Abstract
BackgroundWalker-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 in POMK are the cause of a broad spectrum of alpha-dystroglycanopathies. POMK encodes protein-O-mannose kinase, which is required for proper glycosylation and function of the dystroglycan complex and is crucial for extracellular matrix composition.ResultsHere, 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* in POMK, confirming the clinical diagnosis and supporting the concept that POMK mutations can be causative of WWS.ConclusionOur combined data suggest a more important role for POMK in the pathogenesis of meningoencephalocele. Only eight different pathogenic POMK variants have been published so far, detected in eight families; only five showed the severe WWS phenotype, suggesting that POMK-associated WWS is an extremely rare disease. We expand the phenotypic and mutational spectrum of POMK-associated WWS and provide evidence of the broad phenotypic variability of POMK-associated disease.
Highlights
Walker-Warburg syndrome (WWS) is a rare form of alpha-dystroglycanopathy characterized by muscular dystrophy and severe malformations of the Central nervous system (CNS) and eyes
The protein-O-mannosyl kinase gene (POMK, Online mendelian inheritance in man (OMIM) *615247) encodes a protein involved in the glycosylation of the laminin-binding O-coupled carbohydrate chain of alpha-dystroglycan (α-DG)
It is suspected that Protein-O-Mannose Kinase (POMK) plays an important role in the fetal development of myocytes, and embryonic pomk knockout zebrafish showed reduced embryonic motility and muscular dystrophy 3 days post fertilization [5]
Summary
Walker-Warburg syndrome (WWS) is a rare form of alpha-dystroglycanopathy characterized by muscular dystrophy and severe malformations of the CNS and eyes. POMK encodes protein-O-mannose kinase, which is required for proper glycosylation and function of the dystroglycan complex and is crucial for extracellular matrix composition. It is suspected that POMK plays an important role in the fetal development of myocytes, and embryonic pomk knockout zebrafish showed reduced embryonic motility and muscular dystrophy 3 days post fertilization [5]. The phenotypic presentation of both animal models accords with the hypothesis that POMK plays a significant role in muscle and nervous tissue, impacting on the differentiation of the respective cell types, and is in line with the concept of POMK as a gene occasionally associated with manifestation of brain malformations
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
