Journal of Inherited Metabolic Disease

, Volume 41, Issue 3, pp 541–553 | Cite as

Recognizable phenotypes in CDG

  • Carlos R. Ferreira
  • Ruqaia Altassan
  • Dorinda Marques-Da-Silva
  • Rita Francisco
  • Jaak Jaeken
  • Eva MoravaEmail author


Pattern recognition, using a group of characteristic, or discriminating features, is a powerful tool in metabolic diagnostic. A classic example of this approach is used in biochemical analysis of urine organic acid analysis, where the reporting depends more on the correlation of pertinent positive and negative findings, rather than on the absolute values of specific markers. Similar uses of pattern recognition in the field of biochemical genetics include the interpretation of data obtained by metabolomics, like glycomics, where a recognizable pattern or the presence of a specific glycan sub-fraction can lead to the direct diagnosis of certain types of congenital disorders of glycosylation. Another indispensable tool is the use of clinical pattern recognition–or syndromology–relying on careful phenotyping. While genomics might uncover variants not essential in the final clinical expression of disease, and metabolomics could point to a mixture of primary but also secondary changes in biochemical pathways, phenomics describes the clinically relevant manifestations and the full expression of the disease. In the current review we apply phenomics to the field of congenital disorders of glycosylation, focusing on recognizable differentiating findings in glycosylation disorders, characteristic dysmorphic features and malformations in PMM2-CDG, and overlapping patterns among the currently known glycosylation disorders based on their pathophysiological basis.



This study is supported by the 1805218 N FWO subsidie, in part by the Hayward Foundation and by 1 U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds the Louisiana Clinical and Translational Science Center. Additionally this work was supported by the European Union’s Horizon 2020 research and innovation program under the ERA-NET Cofund action N° 643578 –EURO-CDG-2.

Compliance with ethical standards

Conflicts of interest

C. Ferreira, R. Altassan, R. Francesco, D. Marquez-Da-Silva, J. Jaeken and E. Morava declare that they have no conflict of interest.

Supplementary material

10545_2018_156_MOESM1_ESM.xlsx (47 kb)
ESM 1 (XLSX 47 kb)


