Holubova Veronika, Barone Rita, Grunewald Stephanie, Tesařová Markéta, Hansíková Hana, Augustínová Jana, Sykut-Cegielska Jolanta, De Nictolis Francesca, Diaz-Moreno Unai, Elangovan Ramyia, Epifani Florencia, Gasperini Serena, Jansen Mirian, Lefeber Dirk, Maksym-Gasiorek Dorota, Diego Martinelli, Ounap Katrin, Pettinato Fabio, Põder Haide, Rymen Daisy, Vals Mari-Anne, Serrano Mercedes, Witters Peter, Honzík Tomáš
Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
Child Neuropsychiatry-Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
J Inherit Metab Dis. 2025 Jan;48(1):e12826. doi: 10.1002/jimd.12826. Epub 2024 Dec 5.
Cardiac involvement (CI) in phosphomannomutase 2-congenital disorders of glycosylation (PMM2-CDG) is part of the multisystemic presentation contributing to high mortality rates. The most common cardiac manifestations are pericardial effusion, cardiomyopathy, and structural heart defects. A genotype-phenotype correlation with organ involvement has not yet been described. We analyzed clinical, biochemical, and molecular genetic data of 222 patients from eight European centers and characterized the natural course of patients with CI. Fifty-seven patients (45 children) presented with CI, of whom 24 died (median age 21 months, standard deviation 49.8). Pericardial effusion was the most frequent manifestation (55.4%), occurring mostly within the first 6 months of life. The most common pathogenic variants in patients with CI were p.(Arg141His) in 74%, followed by p.(Val231Met) in 36%, which is 3.5 times higher than in PMM2-CDG patients without CI (p < 0.0001). Twenty-one out of 36 patients with p.(Val231Met) had CI; among them, 15 died, compared to 33 out of 166 patients without p.(Val231Met) who had CI (p < 0.0001). Nine out of 33 patients died (p = 0.0015), indicating greater clinical severity. Furthermore, the p.(Val231Met) variant is predominant in Eastern Europe, suggesting a founder effect. Cardiac complications in PMM2-CDG patients are common and serious. The variant p.(Val231Met) profoundly influences the extent of CI and mortality rates. Therefore, we recommend cardiac surveillance be included in the follow-up protocols for PMM2-CDG.
磷酸甘露糖变位酶2先天性糖基化障碍（PMM2-CDG）中的心脏受累（CI）是导致高死亡率的多系统表现的一部分。最常见的心脏表现是心包积液、心肌病和结构性心脏缺陷。目前尚未描述与器官受累的基因型-表型相关性。我们分析了来自八个欧洲中心的222例患者的临床、生化和分子遗传学数据，并对CI患者的自然病程进行了特征描述。57例患者（45名儿童）出现CI，其中24例死亡（中位年龄21个月，标准差49.8）。心包积液是最常见的表现（55.4%），大多发生在生命的前6个月内。CI患者中最常见的致病变体是p.(Arg141His)，占74%，其次是p.(Val231Met)，占36%，这比无CI的PMM2-CDG患者高3.5倍（p<0.0001）。36例p.(Val231Met)患者中有21例出现CI；其中15例死亡，而166例无p.(Val231Met)的CI患者中有33例死亡（p<0.0001）。33例患者中有9例死亡（p=0.0015），表明临床严重程度更高。此外，p.(Val231Met)变体在东欧占主导地位，提示存在奠基者效应。PMM2-CDG患者的心脏并发症常见且严重。p.(Val231Met)变体对CI的程度和死亡率有深远影响。因此，我们建议在PMM2-CDG的随访方案中纳入心脏监测。
