Walker-Warburg syndrome (WWS) is an inherited disorder that affects the development of muscles, eyes, and the brain. It is the most severe form of congenital muscular dystrophy, with most affected individuals not surviving past age 3.

While the incidence of WWS is unknown, based on an Italian study, it is estimated to affect 1.2 in 100,000 newborns.

Symptoms

Babies with WWS are born with muscular dystrophy and have a weak muscle tone (hypotonia). Skeletal muscle weakness and atrophy get worse over time.

The condition also causes brain abnormalities. Instead of the folds and grooves usually seen on its surface, the brain has a cobblestone-like appearance. This phenomenon is referred to as cobblestone lissencephaly (smooth brain). Another abnormality is a build-up of fluid in the brain, known as hydrocephalus. Malformations in certain parts of the brain, such as the cerebellum and the brainstem, also can occur. These brain characteristics cause delayed development and intellectual disability. Affected babies also may experience seizures.

Eye abnormalities that occur in WWS are very individual-specific. Affected babies may have unusually small eyeballs (microphthalmia) or enlarged eyeballs — caused by increased pressure in the eyes. Other issues include clouding of the eye lenses (cataracts), or problems with the nerve that transmits visual information from the eyes to the brain (the optic nerve). All of these eye problems cause visual impairment.

Causes

Mutations in at least 14 different genes have been linked to WWS. The most common mutations occur in the POMT1, POMT2, CRPPA, FKTN, FKRP, and LARGE1 genes.

Researchers keep identifying new gene mutations that cause the disorder. Thus, it is likely that not all the genes that, when mutated, can cause WWS are yet known.

All of the mutated genes in people with WWS are involved in the modification of the so-called α-dystroglycan protein. The proteins produced from these genes help attach sugar molecules to α-dystroglycan, a process that is known as glycosylation. This modification is essential for α-dystroglycan to function.

α-dystroglycan protects and stabilizes muscle fibers. Without the α-dystroglycan-mediated protection, muscle damage caused by muscle contractions accumulates over time. That leads to progressive weakness of muscle fibers.

The protein α-dystroglycan also is involved in the migration or movement of nerve cells in the brain during early development. Scientists think that migration abnormalities cause the cobblestone lissencephaly seen in this disorder.

It is not well understood how α-dystroglycan functions in the eyes and other parts of the body.

Inheritance

WWS is inherited in an autosomal recessive pattern. That means that both copies of the gene — one from the mother and one from the father — have to be mutated for the disease to manifest. Both parents of affected individuals have one mutated gene copy but show no symptoms. In such cases, a child has a 25% chance of inheriting mutated gene copies from both parents.

Diagnosis

Diagnosis is primarily based on symptoms. Brain abnormalities can be best detected by magnetic resonance imaging (MRI), which gives detailed pictures of the brain. The fluid-filled ventricles also can be seen with ultrasound or computed tomography (a CT scan). Brain abnormalities can be detected before a baby is born with the use of ultrasound or fetal MRI.

A blood test to measure levels of a protein called creatine kinase — needed by muscle cells in the body to properly function — can confirm muscle damage. A muscle biopsy also can detect muscle damage and α-dystroglycan abnormalities.

Genetic testing can confirm the diagnosis when mutations occur in one of the known genes. However, because not all disease-causing genes have been identified, the test may sometimes come back with a false negative in affected individuals.

Prenatal genetic testing is usually performed in families with genetic mutations known to cause WWS.

Treatment

There is no specific treatment available for Walker-Warburg, and the management of the disease is very individual-specific, depending on the symptoms.

Babies who experience seizures are usually treated with anticonvulsants.

Physiotherapy, or physical therapy, can help to prevent the worsening of contractures. Gastrostomy tubes, known as g-tubes, can help with feeding difficulties.

 

Last updated: August 22, 2019

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