Journal of Inherited Metabolic Disease

, Volume 40, Issue 2, pp 195–207 | Cite as

Liver involvement in congenital disorders of glycosylation (CDG). A systematic review of the literature

  • D. Marques-da-Silva
  • V. dos Reis Ferreira
  • M. Monticelli
  • P. Janeiro
  • P. A. Videira
  • P. Witters
  • J. JaekenEmail author
  • D. CassimanEmail author


Congenital disorders of glycosylation (CDG) are a rapidly growing family of genetic diseases caused by defects in glycosylation. Nearly 100 CDG types are known so far. Patients present a great phenotypic diversity ranging from poly- to mono-organ/system involvement and from very mild to extremely severe presentation. In this literature review, we summarize the liver involvement reported in CDG patients. Although liver involvement is present in only a minority of the reported CDG types (22 %), it can be debilitating or even life-threatening. Sixteen of the patients we collated here developed cirrhosis, 10 had liver failure. We distinguish two main groups: on the one hand, the CDG types with predominant or isolated liver involvement including MPI-CDG, TMEM199-CDG, CCDC115-CDG, and ATP6AP1-CDG, and on the other hand, the CDG types associated with liver disease but not as a striking, unique or predominant feature, including PMM2-CDG, ALG1-CDG, ALG3-CDG, ALG6-CDG, ALG8-CDG, ALG9-CDG, PGM1-CDG, and COG-CDG. This review aims to facilitate CDG patient identification and to understand CDG liver involvement, hopefully leading to earlier diagnosis, and better management and treatment.


Liver Involvement Cutis Laxa Ductal Plate Malformation Conserve Oligomeric Golgi PMM2 Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.





Alkaline phosphatase


Alanine aminotransferase


Aspartate aminotransferase




Congenital disorder(s) of glycosylation


Creatine kinase


Endoplasmic reticulum


Endoplasmic reticulum-Golgi intermediate compartment


Gamma-glutamyl transferase




Prothrombin time


Partial thromboplastin time





Dorinda Marques da Silva acknowledges support from the “Second Liliana Scientific Scholarship 2016”. We also thank the CDG & Allies – Professionals and Patient Associations International Network (CDG & Allies PPAIN), whose network expertise greatly helped this manuscript. We are grateful to Diogo Sampaio (, who helped design Fig. 1 of this publication.

Compliance with ethics guidelines

Conflict of interests

Vanessa dos Reis Ferreira is President and founder of the Portuguese Association for CDG and other Rare Metabolic Diseases (APCDG-DMR). All other authors declare no competing financial interests.


This work was supported by the CDG Professionals and Patient Associations International Network(CDG & Allies – PPAIN) and Liliana Fellowships from APCDG attributed to Marques-da-Silva D. and Monticelli M. The authors confirmed independence from the sponsors, the content of the article has not been influenced by sponsors.

Supplementary material

10545_2016_12_MOESM1_ESM.docx (70 kb)
ESM 1 (DOCX 69 kb)