  1. Al Teneiji A, Bruun TUJ, Sidky S et al (2017) Phenotypic and genotypic spectrum of congenital disorders of glycosylation type I and type II. Mol Genet Metab 120:235–242CrossRefPubMedGoogle Scholar
  2. Al-Maawali AA, Miller E, Schulze A et al (2014) Subcutaneous fat pads on body MRI--an early sign of congenital disorder of glycosylation PMM2-CDG (CDG1a). Pediatr Radiol 44:222–225CrossRefPubMedGoogle Scholar
  3. Antoun H, Villeneuve N, Gelot A et al (1999) Cerebellar atrophy: an important feature of carbohydrate deficient glycoprotein syndrome type 1. Pediatr Radiol 29:194–198CrossRefPubMedGoogle Scholar
  4. Artigas J, Cardo E, Pineda M et al (1998) Phosphomannomutase deficiency and normal pubertal development. J Inherit Metab Dis 21:78–79CrossRefPubMedGoogle Scholar
  5. Barone R, Carrozzi M, Parini R et al (2015) A nationwide survey of PMM2-CDG in Italy: high frequency of a mild neurological variant associated with the L32R mutation. J Neurol 262:154–164CrossRefPubMedGoogle Scholar
  6. Barone R, Sturiale L, Sofia V et al (2008) Clinical phenotype correlates to glycoprotein phenotype in a sib pair with CDG-Ia. Am J Med Genet A 146A:2103–2108CrossRefPubMedGoogle Scholar
  7. Bengtson P, Ng BG, Jaeken J et al (2016) Serum transferrin carrying the xeno-tetrasaccharide NeuAc-gal-GlcNAc2 is a biomarker of ALG1-CDG. J Inherit Metab Dis 39(1):107–114CrossRefPubMedGoogle Scholar
  8. Bortot B, Cosentini D, Faletra F et al (2013) PMM2-CDG: phenotype and genotype in four affected family members. Gene 531:506–509CrossRefPubMedGoogle Scholar
  9. Briones P, Vilaseca MA, Schollen E et al (2002) Biochemical and molecular studies in 26 Spanish patients with congenital disorder of glycosylation type Ia. J Inherit Metab Dis 25:635–646CrossRefPubMedGoogle Scholar
  10. Brum JM, De Rizzo IMPO, de Mello WD, Speck-Martins CE (2008) Congenital disorder of glycosylation type Ia: a non-progressive encephalopathy associated with multisystemic involvement. Arq Neuropsiquiatr 66:545–548CrossRefPubMedGoogle Scholar
  11. Bubel S, Peters V, Klein C et al (2002) CDG (congenital disorders of glycosylation). Differential hereditary ataxia in adulthood diagnosis. Nervenarzt 73:754–760CrossRefPubMedGoogle Scholar
  12. Buczkowska A, Swiezewska E, Lefeber DJ (2015) Genetic defects in dolichol metabolism. J Inherit Metab Dis 38(1):157–169CrossRefPubMedGoogle Scholar
  13. Clayton PT, Winchester BG, Keir G (1992) Hypertrophic obstructive cardiomyopathy in a neonate with the carbohydrate-deficient glycoprotein syndrome. J Inherit Metab Dis 15:857–861CrossRefPubMedGoogle Scholar
  14. Cossins J, Belaya K, Hicks D et al (2013) Congenital myasthenic syndromes due to mutations in ALG2 and ALG14. Brain J Neurol 136:944–956CrossRefGoogle Scholar
  15. de Lonlay P, Seta N, Barrot S et al (2001) A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases. J Med Genet 38:14–19CrossRefPubMedPubMedCentralGoogle Scholar
  16. de Michelena MI, Franchi LM, Summers PG et al (1999) Carbohydrate-deficient glycoprotein syndrome due to phosphomannomutase deficiency: the first reported cases from Latin America. Am J Med Genet 84:481–483CrossRefPubMedGoogle Scholar
  17. Dörre K, Olczak M, Wada Y et al (2015) A new case of UDP-galactose transporter deficiency (SLC35A2-CDG): molecular basis, clinical phenotype, and therapeutic approach. J Inherit Metab Dis 38(5):931–940CrossRefPubMedGoogle Scholar
  18. Edwards M, McKenzie F, O’callaghan S et al (2006) Prenatal diagnosis of congenital disorder of glycosylation type Ia (CDG-Ia) by cordocentesis and transferrin isoelectric focussing of serum of a 27-week fetus with non-immune hydrops. Prenat Diagn 26:985–988CrossRefPubMedGoogle Scholar
