Walker-Warburg syndrome (WWS) is a rare, inherited disorder that significantly affects the muscles, brain, and eyes. It is a form of congenital muscular dystrophy (CMD), a group of genetic muscle diseases that become apparent within the first two years after birth. It is also the most severe form of a group of disorders known as α-dystroglycanopathies, which result from abnormal glycosylation (a type of sugar modification) of the α-dystroglycan protein. The exact prevalence of WWS is unknown, but the condition is considered extremely rare and likely underdiagnosed. Estimates vary among populations, but the disorder is thought to affect fewer than 1–2 per 100,000 live births worldwide.
Cause of WWS
In healthy individuals, the α-dystroglycan protein helps maintain muscle integrity and normal development of the brain and eyes before birth. Most cases of WWS are caused by disease-causing (pathogenic) variants in genes involved in the glycosylation of α-dystroglycan. When this process is disrupted, α-dystroglycan cannot function normally, leading to abnormal development of multiple organ systems. WWS represents the most severe end of the α-dystroglycanopathy spectrum, which also includes milder conditions such as muscle-eye-brain disease and some limb-girdle muscular dystrophies.
Pathogenic variants in more than 20 genes have been associated with WWS or related α-dystroglycanopathies. However, a genetic cause is not identified in all individuals with WWS, and ongoing research continues to uncover additional disease-associated genes. The most commonly implicated genes include:
- B3GALNT2
- B4GAT1
- CRPPA (formerly ISPD)
- DAG1
- FKRP
- FKTN
- GMPPB
- LARGE1
- POMGNT1
- POMGNT2 (formerly GTDC2)
- POMT1
- POMT2
- TMEM5
WWS is inherited in an autosomal recessive pattern, which means that two copies of the causative gene, one from each parent, are needed to develop the disorder.
Symptoms of WWS
The symptoms of WWS typically begin at or shortly after birth and involve the muscles, brain, and eyes. Although WWS is generally considered very severe, the specific features can vary among affected individuals. While most children with WWS do not survive beyond early childhood, some may live longer with advances in supportive care. Common symptoms in babies with WWS may include:
Muscle involvement
- Severe muscle weakness (congenital muscular dystrophy)
- Low muscle tone (“floppiness”)
- Feeding difficulties and delayed motor development
- Joint stiffness (contractures)
Brain involvement
- Abnormal brain development, including a characteristic cobblestone brain malformation
- Hydrocephalus (excess fluid around the brain) and other structural brain abnormalities
- Seizures
- Profound developmental delays affecting movement, communication, and learning
- Smaller-than-average head size (microcephaly) in some children
Eye involvement
- Abnormal development of the retina, optic nerve, cornea, or other eye structures
- Cataracts, cloudy corneas, or unusually small eyes (microphthalmia)
- Severe vision impairment or blindness
Feeding and breathing complications
- Difficulty swallowing and feeding
- Aspiration (food or liquid entering the lungs)
- Recurrent respiratory infections
- Breathing problems that may require feeding tubes, respiratory support, or both
To learn more about the signs, symptoms, and causes of WWS, the following review article may be helpful:
- Orphanet Journal of Rare Diseases article by Vajsar and Schachter (2006)
Diagnosis of WWS
Diagnosis of WWS involves a combination of clinical findings, brain and eye imaging, laboratory testing, and genetic testing. While muscle biopsy was historically used in WWS diagnosis, it is no longer routinely required. Genetic testing is now the preferred approach for most patients. Evaluation for WWS may include:
- Neurological examination
- Brain MRI to identify characteristic abnormalities
- Comprehensive eye examination by a pediatric ophthalmologist
- Blood testing showing mildly to moderately elevated creatine kinase (CK) levels, a marker of muscle damage
- Genetic testing to identify the underlying disease-causing variant(s)
Notably, prenatal diagnosis may be possible for some cases of WWS. If the disease-causing gene variants have been identified in a family, chorionic villus sampling (CVS) or amniocentesis can be used to test for the known gene variants. Characteristic features may also be detected before birth using prenatal ultrasound and fetal MRI. Findings that may raise suspicion for WWS include enlarged brain ventricles (ventriculomegaly), hydrocephalus, abnormal development of the brain surface, underdevelopment of the cerebellum or brainstem, and eye abnormalities. Since these findings can occur in other conditions, however, genetic testing may help to confirm the diagnosis.
Current management of WWS
There is currently no cure or disease-modifying therapy for WWS. Treatment focuses on supportive care and management of complications.
Care may include:
- Respiratory monitoring and support
- Nutritional support and feeding tube placement when needed
- Management of seizures and other neurological complications
- Physical and occupational therapy to help maintain mobility and prevent contractures, as appropriate
- Ophthalmologic care to monitor and manage vision problems
- Orthopedic management of joint contractures and other musculoskeletal complications
- Genetic counseling for affected families
- Palliative care and psychosocial support for affected children and their families
Since WWS affects multiple organ systems, care is typically coordinated by a multidisciplinary team that may include neurologists, pulmonologists, ophthalmologists, rehabilitation specialists, geneticists, neurosurgeons, gastroenterologists, nutrition specialists, and palliative care providers.
Evolving research and treatment landscape
The standard of care for WWS is still symptom management, but research advances offer hope for children living with WWS. Researchers have identified many gene defects that cause WWS. These discoveries have led to better understanding of disease mechanisms, as well as improved diagnosis.
Importantly, advances in gene replacement, gene editing, RNA-based therapies, and improved viral delivery technologies have transformed the treatment landscape for several neuromuscular diseases. Although these approaches are not yet available for WWS, researchers are exploring how similar strategies might one day be adapted for forms of α-dystroglycanopathy.
There are currently no clinical trials enrolling for WWS therapeutic candidates, however, several natural history studies aim to better understand the disease course of WWS and related congenital muscular dystrophies. Examples include:
- Congenital Muscle Disease Study of Patient and Family Reported Medical Information (CMDPROS) (Cure CMD)
- Global FKRP Registry (Newcastle University)
- Clinical Trial Readiness for the Dystroglycanopathies (University of Iowa)
MDA’s work to further cutting-edge WWS research
Since its inception, MDA has invested more than $39million in research on congenital muscular dystrophies, including WWS. Together with support from partner advocacy organizations and the National Institutes of Health (NIH), researchers have identified many of the genes responsible for WWS and related disorders, improving diagnosis and understanding of how these disorders develop. While significant challenges remain, continued research is laying the foundation for future therapies and improving care for individuals and families affected by these rare conditions.
MDA’s Resource Center provides support, guidance, and resources for patients and families, including information about Walker-Warburg syndrome, open clinical trials, and other services. Contact the MDA Resource Center at 1-833-ASK-MDA1 or ResourceCenter@mdausa.org.
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