  1. AlSubhi S, AlHashem A, AlAzami A et al (2015) Further delineation of the ALG9-CDG phenotype. JIMD Rep 27:107–112CrossRefPubMedPubMedCentralGoogle Scholar
  2. Arnoux JB, Boddaert N, Valayannopoulos V et al (2008) Risk assessment of acute vascular events in congenital disorder of glycosylation type Ia. Mol Genet Metab 93:444–449CrossRefPubMedGoogle Scholar
  3. Aronica E, van Kempen AAMW, van der Heide M et al (2005) Congenital disorder of glycosylation type Ia: a clinicopathological report of a newborn infant with cerebellar pathology. Acta Neuropathol 109:433–442CrossRefPubMedGoogle Scholar
  4. Babovic-Vuksanovic D, Patterson MC, Schwenk WF et al (1999) Severe hypoglycemia as a presenting symptom of carbohydrate-deficient glycoprotein syndrome. J Pediatr 135:775–781CrossRefPubMedGoogle Scholar
  5. Barone R, Sturiale L, Fiumara A, Uziel G, Garozzo D, Jaeken J (2007) Borderline mental development in a congenital disorder of glycosylation (CDG) type Ia patient with multisystemic involvement (intermediate phenotype). J Inherit Metab Dis 30:107CrossRefPubMedGoogle Scholar
  6. Blomme B, Van Steenkiste C, Callewaert N, Van Vlierberghe H (2009) Alteration of protein glycosylation in liver diseases. J Hepatol 50:592–603CrossRefPubMedGoogle Scholar
  7. Chantret I, Dancourt J, Dupre T et al (2003) A deficiency in dolichyl-P-glucose: Glc1Man9GlcNAc2-PP-dolichyl alpha3-glucosyltransferase defines a new subtype of congenital disorders of glycosylation. J Biol Chem 298:9962–9971CrossRefGoogle Scholar
  8. Choi R, Woo HI, Choe B-H (2015) Application of whole exome sequencing to a rare inherited metabolic disease with neurological and gastrointestinal manifestations: a congenital disorder of glycosylation mimicking glycogen storage disease. Clin Chim Acta 444:50–53CrossRefPubMedGoogle Scholar
  9. Damen G, de Klerk H, Huijmans J, den Hollander J, Sinaasappel M (2004) Gastrointestinal and other clinical manifestations in 17 children with congenital disorders of glycosylation type Ia, Ib, and Ic. J Pediatr Gastroenterol Nutr 38:282–287CrossRefPubMedGoogle Scholar
  10. de Koning TJ, Dorland L, van Diggelen OP et al (1998) A novel disorder of N-glycosylation due to phosphomannose isomerase deficiency. Biochem Biophys Res Commun 245:38–42CrossRefPubMedGoogle Scholar
  11. de Lonlay P, Seta N (2009) The clinical spectrum of phosphomannose isomerase deficiency, with an evaluation of mannose treatment for CDG-Ib. Biochim Biophys Acta 1792:841–843CrossRefPubMedGoogle Scholar
  12. 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
  13. Eklund EA, Sun L, Westphal V, Northrop JL, Freeze HH, Scaglia F (2005) Congenital disorder of glycosylation (CDG)-Ih patient with a severe hepato-intestinal phenotype and evolving central nervous system pathology. J Pediatr 147:847–850CrossRefPubMedGoogle Scholar
  14. Eklund EA, Sun L, Yang SP, Pasion RM, Thorland EC, Freeze HH (2006) Congenital disorder of glycosylation Ic due to a de novo deletion and an hALG-6 mutation. Biochem Biophys Res Commun 339:755–760CrossRefPubMedGoogle Scholar
  15. Ferro JM, Viana P, Santos P (2016) Management of neurologic manifestations in patients with liver disease. Curr Treat Options Neurol 18:37CrossRefPubMedGoogle Scholar
  16. Foulquier F, Vasile E, Schollen E et al (2006) Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II. PNAS 103:3764–3769CrossRefPubMedPubMedCentralGoogle Scholar
  17. Frank CG, Grubenmann CE, Eyaid W, Berger EG, Aebi M, Hennet T (2004) Identification and functional analysis of a defect in the human ALG9 Gene: definition of congenital disorder of glycosylation type IL. Am J Hum Genet 75:146–150CrossRefPubMedPubMedCentralGoogle Scholar
  18. Freeze HH, Chong JX, Bamshad MJ, Ng BG (2014) Solving glycosylation disorders: fundamental approaches reveal complicated pathways. Am J Hum Genet 94:161–175CrossRefPubMedPubMedCentralGoogle Scholar
  19. Fung CW, Matthijs G, Sturiale L et al (2012) COG5-CDG with a mild neurohepatic presentation. JIMD Rep 3:67–70CrossRefPubMedGoogle Scholar
  20. Grubenmann CE, Frank CG, Hülsmeier AJ et al (2004) Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik. Hum Mol Genet 13:535–542CrossRefPubMedGoogle Scholar
  21. Grünewald S (2009) The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia). Biochim Biophys Acta 1792:827–834CrossRefPubMedGoogle Scholar
  22. Grünewald S, De Vos R, Jaeken J (2003) Abnormal lysosomal inclusions in liver hepatocytes but not in fibroblasts in congenital disorders of glycosylation (CDG). J Inherit Metab Dis 26:49–54CrossRefPubMedGoogle Scholar
