Review

. 2017 Dec;54(12):843-851.

doi: 10.1136/jmedgenet-2017-104903. Epub 2017 Sep 27.

Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature

Manuel Schiff^{1

2}, Céline Roda³, Marie-Lorraine Monin⁴, Alina Arion⁵, Magali Barth^{6

7}, Nathalie Bednarek⁸, Maud Bidet⁹, Catherine Bloch¹⁰, Nathalie Boddaert^{11

12

13}, Delphine Borgel^{6

7}, Anaïs Brassier³, Alexis Brice^{14

15

16

17}, Arnaud Bruneel¹⁸, Roger Buissonnière¹⁹, Brigitte Chabrol²⁰, Marie-Chantal Chevalier²¹, Valérie Cormier-Daire^{22

23

24}, Claire De Barace²⁵, Emmanuel De Maistre²⁶, Anne De Saint-Martin²⁷, Nathalie Dorison²⁸, Valérie Drouin-Garraud²⁹, Thierry Dupré, Bernard Echenne³⁰, Patrick Edery³¹, François Feillet³², Isabelle Fontan³³, Christine Francannet³⁴, François Labarthe³⁵, Cyril Gitiaux³⁶, Delphine Héron³⁷, Marie Hully³, Sylvie Lamoureux³⁸, Dominique Martin-Coignard³⁹, Cyril Mignot⁴, Gilles Morin⁴⁰, Tiffany Pascreau^{6

7}, Olivier Pincemaille⁴¹, Michel Polak⁹, Agathe Roubertie, Christel Thauvin-Robinet⁴², Annick Toutain⁴³, Géraldine Viot⁴⁴, Sandrine Vuillaumier-Barrot¹⁸, Nathalie Seta¹⁸, Pascale De Lonlay³

Affiliations

¹ Reference Center for Inherited Metabolic Diseases, AP-HP, Robert Debré Hospital, University Paris Diderot-Sorbonne Paris Cité, Paris, France.
² INSERM U1141, Paris, France.
³ Reference Center for Inherited Metabolic Disease, AP-HP, Necker-Enfants Malades Hospital, IMAGINE Institute affiliate, University Paris Descartes-Sorbonne Paris Cité, Paris, France.
⁴ Department of Genetics, Molecular and Cellular Neurogenetics Unit, Reference Center for Intellectual of Rare Causes, AP-HP, GH Pitié-Salpêtrière, Paris, France.
⁵ Department of Paediatrics, Paediatric Care Unit, Caen Hospital, Caen, France.
⁶ Hematology Unit, AP-HP, Necker-Enfants Malades Hospital, Paris, France.
⁷ UMR INSERM 1176, Le Kremlin-Bicêtre, Paris, France.
⁸ Neonatal Intensive Care Unit, Institute of Alix de Champagne, Reims University Hospital, Reims, France.
⁹ Department of Paediatric Endocrinology, Gynaecology, and Diabetology, AP-HP, Necker-Enfants Malades Hospital, IMAGINE Institute affiliate, Paris, France.
¹⁰ Paediatric Unit, Fondation Lenval, Nice, France.
¹¹ Department of Paediatric Radiology, AP-HP, Necker-Enfants Malades Hospital, IMAGINE Institute affiliate, Paris, France.
¹² Sorbonne Paris Cité, INSERM U1000, Paris, France.
¹³ UMR 1163, Paris, France.
¹⁴ Sorbonne Universités, UPMC Univ Paris 06, UMR S1127, Paris, France.
¹⁵ INSERM U1127, Paris, France.
¹⁶ CNRS UMR7225, Paris, France.
¹⁷ Brain and Spine Institute (ICM), Paris, France.
¹⁸ Department of Biochemistry, AP-HP, Bichat Hospital, Rouen, France.
¹⁹ Pediatric Unit, André Mignot Hospital, Versailles, France.
²⁰ Reference Center for Inherited Metabolic Diseases, Timone Enfants University Hospital, Marseille, France.
²¹ Department of Paediatrics, Le Mans Hospital, Le Mans, France.
²² Departement of Genetics, Centre of Reference for Skeletal Dysplas, AP-HP, Necker-Enfants Malades Hospital, Paris, France.
²³ INSERM UMR1163, IMAGINE Institute affiliate, Paris, France.
²⁴ University Paris Descartes-Sorbonne Paris Cité, Paris, France.
²⁵ Paediatric Unit, Saint Brieuc Hospital, Saint Brieuc, France.
²⁶ Haematological Laboratory, Dijon Hospita, Dijon, France.
²⁷ Paediatric Neurology, Department of Pediatrics, University Hospital, Strasbourg, France.
²⁸ Pediatric Neurology Department and Neurofibromatosis Reference Center, AP-HP, Armand Trousseau Hospital, Paris, France.
²⁹ Medical Genetics Unit, Rouen University Hospital, Rouen, France.
³⁰ Paediatric Neurology Unit, University of Montpellier I, Montpellier, France.
³¹ Department of Genetic, Lyon University Hospitals, Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France.
³² Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France.
³³ Department of Dermatology and Paediatric Dermatology, Bordeaux University Hospitals, Bordeaux, France.
³⁴ Medical Genetics Unit, Clermont-Ferrand Hospital, Clermont-Ferrand, France.
³⁵ Department of Paediatric, Tours Regional University Hospitals, Tours, France.
³⁶ Department of Child Neurology, Reference Centre for Neuromuscular Diseases, AP-HP, Necker-Enfants Malades Hospital, Paris, France.
³⁷ GRC Intellectual Disability and Autism, UPMC Univ Paris 6, Paris, France.
³⁸ Department of Paediatric, Henri-Duffaut Hospital, Avignon, France.
³⁹ Department of Genetic, Le Mans Hospital, Le Mans, France.
⁴⁰ Department of Genetic, Amiens University Hospital, Amiens, France.
⁴¹ Department of Paediatrics, Grasse Hospital, France.
⁴² Departement of Genetic, Children's Hospital, Dijon, France.
⁴³ Division of Genetics, Bretonneau Hospital, Tours, France.
⁴⁴ Department of Gynecology-Obstetrics, Faculty of Medicine, AP-HP, Cochin Hospital, Paris Descartes University‒Sorbonne Paris Cité, Paris, France.

