NORD gratefully acknowledges Christopher A. Walsh, MD, PhD, Chief, Division of Genetics and Genomics, Boston Children's Hospital, Bullard Professor of Neurology and Pediatrics, Harvard Medical School; M. Chiara Manzini, PhD, Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences; and Haley Hill, Jennifer N. Partlow, MS, CGC and Brenda Barry, MS, CGC, from Boston Children's Hospital for assistance in the update and preparation of this report.
Walker-Warburg syndrome (WWS) is a rare multisystem disorder characterized by muscle, brain and eye abnormalities. 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 (congenital muscular dystrophy). WWS often leads to death in the first year of life, however, the specific symptoms and severity can vary greatly from person to person. 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 form of congenital muscular dystrophy (CMD), which is a broad spectrum of over 30 disorders characterized by weakness and atrophy of various voluntary muscles of the body. These disorders affect different muscles, can have other body systems involved, and have different ages of onset, severity and inheritance patterns. Several forms of CMD are grouped under the name dystroglycanopathies, due to functional defects in the dystroglycan protein described below. WWS is the most severe dystroglycanopathy.
The main symptoms of WWS are muscular dystrophy 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), which might be noted as “floppy baby” syndrome. Muscle weakness and atrophy (wasting away) typically gets worse over time. Some affected individuals develop abnormally fixed joints (contractures) 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 lissencephaly (smooth brain), hydrocephalus (enlarged ventricles) and malformations in the back of the brain. The type of lissencephaly involved in WWS is described as type 2, or cobblestone lissencephaly. This is because the surface of the brain is smooth and has a cobblestone appearance due to the collection of clumps of brain cells (neurons) at the surface. 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 underdevelopment (hypoplasia) 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 protrusion of part of the brain through the skull bone (encephalocele) and/or absence of the corpus callosum, which is the band of white matter that normally connects the two brain hemispheres.
The eye (ocular) abnormalities associated with WWS vary widely from person to person and can include any of the following: abnormally small eyes (microphthalmia), absent or underdeveloped optic nerves (optic nerve hypoplasia), malformations of the fluid-filled space within the eyes behind the cornea and in front of the iris, and malformation of the retina, which could cause the retina to become detached (retinal dysplasia). Additional eye symptoms can include cataracts, a cleft or loss of tissue of the retina or iris (colobomas), abnormally large and protruding eyes (buphthalmos), or increased pressure within the eyes (glaucoma). Most of these abnormalities lead to partial or complete blindness.
The brain malformations associated with WWS cause serious, life-threatening complications during infancy. Children born with WWS display varying degrees of intellectual disability and often have seizures. 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. Occasionally, additional symptoms in different body systems could 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 can have other features, such as low-set or prominent ears, cleft palate or cleft lip.
WWS is due to abnormally functioning or non-working genes that are important in brain, eye and muscle development. It is inherited in an autosomal recessive manner and thus 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 in deficiencies or complete lack of specific proteins that play an essential role in the proper development and function of the brain, eyes and muscle. These proteins function together with another protein called α-dystroglycan, which is found in the membranes of muscle cells and nerve cells. α-dystroglycan normally functions to stabilize muscle cells and aid the migration of nerve cells in the brain during development. WWS-related proteins are required for the attachment of sugar molecules to α-dystroglycan, in a process called glycosylation, which is needed for α-dystroglycan to function correctly. In individuals with WWS, the genes that encode one of the proteins involved in glycosylation are mutated and therefore α-dystroglycan is not properly glycosylated and cannot carry out its normal functions. Defects in α-dystroglycan glycosylation lead to the brain, eye and muscular features of WWS and related dystroglycanopathies.
WWS has been linked to at least 14 different genes that are normally responsible for making proteins involved in the glycosylation process described above. Listed alphabetically, the genes identified thus far are:
•B3GALNT2: Beta-1,3-N-acetylgalactosaminyltransferase 2 protein
•B4GAT1: 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: O-mannose beta-1,4-N-acetylglucosaminyltransferase 2 protein
•POMK: Protein-O-mannose kinase
•TMEM5: Transmembrane protein 5
Recent advances in genetic research and techniques, such as whole genome and whole exome sequencing technology, have permitted the identification and association of the above genes with WWS. The discovery of these genes and the characterization of symptoms they cause when mutated has revealed notable 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 mutations in all these genes can also cause less severe forms of dystroglycanopathies. Despite the numerous known genetic causes of WWS, genetic testing might not reveal the causative gene in every family. Therefore, it is 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. Its incidence is unknown, but is estimated to be less than 1 in 200,000.
