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.
- congenital disorders of glycosylation
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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.