Walker-Warburg Syndrome: POMT2 Gene Deletion/Duplication

The congenital muscular dystrophies are a group of genetically and clinically heterogeneous hereditary myopathies characterized by congenital hypotonia and muscle weakness, contractures, and delayed motor development. Muscle biopsy usually reveals a nonspecific dystrophic pattern. The clinical course is broadly variable and can involve the brain and eyes. Initial testing often includes clinical evaluation, muscle imaging, electromyography, and muscle biopsy, followed by targeted genetic testing.

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.

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.

References

• 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
• 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 in an individual in whom sequence analysis was negative
• Carrier testing in adults with a family history of Walker-Warburg syndrome in whom sequence analysis was negative

DNA isolated from peripheral blood is hybridized to a CGH array to detect deletions and duplications. The targeted CGH array has overlapping probes which cover the entire genomic region.

• Sequence analysis of the POMT2 gene is required before deletion/duplication analysis
• Analysis of the POMT1, FKTN, FKRP, POMGNT1, and LARGE genes is also available.
• 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.

Requisition Forms

• Comprehensive Molecular Test Requisition Form
• Neurology, Neuromuscular, and Cardiology Test Requisition Form

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