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Walker Warburg Syndrome

NORD is very grateful to Christopher A. Walsh, MD, PhD, Chief, Division of Genetics, Children's Hospital Boston, Bullard Professor of Neurology and Pediatrics; M.Chiara Manzini, PhD and Brenda Barry, MS, CGC, Genetic Counselor and Research Coordinator, from Children's Hospital Boston, Harvard Medical School, for assistance in the update and preparation of this report.

Synonyms of Walker Warburg Syndrome

  • cerebroocular dysgenesis (COD)
  • cerebroocular dysplasia-muscular dystrophy syndrome (COD-MD syndrome)
  • Chemke syndrome congenital muscular dystrophy-
  • dystroglycanopathy type A [with brain and eye anomalies] (MDDGA)
  • hydrocephalus, agyria, and retinal dysplasia (HARD syndrome)
  • Pagon syndrome
  • Warburg syndrome

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Walker-Warburg syndrome (WWS) is a rare multisystem disorder characterized by muscle, brain and eye abnormalities, often leading to death in the first weeks of life. However, the specific symptoms and severity of WWS can vary greatly from case to case. The most consistent features are (1) a smooth appearance of the surface of the brain due to lack of normal folding pattern (lissencephaly or agyria), often with malformations of other brain structures including the cerebellum and brain stem, (2) various developmental abnormalities of the eye and (3) progressive degeneration and weakness of the voluntary muscles which is called congenital muscular dystrophy. WWS demonstrates autosomal recessive inheritance, with a recurrence risk of 1 in 4 or 25% for a couple who has previously had a child diagnosed with this genetic condition.

WWS is a severe form of the broader spectrum of conditions referred to as CMD (congenital muscular dystrophy), which is a group of disorders characterized by weakness and atrophy of various voluntary muscles of the body. Approximately 30 different disorders make up the muscular dystrophies. These disorders affect different muscles, may or may not have other body systems involved, and have different ages of onset, severity and inheritance patterns. The disorder was first reported in the medical literature in 1942.


The main symptoms of WWS are the congenital muscular dystrophy and abnormalities of the brain and eyes. WWS shows overlap with muscle-eye-brain (MEB) diseases. Symptoms of WWS are present at birth, or congenital, and some of the brain abnormalities can be detected on late stage prenatal ultrasound or MRI.

Affected neonates usually have a variety of serious brain findings, including lissencephaly and hydrocephalus. The lissencephaly is often described as showing a cobblestone appearance. Hydrocephalus, which is caused by too much cerebrospinal fluid (CSF) in the ventricles of the brain, can be quite severe. Additional brain malformations of the back portions of the brain may occur, including underdevelopment, or hypoplasia, of the cerebellum, or little brain, which helps coordinate voluntary muscle movement, and hypoplasia of the brain stem which helps control basic functions such as breathing, coordinating movement, salivation and heart rate. The abnormalities near the back of the brain may be referred to as Dandy-Walker malformation. This is a malformation of the brain usually described as an abnormally enlarged space at the back of the brain. In some WWS patients there is protrusion of part of the brain through the skull (encephalocele), or absence of the corpus callosum which is the band of white matter that connects the two cerebral hemispheres.

The brain defects associated with WWS cause serious, life-threatening complications during infancy. Children born with WWS display varying degrees of mental retardation and often have seizures. The combined brain and muscle abnormalities lead to significant delays in reaching developmental milestones (e.g., sitting up, grabbing, crawling, talking) and can be so severe as to cause difficulties in breathing and swallowing.

The eye or ocular, abnormalities associated with WWS vary widely from patient to patient and can include any of the following: abnormally small eyes (microphthlamia), absent or underdeveloped optic nerves (optic nerve hypoplasia or ONH), malformations of the fluid-filled space within the eyes behind the cornea and in front of the iris , and malformation of the retina (retinal dysplasia), which may cause the retina to become detached. Additional eye symptoms may include cataracts, colobomas which are a cleft or loss of tissue of the retina or iris, and abnormally large, protruding eyes (buphthalmos), or increased pressure within the eyes (infantile glaucoma. Most of these abnormalities lead to partial or complete blindness.

Muscular dystrophy causes affected infants to have severe hypotonia, which is diminished muscle tone, at birth. This condition maybe noted as "floppy baby" syndrome. Muscle weakness and atrophy or loss of muscle tissue is progressive. Some affected individuals develop abnormally fixed joints, or contractures, that occur when thickening and shortening of tissue such as muscle fibers cause deformity and restrict movement of an affected area

Occasionally additional symptoms may be present. In some affected children, genitourinary abnormalities may occur, causing urinary tract obstruction and pelvic dilation (hydronephrosis) or in boys there may be failure of the testes to descend into the scrotum (cryptorchidism). Some affected children may have low-set or prominent ears, cleft palate or cleft lip.


WWS is due to abnormally functioning genes that are important in brain, eye and muscle development. It is inherited in an autosomal recessive manner, meaning that each parent is typically an asymptomatic carrier Recessive genetic disorders occur when an individual inherits two abnormal copies of a gene, one from each parent. If an individual receives one normal or functioning gene and one non-working gene related to the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents who have children together to both pass the defective gene and have an affected child is 25% or one in 4 with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for offspring to receive two normally functioning genes from two carrier parents for that particular trait is 25% with each pregnancy. The risk is the same for males and females.

The genetic abnormalities result in deficiencies or complete lack of specific proteins which play an essential role in the proper development and function of brain, eyes and muscle. These proteins are necessary for the normal attachment or binding of sugar molecules, a process called glycosylation, to dystroglycan, which is a protein found on the membrane of muscle cells and nerve cells. The process by which improper glycosylation of dystroglycan causes the symptoms associated with WWS is not fully understood. Because of the role of dystroglycan, WWS and related disorders are sometimes referred to as dystroglycanopathies.

