COL4A1 gene not directly related to posttranslational modification of dystroglycan has been identified in WWS patients.

Diagnostic methods

Laboratory investigations usually show elevated creatine kinase, myopathic/dystrophic muscle pathology with altered alpha-dystroglycan expression.

Differential diagnosis

Differential diagnoses include other types of congenital muscular dystrophies and myopathies (see these terms).

Antenatal diagnosis

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.

Genetic counseling

Transmission is autosomal recessive.

Management and treatment

No specific treatment is available. Management is only supportive and preventive.


WWS is the most severe form of congenital muscular dystrophy with most children dying before the age of three years.

Expert reviewer(s)

  • Dr Harry SCHACHTER
  • Dr Jiri VAJSAR

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