Information on the following diseases can be found in the Related Disorders section of this report:

• congenital muscular dystrophy (CMD)
• lissencephaly

The main symptoms of WWS are congenital muscular dystrophy and abnormalities of the brain and eyes. WWS is sometimes referred to as one of the muscle-eye-brain diseases. The symptoms and severity of WWS vary greatly. Symptoms of WWS are present at birth (congenital). Some of the brain abnormalities can be detected on late stage prenatal ultrasound.

Affected neonates usually have a variety of serious complications including cobblestone (type II) lissencephaly, a condition in which the brain is smooth, lacking the normal folds or ridges (agyria), and severe hydrocephalus, which is caused by accumulation of cerebrospinal fluid in the ventricles of the brain. Additional brain malformations include underdevelopment (hypoplasia) of certain areas including the back lower portion of the brain concerned with coordinating voluntary muscle movement (cerebellum), and underdevelopment of the part of the brain just above the spinal cord (brain stem) involved in controlling basic functions such as breathing, coordinating movement, salivation, heart rate. In some WWS patients there is protrusion of part of the brain through the skull (encephalocele), and/or absence (agenesis) of the area of the brain that connects the two cerebral hemispheres (corpus callosum).

A specific brain defect known as Dandy-Walker malformation may also occur. Dandy-Walker malformation is a rare malformation of the brain usually described as an abnormally enlarged space at the back of the brain (cystic 4th ventricle) that interferes with the normal flow of cerebrospinal fluid through the openings between the ventricle and other parts of the brain.

The brain defects associated with WWS often cause serious, life-threatening complications during infancy. As affected individuals age they may display varying degrees of mental retardation and episodes of electrical disturbances in the brain (seizures). The combined brain and muscle abnormalities usually 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 (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, malformations of the fluid-filled space within the eyes behind the cornea and in front of the iris (anterior chamber), and malformation of the retina (retinal dysplasia), which may cause the retina to become detached. Additional symptoms may include cataracts, a cleft or loss of tissue (coloboma) especially in the retina, and abnormally large, protruding eyes (buphthalmos), and increased pressure within the eyes (infantile glaucoma not necessarily linked to bupthalmos). Most of these abnormalities lead to partial or complete blindness.

Muscular dystrophy causes affected infants to have diminished muscle tone (hypotonia) at birth, a condition sometimes referred to as "floppy baby". Muscle weakness and degeneration (atrophy) is progressive. Some affected individuals develop abnormally fixed joints that occur when thickening and shortening of tissue such as muscle fibers cause deformity and restrict movement of an affected area (contractures).

In rare cases, additional symptoms may be present. In some affected children, genitourinary abnormalities may occur, causing urinary tract obstruction and pelvic dilation (hydronephrosis) or 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 inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25% with each pregnancy. The risk is the same for males and females.

WWS is caused by deficiency or lack of specific proteins (enzymes) 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 (glycosylation) to dystroglycan, 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 in this disorder, 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 (encode) 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.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 9q34.1" refers to band 34.1 on the long arm of chromosome 9. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The POMT1 gene is located on the long arm (q) of chromosome 9 (9q34.1). The POMT2 gene is located on the long arm (q) of chromosome 14 (14q24.3). The POMGNT1 gene is located on the short arm (p) of chromosome 1 (1p34.1). The FKTN gene is located on the long arm (q) of chromosome 9 (9q31). The FKRP gene is located on the long arm (q) of chromosome 19 (19q13.3). The LARGE gene is located on the long arm (q) of chromosome 22 (22q12.3).

Although the six above-mentioned genes have been identified as causes of WWS, they only account for approximately 40 percent of cases. In most cases, the primary genetic defect has not yet been identified. All six genes should be tested to reach a genetic diagnosis, starting with POMT1, which is a more frequent cause of the disease. 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.

WWS affects males and females in equal numbers. Although the disorder has been reported worldwide, its incidence is unknown.

Walker-Warburg syndrome has been known by several different names in the past including the HARD +/-E syndrome - an acronym for (H)ydrocephalus, (A)gyria, (R)etinal (D)ysplasia and, in some cases, (E)ncephalocele. The disorder was first reported in the medical literature in 1942.

Symptoms of the following disorders can be similar to those of WWS. Comparisons may be useful for a differential diagnosis.