PMID: 28954837
DOI: 10.1136/jmedgenet-2017-104903

Review

Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature

Manuel Schiff et al. J Med Genet. 2017 Dec.

. 2017 Dec;54(12):843-851.

doi: 10.1136/jmedgenet-2017-104903. Epub 2017 Sep 27.

Authors

Affiliations

¹ Reference Center for Inherited Metabolic Diseases, AP-HP, Robert Debré Hospital, University Paris Diderot-Sorbonne Paris Cité, Paris, France.
² INSERM U1141, Paris, France.
³ Reference Center for Inherited Metabolic Disease, AP-HP, Necker-Enfants Malades Hospital, IMAGINE Institute affiliate, University Paris Descartes-Sorbonne Paris Cité, Paris, France.
⁴ Department of Genetics, Molecular and Cellular Neurogenetics Unit, Reference Center for Intellectual of Rare Causes, AP-HP, GH Pitié-Salpêtrière, Paris, France.
⁵ Department of Paediatrics, Paediatric Care Unit, Caen Hospital, Caen, France.
⁶ Hematology Unit, AP-HP, Necker-Enfants Malades Hospital, Paris, France.
⁷ UMR INSERM 1176, Le Kremlin-Bicêtre, Paris, France.
⁸ Neonatal Intensive Care Unit, Institute of Alix de Champagne, Reims University Hospital, Reims, France.
⁹ Department of Paediatric Endocrinology, Gynaecology, and Diabetology, AP-HP, Necker-Enfants Malades Hospital, IMAGINE Institute affiliate, Paris, France.
¹⁰ Paediatric Unit, Fondation Lenval, Nice, France.
¹¹ Department of Paediatric Radiology, AP-HP, Necker-Enfants Malades Hospital, IMAGINE Institute affiliate, Paris, France.
¹² Sorbonne Paris Cité, INSERM U1000, Paris, France.
¹³ UMR 1163, Paris, France.
¹⁴ Sorbonne Universités, UPMC Univ Paris 06, UMR S1127, Paris, France.
¹⁵ INSERM U1127, Paris, France.
¹⁶ CNRS UMR7225, Paris, France.
¹⁷ Brain and Spine Institute (ICM), Paris, France.
¹⁸ Department of Biochemistry, AP-HP, Bichat Hospital, Rouen, France.
¹⁹ Pediatric Unit, André Mignot Hospital, Versailles, France.
²⁰ Reference Center for Inherited Metabolic Diseases, Timone Enfants University Hospital, Marseille, France.
²¹ Department of Paediatrics, Le Mans Hospital, Le Mans, France.
²² Departement of Genetics, Centre of Reference for Skeletal Dysplas, AP-HP, Necker-Enfants Malades Hospital, Paris, France.
²³ INSERM UMR1163, IMAGINE Institute affiliate, Paris, France.
²⁴ University Paris Descartes-Sorbonne Paris Cité, Paris, France.
²⁵ Paediatric Unit, Saint Brieuc Hospital, Saint Brieuc, France.
²⁶ Haematological Laboratory, Dijon Hospita, Dijon, France.
²⁷ Paediatric Neurology, Department of Pediatrics, University Hospital, Strasbourg, France.
²⁸ Pediatric Neurology Department and Neurofibromatosis Reference Center, AP-HP, Armand Trousseau Hospital, Paris, France.
²⁹ Medical Genetics Unit, Rouen University Hospital, Rouen, France.
³⁰ Paediatric Neurology Unit, University of Montpellier I, Montpellier, France.
³¹ Department of Genetic, Lyon University Hospitals, Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France.
³² Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France.
³³ Department of Dermatology and Paediatric Dermatology, Bordeaux University Hospitals, Bordeaux, France.
³⁴ Medical Genetics Unit, Clermont-Ferrand Hospital, Clermont-Ferrand, France.
³⁵ Department of Paediatric, Tours Regional University Hospitals, Tours, France.