  19. Endo T (2015) Glycobiology of α-dystroglycan and muscular dystrophy. J Biochem 157(1):1–12CrossRefPubMedGoogle Scholar
  20. Enns GM, Steiner RD, Buist N et al (2002) Clinical and molecular features of congenital disorder of glycosylation in patients with type 1 sialotransferrin pattern and diverse ethnic origins. J Pediatr 141:695–700CrossRefPubMedGoogle Scholar
  21. Erlandson A, Bjursell C, Stibler H et al (2001) Scandinavian CDG-Ia patients: genotype/phenotype correlation and geographic origin of founder mutations. Hum Genet 108:359–367CrossRefPubMedGoogle Scholar
  22. Garel C, Baumann C, Besnard M et al (1998) Carbohydrate-deficient glycoprotein syndrome type I: a new cause of dysostosis multiplex. Skelet Radiol 27:43–45CrossRefGoogle Scholar
  23. Grünewald S, Schollen E, Van Schaftingen E et al (2001) High residual activity of PMM2 in patients’ fibroblasts: possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency). Am J Hum Genet 68:347–354CrossRefPubMedPubMedCentralGoogle Scholar
  24. Harding BN, Dunger DB, Grant DB, Erdohazi M (1988) Familial olivopontocerebellar atrophy with neonatal onset: a recessively inherited syndrome with systemic and biochemical abnormalities. J Neurol Neurosurg Psychiatry 51:385–390CrossRefPubMedPubMedCentralGoogle Scholar
  25. Hertz-Pannier L, Déchaux M, Sinico M et al (2006) Congenital disorders of glycosylation type I: a rare but new cause of hyperechoic kidneys in infants and children due to early microcystic changes. Pediatr Radiol 36(2):108–114CrossRefPubMedGoogle Scholar
  26. Höck M, Wegleiter K, Ralser E et al (2015) ALG8-CDG: novel patients and review of the literature. Orphanet J Rare Dis 10:73CrossRefPubMedPubMedCentralGoogle Scholar
  27. Honzík T, Magner M, Krijt J et al (2012) Clinical picture of S-adenosylhomocysteine hydrolase deficiency resembles phosphomannomutase 2 deficiency. Mol Genet Metab 107:611–613CrossRefPubMedGoogle Scholar
  28. Imtiaz F, Worthington V, Champion M et al (2000) Genotypes and phenotypes of patients in the UK with carbohydrate-deficient glycoprotein syndrome type 1. J Inherit Metab Dis 23:162–174CrossRefPubMedGoogle Scholar
  29. Işıkay S, Başpınar O, Yılmaz K (2014) A case of congenital disorder of glycosylation ia presented with recurrent pericardial effusion. Iran J Pediatr 24:652–654PubMedPubMedCentralGoogle Scholar
  30. Jaeken J, Péanne R (2017) What is new in CDG? J Inherit Metab Dis 40(4):569–586CrossRefPubMedGoogle Scholar
  31. Kasapkara ÇS, Barış Z, Kılıç M et al (2017) PMM2-CDG and sensorineural hearing loss. J Inherit Metab Dis 40:629-630Google Scholar
  32. Kjaergaard S, Schwartz M, Skovby F (2001) Congenital disorder of glycosylation type Ia (CDG-Ia): phenotypic spectrum of the R141H/F119L genotype. Arch Dis Child 85:236–239CrossRefPubMedPubMedCentralGoogle Scholar
  33. Krasnewich DM, Holt GD, Brantly M et al (1995) Abnormal synthesis of dolichol-linked oligosaccharides in carbohydrate-deficient glycoprotein syndrome. Glycobiology 5(5):503–510CrossRefPubMedGoogle Scholar
  34. Laplace O, Voegtle R, Rigolet M-H et al (2003) Early ocular manifestations in an infant with carbohydrate-deficient glycoprotein syndrome type Ia. J Pediatr Ophthalmol Strabismus 40:179–181PubMedGoogle Scholar
  35. Léticée N, Bessières-Grattagliano B, Dupré T et al (2010) Should PMM2-deficiency (CDG Ia) be searched in every case of unexplained hydrops fetalis? Mol Genet Metab 101:253–257CrossRefPubMedGoogle Scholar
  36. Lumaka A, Cosemans N, Lulebo Mampasi A et al (2017) Facial dysmorphism is influenced by ethnic background of the patient and of the evaluator. Clin Genet 92:166–171CrossRefPubMedGoogle Scholar
