Walker-Warburg syndrome (WWS) is the most severe of the dystroglycanopathies. Features are similar to muscle-eye-brain disease, but there is phenotypic heterogeneity. Affected individuals lack spontaneous movement at birth, have a weak cry and suck, and have generalized hypotonia and weakness. Feeding difficulties can require gastronomy feeding. They may have microcephaly, hydrocephalus, contractures, cleft lip and palate, seizures, genital anomalies in males, and encephalocele. Eye abnormalities can include congenital cataracts, microphthalmia, glaucoma, and iris malformations. Brain malformations can include complete lissencephaly type II with pontocerebellar hypoplasia with Dandy-Walker malformation, fusion of the hemispheres, and absence of corpus callosum. Life expectancy is often a few years.
Serum creatine kinase (CK) levels are elevated at 2-15 times normal. Histology reveals a general myopathic pattern, and immunohistochemistry shows deficiency of glycosylated alpha dystroglycan while laminin alpha 2 (merosin) levels can be normal or reduced.
WWS is an autosomal recessive disorder with genetic heterogeneity. Approximately 20% of individuals with a clinical diagnosis of WWS have mutations in the POMT1 gene (9q34.1). Mutations have also been found in the POMT2, FKTN, FKRP, POMGNT1, and LARGE genes. Other as yet unidentified genes are thought to be a major cause of WWS.
Mutations in the POMT1 gene have also been identified in individuals with a milder form of disease, limb-girdle muscular dystrophy type 2K (LGMD2K). Characteristics include mild, slowly progressive proximal weakness with difficulty climbing stairs and running, along with mild mental retardation with limited language development. Other features include hypertrophy of the calves and thighs, contractures, and microcephaly. Age of onset was approximately 1-3 years with the age at being wheelchair bound was approximately 17 years. CK levels were elevated 20-40 times normal, neuroimaging was normal, and immunohistochemistry showed decreased glycosylated alpha dystroglycan.
For patients with suspected WWS, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.
- Bonnemann, Carsten. Personal communication. July 8, 2009.
- Conti Reed, U. Congenital muscular dystrophy part I: A review of phenotypical and diagnostic aspects. Arq Neuropsiquiatr. 2009; 67:144-168.
- GeneTests: Congenital Muscular Dystrophy Overview. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene∂=cmd-overview
- GeneTests: Limb-Girdle Muscular Dystrophy Overview. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene∂=lgmd-overview
- Mendell, JR et al. The congenital muscular dystrophies: Recent advances and molecular insights. Ped and Dev Pathology. 2006; 9:427-443.
This test is indicated for:
- Confirmation of a clinical diagnosis of Walker-Warburg syndrome.
- Carrier testing in adults with a family history of Walker-Warburg syndrome.
Clinical Sensitivity: Approximately 20% of individuals with a clinical diagnosis of WWS have mutations in the POMT1 gene. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's biochemical phenotype.
Analytical Sensitivity: ~99%.
Submit only 1 of the following specimen types
Preferred specimen type: Whole Blood
Type: Whole Blood
Specimen Requirements:In EDTA (purple top) tube:
Infants (<2 years): 2-3 ml
Children (>2 years): 3-5 ml
Older Children & Adults: 5-10 ml
Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.
Specimen Requirements:OrageneTM Saliva Collection kit (available through EGL) used according to manufacturer instructions.
Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.
Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.
Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.
- Deletion/duplication analysis of the POMT1 gene by CGH array is available for those individuals in whom sequence analysis is negative.
- Analysis of the POMT2, FKTN, FKRP, POMGNT1, and LARGE genes is also available.
- Familial mutation testing is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
- Prenatal testing is available to couples who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.