NORD gratefully acknowledges Claire Barton, MS, Wesley Ho, MS, Megan Yabumoto, MS, and Hannah Wand, MS, CGC, from the Stanford University MS Program in Human Genetics and Genetic Counseling for assistance in the preparation of this report.
Walker-Warburg syndrome (WWS) is a rare inherited disorder that affects the development of the muscles, brain and eyes. WWS is characterized by (1) congenital muscular dystrophy (progressive degeneration and weakness of the voluntary muscles) (2) lissencephaly (a smooth appearance of the surface of the brain due to lack of normal folding pattern) and hydrocephalus (buildup of fluid in the brain), often with malformations of other brain structures including the cerebellum and brain stem and (3) various developmental abnormalities of the eye. The specific symptoms and severity can vary greatly from person to person. WWS is inherited as an autosomal recessive condition, meaning an individual inherits two abnormal copies of a gene, one from each parent. However, genetic testing does not identify a genetic cause in all individuals with a diagnosis of WWS.
WWS belongs to a group of disorders known as the congenital muscular dystrophies (CMD). CMD is a general term for a group of over 30 genetic muscle disorders that cause hypotonia (low muscle tone) and atrophy (progressive muscle weakness) at birth or during infancy. These disorders affect different muscles and have different ages of onset, severity and inheritance patterns. One specific subtype of CMD is known as the dystroglycanopathies, which are caused by disruptions or changes (mutations) in one of the genes involved in the modification of a protein called α-dystroglycan described in the Causes section below. WWS is the most severe dystroglycanopathy and often leads to death in infancy, with most children not surviving past age three.
The main symptoms of WWS are muscular dystrophy (progressive degeneration and weakness of the voluntary muscles) and abnormalities of the brain and eyes. Symptoms of WWS are congenital (present at birth), and some of the brain abnormalities can be detected by prenatal ultrasound and/or fetal MRI in the later stages of pregnancy.
Individuals with WWS have congenital muscular dystrophy, or a weakening and loss of muscle at birth. Muscular dystrophy causes affected infants to have severe hypotonia (low muscle tone), muscle weakness, and atrophy (wasting away) which typically get worse over time. Some affected individuals develop contractures (abnormally fixed joints) that occur when thickening and shortening of tissue, such as muscle fibers, deform and restrict movement of an affected area.
Affected infants usually have a variety of serious brain findings, including type II lissencephaly (smooth brain), hydrocephalus (enlarged ventricles) and malformations in the back of the brain. Type II lissencephaly is also called cobblestone lissencephaly because the surface of the brain has a cobblestone appearance due to the collection of clumps of neurons (brain cells) at the surface. (For more information on this, choose “Lissencephaly” as your search term in the Rare Disease Database.) Hydrocephalus, which is characterized by having too much cerebrospinal fluid in the ventricles of the brain causing an enlargement, can be quite severe and lead to an abnormally large head. Malformations of the back portions of the brain can include hypoplasia (underdevelopment) of the cerebellum and brainstem. The cerebellum helps coordinate voluntary muscle movements, while the brainstem helps control basic functions such as breathing, salivation and heart rate. These posterior malformations can involve an abnormally enlarged space at the back of the brain, sometimes referred to as Dandy-Walker malformation. In some individuals with WWS, there is an encephalocele, which is a protrusion of part of the brain through the skull bone. Individuals with WWS may also have absence of the corpus callosum, which is the band of white matter that normally connects the two brain hemispheres.
The combined brain and muscle abnormalities lead to significant delays in reaching developmental milestones (e.g., sitting up, grabbing objects, crawling, talking) and can be so severe as to cause difficulties in breathing and swallowing. Children born with WWS display intellectual disability and often have seizures.
The eye abnormalities associated with WWS vary widely from person to person and can include any of the following: microphthalmia (abnormally small eyes), optic nerve hypoplasia (absent or underdeveloped optic nerves), retinal dysplasia (malformation of the retina which could cause the retina to become detached) and malformations of the fluid-filled space within the eyes behind the cornea and in front of the iris. Additional eye symptoms can include cataracts, coloboma (a cleft or loss of tissue of the retina or iris), buphthalmos (large and protruding eyes) or glaucoma (increased pressure within the eyes). Most of these abnormalities lead to partial or complete blindness.
Occasionally, additional symptoms in different body systems can also be present. In some affected children, genitourinary abnormalities can occur, causing urinary tract blockage and kidney pelvic dilation (hydronephrosis) or failure of the testes to descend into the scrotum in males (cryptorchidism). Some affected children have other features, such as low-set or prominent ears, cleft lip or palate or cochlear hypoplasia (inner ear malformation).
WWS is due to abnormally functioning or non-working genes that are important in muscle, brain and eye development. It is inherited in an autosomal recessive manner and occurs in an individual who inherits two abnormal copies of a gene, one from each parent. An individual that has one normally functioning copy of the gene and one non-working copy of the gene is a carrier for WWS but usually does not have any symptoms. The risk for two carrier parents who have children together to both pass on the abnormal or non-working gene and therefore have an affected child is 25%, or 1 in 4, with each pregnancy. The risk for these parents to have a child who is a carrier only (unaffected) is 50%, or 1 in 2, with each pregnancy. Their chance to have a child with two normally functioning copies of the gene (unaffected and not a carrier) is 25%, 1 in 4, with each pregnancy. These risks are the same for male and female offspring.