A diagnosis of WWS can be suspected via routine ultrasound and/or fetal MRI during the late stages of pregnancy and confirmed at or shortly after birth following thorough clinical evaluation and identification of characteristic findings that might 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. 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 and microscopic evaluation of 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 is a measure of the breakdown of muscle tissue. 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.
Genetic testing can be done in an effort to provide molecular confirmation of a clinical diagnosis of WWS. Genetic confirmation occurs when two mutations are identified in a known causative gene. Genetic testing can be done in a variety of ways. One genetic testing method is the sequencing of a single known WWS gene and could be done if one particular gene is suspected. It is also possible to test for multiple known WWS or CMD genes at once via a multiple gene panel test. Another genetic testing method is called whole exome sequencing, in which every known gene can be analyzed for mutations at once. Each of these methods has benefits and limitations, and individual circumstances might suggest one method over another. If the affected individual is of Ashkenazi Jewish descent, the FKTN gene should be tested first, since a specific mutation in this gene is common in this population. Otherwise, there is significant overlap of symptoms caused by mutations in all known WWS genes, so it is difficult to determine a specific order for genetic testing.
Since it is likely that not all genes for WWS have yet been identified, genetic testing could be negative. Therefore, a negative result does not exclude a diagnosis of WWS, which is made primarily based on clinical symptoms, and in these cases, re-evaluation of genetic testing opportunities (to include newly identified WWS genes) could be considered periodically in the future.
Genetic counseling for families can help their understanding of autosomal recessive inheritance, the current and ever-changing state of genetic testing for WWS, what the results of genetic testing for a family mean, and the impact of this information on individuals in the 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, orthopedic surgeons, neurologists, eye specialists, 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 implantation of shunts to drain excess cerebrospinal fluid and reduce pressure, and physical therapy to improve muscle strength and prevent contractures. Some affected infants might need a gastric tube to assist with feeding difficulties. Other symptomatic and supportive treatments could also be necessary. Due to the severe brain and muscle abnormalities, life expectancy of children with classic WWS is always reduced.
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Manzini MC, Walsh CA. The Genetics of Brain Malformations. The Genetics of Neurodevelopmental Disorders. 1st ed. Mitchell KJ. Ed. Hoboken, NJ: John Wiley & Sons, Inc; 2015:129-53.
Walsh CA. Walker-Warburg Syndrome. NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:597-8.
Rimoin D, Connor JM, Pyeritz RP, Korf BR. Eds. Emory and Rimoin’s Principles and Practice of Medical Genetics. 4th ed. New York, NY: Churchill Livingstone; 2002:3253-63.
Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th ed. New York, NY: Oxford University Press; 2001:731-2.
Jones KL. Ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W. B. Saunders Co.; 1997:192.
Taniguchi-Ikeda M, Morioka I, Iijima K, Tatsushi T. Mechanistic aspects of the formation of α-dystroglycan and therapeutic research for the treatment of α-dystroglycanopathy: A review. Mol Aspects Med. 2016 Jul 12. doi:10.1016/j.mam.2016.07.003.
Devisme L, Bouchet C, Gonzalès M, et al. Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies. Brain. 2012;135(Pt 2):469-82.
Muntoni F, Torelli S, Wells DJ, Brown SC. Muscular dystrophies due to glycosylation defects: diagnosis and therapeutic strategies. Curr Opin Neurol. 2011;24(5):437-42.
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.
Sparks S, Quijano-Roy S, Harper A, et al. Congenital Muscular Dystrophy Overview. 2001 Jan 22 [Updated 2012 Aug 23]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.Available from: http://www.ncbi.nlm.nih.gov/books/NBK1291/ Accessed September 7, 2016.
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 Update September 4, 2015. Available at: http://omim.org/entry/236670 Accessed September 7, 2016.
Vajsar J, Schachter H. Walker-Warburg Syndrome. Orphanet encyclopedia. Last Update August 3, 2006 www.ojrd.com/content/1/1/29 . August 3, 2006. Accessed September 7, 2016.
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