Clinical severity and cardiac phenotype in phosphomannomutase 2-congenital disorders of glycosylation : Insights into genetics and management recommendations
Por:
Holubova V, Barone R, Grunewald S, Tesarová M, Hansíková H, Augustínová J, Sykut-Cegielska J, De Nictolis F, Diaz-Moreno U, Elangovan R, Epifani F, Gasperini S, Jansen M, Lefeber D, Maksym-Gasiorek D, Diego M, Ounap K, Pettinato F, Põder H, Rymen D, Vals MA, Serrano M, Witters P and Honzík T
Publicada:
1 ene 2025
Ahead of Print:
1 dic 2024
Resumen:
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.
Filiaciones:
Holubova V:
Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
Barone R:
Child Neuropsychiatry-Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
Oasi Research Institute-IRCCS, Troina, Italy
Grunewald S:
Metabolic Unit, Great Ormond Street Hospital and Institute of Child Health, University College London, NHS Trust, London, UK
Tesarová M:
Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
Hansíková H:
Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
Augustínová J:
Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
Sykut-Cegielska J:
Department of Inborn Errors of Metabolism and Paediatrics, Institute of Mother and Child, Warsaw, Poland
De Nictolis F:
Division of Metabolism, Bambino Gesù Children's Research Hospital, Rome, Italy
Diaz-Moreno U:
Neurology Department, Hospital Sant Joan de Déu, U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain
Elangovan R:
Metabolic Unit, Great Ormond Street Hospital and Institute of Child Health, University College London, NHS Trust, London, UK
Epifani F:
Neurology Department, Hospital Sant Joan de Déu, U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain
Gasperini S:
Department of Pediatrics, Milano-Bicocca University, San Gerardo Hospital, Monza, Italy
Jansen M:
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands
Lefeber D:
Department of Human Genetics and Neurology, Translational Metabolic Laboratory, Donders Center for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
Maksym-Gasiorek D:
One Day Clinic, The Institute of Mother and Child, Warsaw, Poland
Diego M:
Division of Metabolism, Bambino Gesù Children's Research Hospital, Rome, Italy
Ounap K:
Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
Department of Clinical Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia
Pettinato F:
Child Neuropsychiatry-Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
Põder H:
Tallinn Children's Hospital, Tallinn, Estonia
Rymen D:
Department of Paediatrics and Metabolic Center, University Hospitals Leuven, Leuven, Belgium
Vals MA:
Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
Children's Clinic, Tartu University Hospital, Tartu, Estonia
Serrano M:
Neurology Department, Hospital Sant Joan de Déu, U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain
Witters P:
Department of Paediatrics and Metabolic Center, University Hospitals Leuven, Leuven, Belgium
Department of Development and Regeneration, KU Leuven, Leuven, Belgium
Honzík T:
Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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