  37. Marques-da-Silva D, Dos Reis FV, Monticelli M et al (2017a) Liver involvement in congenital disorders of glycosylation (CDG). A systematic review of the literature. J Inherit Metab Dis 40(2):195–207CrossRefPubMedGoogle Scholar
  38. Marques-da-Silva D, Francisco R, Webster D et al (2017b) Cardiac complications of congenital disorders of glycosylation (CDG): a systematic review of the literature. J Inherit Metab Dis 40(5):657–672CrossRefPubMedGoogle Scholar
  39. Monin M-L, Mignot C, De Lonlay P et al (2014) 29 French adult patients with PMM2-congenital disorder of glycosylation: outcome of the classical pediatric phenotype and depiction of a late-onset phenotype. Orphanet J Rare Dis 9:207CrossRefPubMedPubMedCentralGoogle Scholar
  40. Morava E, Cser B, Kárteszi J et al (2004) Screening for CDG type Ia in Joubert syndrome. Med Sci Monit Int Med J Exp Clin Res 10:CR469–CR472Google Scholar
  41. Morava E, Tiemes V, Thiel C et al (2016) ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies. J Inherit Metab Dis 39:713–723CrossRefPubMedGoogle Scholar
  42. Noelle V, Knuepfer M, Pulzer F et al (2005) Unusual presentation of congenital disorder of glycosylation type 1a: congenital persistent thrombocytopenia, hypertrophic cardiomyopathy and hydrops-like aspect due to marked peripheral oedema. Eur J Pediatr 164:223–226CrossRefPubMedGoogle Scholar
  43. Panneerselvam K, Freeze HH (1996) Mannose corrects altered N-glycosylation in carbohydrate-deficient glycoprotein syndrome fibroblasts. J Clin invest. 97:1478-87Google Scholar
  44. Pavone L, Fiumara A, Barone R et al (1996) Olivopontocerebellar atrophy leading to recognition of carbohydrate-deficient glycoprotein syndrome type I. J Neurol 243:700–705CrossRefPubMedGoogle Scholar
  45. Pérez B, Briones P, Quelhas D et al (2011) The molecular landscape of phosphomannose mutase deficiency in iberian peninsula: identification of 15 population-specific mutations. JIMD Rep 1:117–123CrossRefPubMedPubMedCentralGoogle Scholar
  46. Regal L, van Hasselt PM, Foulquier F et al (2015) ALG11-CDG: three novel mutations and further characterization of the phenotype. Mol Genet Metab Rep 2:16–19CrossRefPubMedGoogle Scholar
  47. Resende C, Carvalho C, Alegria A et al (2014) Congenital disorders of glycosylation with neonatal presentation. BMJ Case RepGoogle Scholar
  48. Riley LG, Cowley MJ, Gayevskiy V et al (2017) A SLC39A8 variant causes manganese deficiency, and glycosylation and mitochondrial disorders. J Inherit Metab Dis 40(2):261–269CrossRefPubMedGoogle Scholar
  49. Rind N, Schmeiser V, Thiel C et al (2010) A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase hALG11 leads to congenital disorder of glycosylation-Ip. Hum Mol Genet 19:1413–1424CrossRefPubMedGoogle Scholar
  50. Romano S, Bajolle F, Valayannopoulos V et al (2009) Conotruncal heart defects in three patients with congenital disorder of glycosylation type Ia (CDG Ia). J Med Genet 46:287–288CrossRefPubMedGoogle Scholar
  51. Rudaks LI, Andersen C, Khong TY et al (2012) Hypertrophic cardiomyopathy with cardiac rupture and tamponade caused by congenital disorder of glycosylation type Ia. Pediatr Cardiol 33:827–830CrossRefPubMedGoogle Scholar
  52. Senderek J, Müller JS, Dusl M et al (2011) Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. Am J Hum Genet 88:162–172CrossRefPubMedPubMedCentralGoogle Scholar
  53. Serrano M, de Diego V, Muchart J et al (2015) Phosphomannomutase deficiency (PMM2-CDG): ataxia and cerebellar assessment. Orphanet J Rare Dis 10:138CrossRefPubMedPubMedCentralGoogle Scholar
  54. Stark KL, Gibson JB, Hertle RW, Brodsky MC (2000) Ocular motor signs in an infant with carbohydrate-deficient glycoprotein syndrome type Ia. Am J Ophthalmol 130:533–535CrossRefPubMedGoogle Scholar
