Paul Luisa, Rupprich Katrin, Della Marina Adela, Stein Anja, Elgizouli Magdeldin, Kaiser Frank J, Schweiger Bernd, Köninger Angela, Iannaccone Antonella, Hehr Ute, Kölbel Heike, Roos Andreas, Schara-Schmidt Ulrike, Kuechler Alma
Department of Pediatric Neurology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Department of General Pediatrics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Orphanet J Rare Dis. 2020 Sep 9;15(1):242. doi: 10.1186/s13023-020-01454-0.
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 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.
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* in POMK, confirming the clinical diagnosis and supporting the concept that POMK mutations can be causative of WWS.
Our 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.
沃克-沃伯格综合征（WWS）是α-肌营养不良糖蛋白病的一种罕见形式，其特征为肌肉营养不良以及中枢神经系统和眼睛的严重畸形。POMK基因的双等位基因致病性变异是多种α-肌营养不良糖蛋白病的病因。POMK编码蛋白O-甘露糖激酶，该酶对于肌营养不良糖蛋白复合物的正确糖基化和功能是必需的，并且对细胞外基质组成至关重要。
在此，我们报告了一对男性同卵双胞胎，他们患有严重的中枢神经系统畸形（脑积水、皮质畸形、小脑发育不全，最显著的是枕部脑脊膜膨出）、眼部畸形以及肌酸激酶高度升高，提示先天性肌营养不良（α-肌营养不良糖蛋白病）的临床诊断。发现这对双胞胎均携带POMK基因的纯合无义突变c.640C>T，p.214*，证实了临床诊断，并支持POMK突变可导致WWS的观点。
我们的综合数据表明POMK在脑脊膜脑膨出发病机制中起更重要的作用。迄今为止，仅在8个家庭中检测到8种不同的致病性POMK变异；只有5种表现出严重的WWS表型，这表明与POMK相关的WWS是一种极其罕见的疾病。我们扩展了与POMK相关的WWS的表型和突变谱，并提供了与POMK相关疾病广泛表型变异性的证据。