WWS results when certain genes involved in the development and function of the muscle, brain and eyes are not working properly. These WWS-associated genes are required for making proteins that are involved in a process known as glycosylation, which is the adding of sugar molecules to other proteins such that they can function correctly. The genes involved with WWS are required for the proper glycosylation of a protein called α-dystroglycan, as discussed in the Introduction. α-dystroglycan normally functions to stabilize muscle cells and aid in the migration of nerve cells in the brain during development. When these WWS-associated genes are unable to make proteins that normally glycosylate α-dystroglycan, it can lead to issues in the development of the muscle, brain and eyes that are seen in individuals affected by WWS and related dystroglycanopathies.
WWS has been associated with at least 14 different genes that are responsible for making proteins involved in the glycosylation process described above. Listed alphabetically below are the genes identified thus far and the proteins they produce.
•B3GALNT2: Beta-1,3-N-acetylgalactosaminyltransferase 2 protein
•B4GAT1 or B3GNT1: Beta-1,4-glucuronyltransferase 1 protein
•DAG1: Dystrophin-associated glycoprotein 1
•FKRP: Fukutin-related protein
•FKTN: Fukutin protein*
•GMPPB: GDP-mannose pyrophosphorylase B protein
•ISPD: Isoprenoid synthase domain-containing protein
•LARGE: Acetylglucosaminyltransferase-like protein
•POMT1: O-mannosyltransferase 1 protein
•POMT2: O-mannosyltransferase 2 protein
•POMGNT1: O-mannose beta-1,2-N-acetylglucosaminyltransferase protein
•POMGNT2 or GTDC2: O-mannose beta-1,4-N-acetylglucosaminyltransferase 2 protein
•POMK or SGK196: Protein-O-mannose kinase
•TMEM5: Transmembrane protein 5
*FKTN mutations are associated with several other conditions.
Recent advances in genetic research and testing, such as whole genome and whole exome sequencing, have determined that these genes are associated with WWS. The discovery of these genes and the characterization of symptoms they cause when not functioning properly has demonstrated variability in the clinical presentation of WWS in affected individuals. Although the 14 above-mentioned genes have been identified as causes of WWS, they explain only half of known WWS cases, and changes in all these genes can also cause less severe forms of muscular dystrophy. Because of this, genetic testing may not be able to identify a genetic cause of WWS in every individual or family. It is also likely that more genes associated with WWS, and related conditions will be discovered in the future, which could introduce additional variability to the spectrum of WWS.
WWS has been reported worldwide and affects males and females in equal numbers. The incidence is unknown but is estimated to be about 1 in 100,000.
A diagnosis of WWS is based upon the identification of characteristic features, a thorough clinical evaluation and a variety of specialized tests. A diagnosis can be confirmed through molecular genetic testing.
A diagnosis can be suspected via routine ultrasound and/or fetal MRI during the late stages of pregnancy and confirmed at or shortly after birth. During the pregnancy, imaging can suggest WWS when there is type II lissencephaly (smooth brain), cerebellum abnormalities and other early changes in the brain and eye.
Additional tests shortly after birth are necessary to establish a clinical diagnosis of WWS. Identification of the brain findings can be done with magnetic resonance imaging (MRI), which provides detailed pictures of the brain. However, the enlarged ventricles that often accompany a diagnosis of WWS can also be detected by ultrasound and computed tomography (CT) of the head. A biopsy (surgical removal and microscopic examination) of affected muscle tissue might be needed to reveal characteristic changes in muscle fibers. A blood test for creatine kinase (CK) levels is also commonly done, as CK measurement is used to detect muscle damage. The detection of elevated CK levels can confirm that muscle is damaged or inflamed but cannot confirm a diagnosis of WWS specifically. A careful eye exam can also identify the characteristic eye findings of WWS described in the Signs & Symptoms section.
Molecular genetic testing can be performed to identify specific genetic mutations and can be used to confirm a clinical diagnosis of WWS. Genetic confirmation occurs when two mutations are identified in a gene known to be associated with WWS. If the individual is of Ashkenazi Jewish descent, the FKTN gene may be tested first because there is a specific mutation in this gene that is common within this population. However, a more comprehensive genetic test would be most helpful because there is significant overlap of symptoms caused by mutations in the 14 genes linked to WWS. It is possible to test for all genes known to be associated with WWS or congenital muscular dystrophies (CMD) at the same time with a multiple gene panel test. Additionally, exome sequencing can be performed to look at all genes that are known to provide instructions for making proteins. Each test has benefits and limitations that should be discussed with a genetic counselor.
The 14 genes identified to cause for WWS explain only about half of all known cases of WWS. Therefore, genetic testing could come back negative, and an individual can still have a clinical diagnosis of WWS. In these patients, additional genetic testing could be considered periodically over time to include newly identified genes linked to WWS.
Genetic counseling can help families understand autosomal recessive inheritance, the current and ever-changing state of genetic testing for WWS, what the results from genetic testing mean and the impact of this information on the members of the family. Psychosocial support may also be beneficial for the entire family.
There is no cure for WWS at this time and treatment is individualized based on specific symptoms. Medical management can require the coordinated efforts of a team of specialists including pediatricians, geneticists/genetic counselors, orthopedic surgeons, neurologists, ophthalmologists, and other health care professionals to systematically and comprehensively plan an affected child’s treatment.
Treatments might include anti-seizure medication, surgery for hydrocephalus, such as the placement of shunts to drain excess cerebrospinal fluid and reduce pressure in the brain, and physical therapy to improve muscle strength and prevent contractures. Some children might need a gastric tube to assist with feeding. Other symptomatic and supportive treatments could also be necessary. Due to the severe brain and muscle abnormalities, life expectancy is reduced with almost all affected children not surviving past age three.
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