Abstract
Background Walker-Warburg syndrome (WWS) is a rare form of alpha-dystroglycanopathy characterized by muscular dystrophy and severe malformations of the CNS and eyes. Bi-allelic pathogenic variants inPOMKare the cause of a broad spectrum of alpha-dystroglycanopathies.POMKencodes protein-O-mannose kinase, which is required for proper glycosylation and function of the dystroglycan complex and is ...
Abstract
Background Walker-Warburg syndrome (WWS) is a rare form of alpha-dystroglycanopathy characterized by muscular dystrophy and severe malformations of the CNS and eyes. Bi-allelic pathogenic variants inPOMKare the cause of a broad spectrum of alpha-dystroglycanopathies.POMKencodes protein-O-mannose kinase, which is required for proper glycosylation and function of the dystroglycan complex and is crucial for extracellular matrix composition. Results Here, we report on male monozygotic twins with severe CNS malformations (hydrocephalus, cortical malformation, hypoplastic cerebellum, and most prominently occipital meningocele), eye malformations and highly elevated creatine kinase, indicating the clinical diagnosis of a congenital muscular dystrophy (alpha-dystroglycanopathy). Both twins were found to harbor a homozygous nonsense mutation c.640C>T, p.214* inPOMK, confirming the clinical diagnosis and supporting the concept thatPOMKmutations can be causative of WWS. Conclusion Our combined data suggest a more important role forPOMKin the pathogenesis of meningoencephalocele. Only eight different pathogenicPOMKvariants have been published so far, detected in eight families; only five showed the severe WWS phenotype, suggesting thatPOMK-associated WWS is an extremely rare disease. We expand the phenotypic and mutational spectrum ofPOMK-associated WWS and provide evidence of the broad phenotypic variability ofPOMK-associated disease.
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