³⁶ Department of Child Neurology, Reference Centre for Neuromuscular Diseases, AP-HP, Necker-Enfants Malades Hospital, Paris, France.
³⁷ GRC Intellectual Disability and Autism, UPMC Univ Paris 6, Paris, France.
³⁸ Department of Paediatric, Henri-Duffaut Hospital, Avignon, France.
³⁹ Department of Genetic, Le Mans Hospital, Le Mans, France.
⁴⁰ Department of Genetic, Amiens University Hospital, Amiens, France.
⁴¹ Department of Paediatrics, Grasse Hospital, France.
⁴² Departement of Genetic, Children's Hospital, Dijon, France.
⁴³ Division of Genetics, Bretonneau Hospital, Tours, France.
⁴⁴ Department of Gynecology-Obstetrics, Faculty of Medicine, AP-HP, Cochin Hospital, Paris Descartes University‒Sorbonne Paris Cité, Paris, France.

PMID: 28954837
DOI: 10.1136/jmedgenet-2017-104903

Abstract

Background: Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a multisystem inborn error of metabolism.

Objectives: To better characterise the natural history of PMM2-CDG.

Methods: Medical charts of 96 patients with PMM2-CDG (86 families, 41 males, 55 females) were retrospectively reviewed. Data on clinical, laboratory and molecular parameters at diagnosis were analysed. Follow-up data at last examination were reported for 25 patients.

Results: The patients were born between 1963 and 2011. Diagnosis of PMM2-CDG was made at a mean (SD) age of 6.8 (8.5) years. The presenting signs were mostly neurological (hypotonia, intellectual disability, cerebellar syndrome) and observed in almost all the patients. A total of 38 patients (14 males, 24 females) exhibited, in addition to neurological signs, visceral features including at least one of these: feeding difficulty requiring a nutritional support (n=23), cardiac features (n=20; pericarditis: 14, cardiac malformation: 9, cardiomyopathy: 2), hepato-gastrointestinal features (n=12; chronic diarrhoea: 7, protein-losing enteropathy: 1, ascites: 3, liver failure: 1, portal hypertension: 1), kidney features (n=4; nephrotic syndrome: 2, tubulopathy: 2) and hydrops fetalis (n=1). Twelve patients died at a mean age of 3.8 years (especially from pericarditis and other cardiac issues). Laboratory abnormalities mostly included elevated transaminases and abnormal coagulation parameters. High thyreostimulin levels, hypocholesterolemia, hypoalbuminemia and elevated transaminases were associated with the visceral phenotype. Besides the common Arg141His PMM2 variant harboured by half of the patients, 45 different variants were observed.

Conclusions: PMM2-CDG clinical phenotype is heterogeneous in terms of clinical course, with no clear division between neurological and visceral presentations.

Keywords: CDG-I; PMM2-CDG; congenital disorders of glycosylation; phosphomannomutase.

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Conflict of interest statement

Competing interests: None declared.

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Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature

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Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature

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