  55. Schiff M, Roda C, Monin ML et al (2017) 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. J Med Genet 54(12):843–851CrossRefPubMedGoogle Scholar
  56. Tayebi N, Andrews DQ, Park JK et al (2002) A deletion-insertion mutation in the phosphomannomutase 2 gene in an African American patient with congenital disorders of glycosylation-Ia. Am J Med Genet 108:241–246CrossRefPubMedGoogle Scholar
  57. Tham E, Eklund EA, Hammarsjö A et al (2016) A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9. Eur J Hum Genet EJHG 24:198–207CrossRefPubMedGoogle Scholar
  58. Thompson DA, Lyons RJ, Russell-Eggitt I et al (2013) Retinal characteristics of the congenital disorder of glycosylation PMM2-CDG. J Inherit Metab Dis 36:1039–1047CrossRefPubMedGoogle Scholar
  59. Thong MK, Fietz M, Nicholls C et al (2009) Congenital disorder of glycosylation type Ia in a Malaysian family: clinical outcome and description of a novel PMM2 mutation. J Inherit Metab Dis 32(Suppl 1):S41–S44CrossRefPubMedGoogle Scholar
  60. Truin G, Guillard M, Lefeber DJ et al (2008) Pericardial and abdominal fluid accumulation in congenital disorder of glycosylation type Ia. Mol Genet Metab 94:481–484CrossRefPubMedGoogle Scholar
  61. Vabres P, Sevin C, Amoric JC et al (1998) Skin manifestations of protein glycosylation deficiency, the CDG (carbohydrate deficient glycoprotein) type 1 syndrome. Ann Dermatol Venereol 125:715–716PubMedGoogle Scholar
  62. van de Kamp JM, Lefeber DJ, Ruijter GJG et al (2007) Congenital disorder of glycosylation type Ia presenting with hydrops fetalis. J Med Genet 44:277–280CrossRefPubMedGoogle Scholar
  63. Veneselli E, Biancheri R, Di Rocco M, Tortorelli S (1998) Neurophysiological findings in a case of carbohydrate-deficient glycoprotein (CDG) syndrome type I with phosphomannomutase deficiency. Eur J Paediatr Neurol EJPN Off J Eur Paediatr Neurol Soc 2:239–244CrossRefGoogle Scholar
  64. Vermeer S, Kremer HPH, Leijten QH et al (2007) Cerebellar ataxia and congenital disorder of glycosylation Ia (CDG-Ia) with normal routine CDG screening. J Neurol 254:1356–1358CrossRefPubMedGoogle Scholar
  65. Vleugels W, Haeuptle MA, Ng BG et al (2009a) RFT1 deficiency in three novel CDG patients. Hum Mutat 30:1428–1434CrossRefPubMedGoogle Scholar
  66. Vleugels W, Keldermans L, Jaeken J et al (2009b) Quality control of glycoproteins bearing truncated glycans in an ALG9-defective (CDG-IL) patient. Glycobiology 19(8):910–917CrossRefPubMedGoogle Scholar
  67. Wolthuis DFGJ, van Asbeck EV, Kozicz T, Morava E (2013) Abnormal fat distribution in PMM2-CDG. Mol Genet Metab 110:411–413CrossRefPubMedGoogle Scholar
  68. Wu X, Rush JS, Karaoglu D et al (2003) Deficiency of UDP-GlcNAc:dolichol phosphate N-Acetylglucosamine-1 phosphate transferase (DPAGT1) causes a novel congenital disorder of glycosylation type Ij. Hum Mutat 22:144–150CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM 2018

Authors and Affiliations

  1. 1.Medical Genetics Branch National Human Genome Research InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Division of Genetics and MetabolismChildren’s National Medical CenterWashingtonUSA
  3. 3.Metabolic Center, Department of PediatricsUniversity Hospitals LeuvenLeuvenBelgium
  4. 4.Department of Development and Regeneration, Faculty of MedicineKU LeuvenLeuvenBelgium
  5. 5.UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e TecnologiaUniversidade NOVA de LisboaLisboaPortugal
  6. 6.Portuguese Association for CDGLisboaPortugal
  7. 7.Department of Clinical Genomics, Center for Individualized MedicineMayo ClinicRochesterUSA

Personalised recommendations