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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
  1. Manuel Schiff1,2,
  2. Céline Roda3,
  3. Marie-Lorraine Monin4,
  4. Alina Arion5,
  5. Magali Barth6,7,
  6. Nathalie Bednarek8,
  7. Maud Bidet9,
  8. Catherine Bloch10,
  9. Nathalie Boddaert11,12,13,
  10. Delphine Borgel6,7,
  11. Anaïs Brassier3,
  12. Alexis Brice14,15,16,17,
  13. Arnaud Bruneel18,
  14. Roger Buissonnière19,
  15. Brigitte Chabrol20,
  16. Marie-Chantal Chevalier21,
  17. Valérie Cormier-Daire22,23,24,
  18. Claire De Barace25,
  19. Emmanuel De Maistre26,
  20. Anne De Saint-Martin27,
  21. Nathalie Dorison28,
  22. Valérie Drouin-Garraud29,
  23. Thierry Dupré,
  24. Bernard Echenne30,
  25. Patrick Edery31,
  26. François Feillet32,
  27. Isabelle Fontan33,
  28. Christine Francannet34,
  29. François Labarthe35,
  30. Cyril Gitiaux36,
  31. Delphine Héron37,
  32. Marie Hully3,
  33. Sylvie Lamoureux38,
  34. Dominique Martin-Coignard39,
  35. Cyril Mignot4,
  36. Gilles Morin40,
  37. Tiffany Pascreau6,7,
  38. Olivier Pincemaille41,
  39. Michel Polak9,
  40. Agathe Roubertie,
  41. Christel Thauvin-Robinet42,
  42. Annick Toutain43,
  43. Géraldine Viot44,
  44. Sandrine Vuillaumier-Barrot18,
  45. Nathalie Seta18,
  46. Pascale De Lonlay3
  1. 1 Reference Center for Inherited Metabolic Diseases, AP-HP, Robert Debré Hospital, University Paris Diderot-Sorbonne Paris Cité, Paris, France
  2. 2 INSERM U1141, Paris, France
  3. 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. 4 Department of Genetics, Molecular and Cellular Neurogenetics Unit, Reference Center for Intellectual of Rare Causes, AP-HP, GH Pitié-Salpêtrière, Paris, France
  5. 5 Department of Paediatrics, Paediatric Care Unit, Caen Hospital, Caen, France
  6. 6 Hematology Unit, AP-HP, Necker-Enfants Malades Hospital, Paris, France
  7. 7 UMR INSERM 1176, Le Kremlin-Bicêtre, Paris, France
  8. 8 Neonatal Intensive Care Unit, Institute of Alix de Champagne, Reims University Hospital, Reims, France
  9. 9 Department of Paediatric Endocrinology, Gynaecology, and Diabetology, AP-HP, Necker-Enfants Malades Hospital, IMAGINE Institute affiliate, Paris, France
  10. 10 Paediatric Unit, Fondation Lenval, Nice, France
  11. 11 Department of Paediatric Radiology, AP-HP, Necker-Enfants Malades Hospital, IMAGINE Institute affiliate, Paris, France
  12. 12 Sorbonne Paris Cité, INSERM U1000, Paris, France
  13. 13 UMR 1163, Paris, France
  14. 14 Sorbonne Universités, UPMC Univ Paris 06, UMR S1127, Paris, France
  15. 15 INSERM U1127, Paris, France
  16. 16 CNRS UMR7225, Paris, France
  17. 17 Brain and Spine Institute (ICM), Paris, France
  18. 18 Department of Biochemistry, AP-HP, Bichat Hospital, Rouen, France
  19. 19 Pediatric Unit, André Mignot Hospital, Versailles, France
  20. 20 Reference Center for Inherited Metabolic Diseases, Timone Enfants University Hospital, Marseille, France
  21. 21 Department of Paediatrics, Le Mans Hospital, Le Mans, France
  22. 22 Departement of Genetics, Centre of Reference for Skeletal Dysplas, AP-HP, Necker-Enfants Malades Hospital, Paris, France
  23. 23 INSERM UMR1163, IMAGINE Institute affiliate, Paris, France
  24. 24 University Paris Descartes-Sorbonne Paris Cité, Paris, France
  25. 25 Paediatric Unit, Saint Brieuc Hospital, Saint Brieuc, France
  26. 26 Haematological Laboratory, Dijon Hospita, Dijon, France
  27. 27 Paediatric Neurology, Department of Pediatrics, University Hospital, Strasbourg, France
  28. 28 Pediatric Neurology Department and Neurofibromatosis Reference Center, AP-HP, Armand Trousseau Hospital, Paris, France
  29. 29 Medical Genetics Unit, Rouen University Hospital, Rouen, France
  30. 30 Paediatric Neurology Unit, University of Montpellier I, Montpellier, France
  31. 31 Department of Genetic, Lyon University Hospitals, Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France
  32. 32 Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France
  33. 33 Department of Dermatology and Paediatric Dermatology, Bordeaux University Hospitals, Bordeaux, France
  34. 34 Medical Genetics Unit, Clermont-Ferrand Hospital, Clermont-Ferrand, France
  35. 35 Department of Paediatric, Tours Regional University Hospitals, Tours, France
  36. 36 Department of Child Neurology, Reference Centre for Neuromuscular Diseases, AP-HP, Necker-Enfants Malades Hospital, Paris, France
  37. 37 GRC Intellectual Disability and Autism, UPMC Univ Paris 6, Paris, France
  38. 38 Department of Paediatric, Henri-Duffaut Hospital, Avignon, France
  39. 39 Department of Genetic, Le Mans Hospital, Le Mans, France
  40. 40 Department of Genetic, Amiens University Hospital, Amiens, France
  41. 41 Department of Paediatrics, Grasse Hospital, France
  42. 42 Departement of Genetic, Children’s Hospital, Dijon, France
  43. 43 Division of Genetics, Bretonneau Hospital, Tours, France
  44. 44 Department of Gynecology-Obstetrics, Faculty of Medicine, AP-HP, Cochin Hospital, Paris Descartes University‒Sorbonne Paris Cité, Paris, France
  1. Correspondence to Professor Pascale De Lonlay, Reference Center for Inherited Metabolic Diseases, Université Paris Descartes, Hôpital Necker-Enfants Malades, Imagine Institute, Paris, 75015, France; pascale.delonlay{at}


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.

  • CDG-I
  • congenital disorders of glycosylation
  • phosphomannomutase
  • PMM2-CDG

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  • MS and CR contributed equally,

  • NS and PDL contributed equally.

  • Contributors MS, CR, NS and PDL performed the study, analysed the data and wrote the manuscript. SV-B and NS performed molecular studies. AB, TD and NS performed biochemical studies. NB reviewed brain MRIs. DB and TP reviewed coagulation parameters data. M-LM, AA, M Barth, NB, M Bidet, CB, A Brassier, A Brice, RB, BC, M-CC, VC-D, CDB, EDM, ADS-M, ND, VD-G, BE, PE, FF, IF, CF, FL, CG, DH, MH, SL, DM-C, CM, GM, OP, MP, AR, CTR, AT and GV took care of the patients, provided the data and critically reviewed the manuscript.

  • Funding This work was supported by grant ERARE11-135 of the ERA-Net for Research Programs on Rare Diseases Joint Transnational Call 2011 (EURO-CDG) and ANR-15RAR3-0004-06 under the frame of E-RARE-3, the ERA-Net for Research on Rare Diseases.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Necker Hospital Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.