Congenital muscular dystrophy (CMD) is a general term for a group of genetic muscle diseases whose symptoms are seen at birth (congenital). CMDs are generally characterized by diminished muscle tone (hypotonia), which is sometimes referred to as "floppy baby"; progressive muscle weakness and degeneration (atrophy); abnormally fixed joints that occur when thickening and shortening of tissue such as muscle fibers cause deformity and restrict the movement of an affected area (contractures); and delays in or lack of reaching motor milestones such as sitting or standing unassisted. Some forms of CMD may be associated with structural brain defects and, potentially, mental retardation. 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.)

Lissencephaly is a rare abnormality in brain structure that may occur due to a variety of causes. It is a rare birth defect in which the folds of the brain are incompletely formed; as a result, the brain has a smooth surface instead of the normal folds and grooves. Affected individuals may exhibit additional abnormalities, such as a small head (microcephaly); an unusual facial appearance; seizures; and/or other brain, kidney (renal), heart (cardiac), and gastrointestinal malformations. Severe mental retardation may also be present. Lissencephaly may be due to a spontaneous (de novo) genetic change that occurs for unknown reasons (sporadic), be inherited as an autosomal recessive trait, or be due to and/or occur in association with various underlying disorders. (For more information on this disorder, choose "Lissencephaly" as your search term in the Rare Disease Database.)

Diagnosis
A diagnosis of WWS should be made at or shortly after birth. The key for specific diagnosis is a high resolution x-ray exam called magnetic resonance imaging (MRI). The diagnosis is made by thorough clinical evaluation, identification of characteristic findings, and a variety of tests including surgical removal and microscopic evaluation of affected tissue (muscle biopsy), and specialized blood tests, possibly including genetic testing as mentioned above.

A muscle biopsy reveals characteristic changes to muscle fibers. A MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues such as the brain. In WWS, a MRI reveals characteristic structural brain defects and thus is essential for proper diagnosis. Blood tests may reveal elevated levels of the creatine kinase (CK), an enzyme that is often found in abnormally high levels when muscle is damaged. CK levels are usually elevated in WWS. The detection of elevated CK levels can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis of WWS. Genetic testing can confirm a clinical diagnosis when a mutation in one of the six known causative genes is identified but it cannot exclude the diagnosis at this time.

Treatment
The treatment of WWS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedic surgeons, neurologists, eye specialists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.

Treatment may include anti-seizure (anticonvulsant) medication; surgery for certain brain malformations such as the implantation of shunts to drain excess cerebrospinal fluid; physical therapy to improve muscle strength and prevent contractures; and a complete eye (ophthalmologic) exam to assess abnormalities of the eyes. Some affected infants may need a gastric tube to assist with feeding difficulties.

Other treatment is symptomatic and supportive. Due to the severe brain and muscle abnormalities, life expectancy of children with classic WWS is usually reduced.

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

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. 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
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

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Rimoin D, Connor JM, Pyeritz RP, Korf BR. Eds. Emory and Rimoinís Principles and Practice of Medical Genetics. 4th ed. Churchill Livingstone. New York, NY; 2002:3253-63.

JOURNAL ARTICLES
Manzini MC, Gleason D, Chang BS, et al., Ethnically diverse causes of Walker-Warburg syndrome (WWS): FCMD mutations are a more common cause of WWS outside of the Middle East. Hum Mut. 2008;29:E231-41

Martin PT. The dystroglycanopathies: the new disorders of O-linked glycosylation. Semin Pediatr Neurol. 2005;12:152-8.

Mercuri E, Longman C. Congenital muscular dystrophy. Pediatr Ann. 2005;34:560-2, 564-8.

Scheffer H, Brockington M, Muntoni F, et al., POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome. J Med Genet. 2005;42:907-12.

Muntoni F, Voit T. The congenital muscular dystrophies in 2004: a century of exciting progress. Neuromuscul Disord. 2004;14;635-49.

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.

Mercuri E, Brockington C, Straub V, et al., Phenotypic spectrum associated with mutations in the fukutin-related protein gene. Ann Neurol. 2003;53:537-42.

ON THE INTERNET
Gordon E, Hoffman EP, Pegoraro E. Updated:12/22/2006. Congenital Muscular Dystrophy Overview. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org.

Vajsar J, Schachter H. Walker-Warburg Syndrome. Orphanet encyclopedia, August 2006. Available at: Accessed on: www.ojrd.com/content/1/1/29 Accessed on: January 9, 2007.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:236670; Last Update:05/24/2006. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=236670 Accessed on: January 9, 2007.