WWS has been linked to at least six different disease genes that contain instructions to produce specific proteins involved in glycosylation: the protein O-mannosyltransferase 1 (POMT1) gene; the protein O-mannosyltransferase 2 (POMT2) gene; the protein O-mannose beta-1,2-N-acetylglucosaminyltransferase (POMGNT1) gene; the fukutin (FKTN) gene; the fukutin-related protein (FKRP) gene; and the LARGE gene. It is expected that advances in genetic research and techniques, such as whole genome and whole exome technology, will permit the identification of additional genes associated with this disorder in the future.

Although the six above-mentioned genes have been identified as causes of WWS, mutations in these genes are found on fewer than half known cases of WWS. Many times the primary genetic defect may not be known. Ideally, all six genes should be tested to reach a genetic diagnosis, starting with POMT1, which is a more frequent cause of the disease in the general population according to previous studies. However, if the patient is of Ashkenazi Jewish descent, FKTN should be tested first, since a mutation in this gene is common in this population. Other than these guidelines, there is significant overlap in symptom so it is difficult to currently determine a specific order for testing.

Affected Populations

WWS affects males and females in equal numbers. Although the disorder has been reported worldwide, its incidence is unknown. As with any recessive condition, the chance of having a child a recessively inherited condition is increased if parents are closely related by blood.

Related Disorders

Symptoms of several disorders can show overlap with WWS. As noted earlier, CMD is a general term for a group of muscle diseases that includes several different names. Some forms of CMD, like WWS, may be associated with structural brain defects and intellectual disability, while others do not usually involve the central nervous system. The severity, specific symptoms, and progression of these disorders vary greatly. Almost all known forms of CMD are inherited as autosomal recessive traits. Two specific forms of CMD, Fukuyama CMD and muscle-eye-brain disease have similar symptoms as WWS, though they are generally less severe. (For more information on this disorder, choose "congenital muscular dystrophy" as your search term in the Rare Disease Database.)

The brain findings seen in WWS can also occur alone or in combination with other findings. WWS is only suspected when other body systems involving the eye or muscles are also affected. The most striking brain feature, lissencephaly may be seen in several conditions. Individuals with lissencephaly may have no other symptoms, which is classified as isolated lissencephaly. However, lissencephaly can also occur in children who also have microcephaly (small head size), other structural brain abnormalities such as a very small cerebellum, or an unusual facial appearance or even kidney, heart and gastrointestinal malformations. When a brain MRI shows agyria or true lissencephaly, severe delays resulting in motor and intellectual disability are typically present. Lissencephaly may be due to a spontaneous (de novo) genetic change that occurs for the first time in the child, it may be inherited as part of an autosomal recessive condition or as an X-linked condition, or may occur in association with other underlying disorders. (For more information on this disorder, choose "Lissencephaly" as your search term in the Rare Disease Database.)

Standard Therapies

A diagnosis of WWS is often made at or shortly after birth. The diagnosis is made after thorough clinical evaluation, identification of characteristic findings, and may require a variety of tests.

Identification of the brain findings is best made using magnetic resonance imaging (MRI) which provides detailed pictures of the brain, though the enlarged ventricles may also be detected on head ultrasounds and CT scans. A biopsy and microscopic evaluation of muscle tissue may be needed to reveal characteristic changes to muscle fibers. Blood tests for CK levels that measure breakdown of muscle tissue can also be helpful. The detection of elevated CK levels can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis of WWS. A careful eye exam can also identify the characteristic eye findings.

Last but not least, genetic testing can provide molecular confirmation of a clinical diagnosis. This occurs when two mutations are found in one of the six known causative genes is identified. However, not all genes for WWS have been identified so genetic testing may be negative but this does not exclude the diagnosis which is primarily based on the clinical symptoms.

There is no cure for WWS at this time and treatment is individualized based on specific symptoms. Treatment may require the coordinated efforts of a team of specialists including pediatricians, geneticists, orthopedic surgeons, neurologists, eye specialists, and other health care professionals to systematically and comprehensively plan an affected child's treatment.

Treatments may include anti-seizure medication, surgery for hydrocephalus such as the implantation of shunts to drain excess cerebrospinal fluid and reduce pressure and physical therapy to improve muscle strength and prevent contractures. Some affected infants may need a gastric tube to assist with feeding difficulties. Other symptomatic and supportive treatments may also be necessary. Due to the severe brain and muscle abnormalities, life expectancy of children with classic WWS is usually reduced.

Genetic counseling for families can help promote an understanding of autosomal recessive inheritance, the current state of genetic testing for WWS, and the impact of this information on individuals in the family.

Investigational Therapies

Information on current clinical trials is posted on the Internet at All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010

For information about clinical trials sponsored by private sources, contact:

Walker Warburg Syndrome Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at

Other Organizations:


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Beltran-Valero de Bernabe 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;41:e61.

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Sparks S, Quijano-Roy S, Amy Harper A, et al. (Updated January 4, 2011).Congenital Muscular Dystrophy Overview. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2012. Available at Accessed April 10, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Muscular Dystrophy-Dystroglycanopathy (Congenital with Brain and Eye Anomalies), Type A, 1; MDDGA1. Entry No: 236670. Last Edited November 10, 2010. Available at: Accessed April 10, 2012.

Vajsar J, Schachter H. Walker-Warburg Syndrome. Orphanet encyclopedia. August 3, 2006. Accessed April 10, 2012.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2012/04/24 00:00:00 GMT+0

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