  23. Hendriksz CJ, McClean P, Henderson MJ et al (2001) Successful treatment of carbohydrate deficient glycoprotein syndrome type 1b with oral mannose. Arch Dis Child 85:339–340CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hernández EM, Vega Pajares AIV, González BP et al (2008) Defecto congénito de glucosilación tipo Ib. experiencia en el tratamiento con manosa. An Pediatr (Barc) 69:358–365CrossRefGoogle Scholar
  25. Höck M, Wegleiter K, Ralser E et al (2015) ALG8-CDG: novel patients and review of the literature. Orphanet J Rare Dis 10:73–80CrossRefPubMedPubMedCentralGoogle Scholar
  26. Jaeken J, Morava E (2016) Congenital disorders of glycosylation and dolichol and glycosylphosphatidylinositol metabolism. In: Saudubray, Baumgartner, Walter (ed) Inborn metabolic diseases. diagnosis and treatment, 6th edn. Springer, Berlin, pp 607–622CrossRefGoogle Scholar
  27. Jaeken J, Stibler H, Hagberg B (1991) The carbohydrate-deficient glycoprotein syndrome. a new inherited multisystemic disease with severe nervous system involvement. Acta Paediatr Scand Suppl 375:1–71PubMedGoogle Scholar
  28. Jaeken J, Matthijs G, Saudubray J-M et al (1998) Phosphomannose isomerase deficiency: a carbohydrate-deficient glycoprotein syndrome with hepatic-intestinal presentation. Am J Hum Genet 62:1535–1539CrossRefPubMedPubMedCentralGoogle Scholar
  29. Jaeken J, Lefeber D, Matthijs G (2014) Clinical utility gene card for: phosphomannose isomerase deficiency. Eur J Hum Genet. doi: 10.1038/ejhg.2014.29 Google Scholar
  30. Jaeken J, Lefeber D, Matthijs G (2015a) Clinical utility gene card for: ALG1 defective congenital disorder of glycosylation. Eur J Hum Genet. doi: 10.1038/ejhg.2015.9 Google Scholar
  31. Jaeken J, Lefeber D, Matthijs G (2015b) Clinical utility gene card for: ALG6 defective congenital disorder of glycosylation. Eur J Hum Genet. doi: 10.1038/ejhg.2014.146 Google Scholar
  32. Jansen JC, Timal S, van Scherpenzeel M et al (2016a) TMEM199 deficiency is a disorder of Golgi homeostasis characterized by elevated aminotransferases, alkaline phosphatase, and cholesterol and abnormal glycosylation. Am J Hum Genet 98:322–330CrossRefPubMedPubMedCentralGoogle Scholar
  33. Jansen JC, Cirak S, van Scherpenzeel M et al (2016b) CCDC115 deficiency causes a disorder of golgi homeostasis with abnormal protein glycosylation. Am J Hum Genet 98:310–321CrossRefPubMedPubMedCentralGoogle Scholar
  34. Jansen EJR, Timal S, Ryan M et al (2016c) ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation. Nat Commun 7:11600CrossRefPubMedPubMedCentralGoogle Scholar
  35. Janssen MCH, de Kleine RH, van den Berg AP et al (2014) Successful liver transplantation and long-term follow-up in a patient with MPI-CDG. Pediatrics 134:e279–e283CrossRefPubMedGoogle Scholar
  36. Kelly DF, Boneh A, Pitsch S et al (2001) Carbohydrate-deficient glycoprotein syndrome 1b: a new answer to an old diagnostic dilemma. J Paediatr Child Health 37:510–512CrossRefPubMedGoogle Scholar
  37. 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
  38. Kodera H, Ando N, Yuasa I et al (2015) Mutations in COG2 encoding a subunit of the conserved oligomeric golgi complex cause a congenital disorder of glycosylation. Clin Genet 87:455–460CrossRefPubMedGoogle Scholar
  39. Kornak U, Reynders E, Dimopoulou A et al (2008) Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2. Nat Genet 40:32–34CrossRefPubMedGoogle Scholar
  40. Lepais L, Cheillan D, Frachon SC et al (2015) ALG3-CDG: report of two siblings with antenatal features carrying homozygous p.Gly96Arg Mutation. Am J Med Genet 167A:2748–2754CrossRefPubMedGoogle Scholar
  41. Liem YS, Bode L, Freeze HH, Leebeek FWG, Zandbergen AAM, Wilson JHP (2008) Using heparin therapy to reverse protein-losing enteropathy in a patient with CDG-Ib. Nat Clin Pract Gastroenterol Hepatol 5:220–224CrossRefPubMedGoogle Scholar
  42. Mention K, Lacaille F, Valayannopoulos V et al (2008) Development of liver disease despite mannose treatment in two patients with CDG-Ib. Mol Genet Metabol 93:40–43CrossRefGoogle Scholar
  43. Miura Y, Tay SKH, Aw MM, Eklund E, Freeze HH (2005) Clinical and biochemical characterization of a patient with congenital disorder of glycosylation (CDG) IIX. J Pediatr 147:851–853CrossRefPubMedGoogle Scholar
  44. Monin ML, 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
  45. Monticelli M, Ferro T, Jaeken J, Dos Reis Ferreira V, Videira PA (2016) Immunological aspects of congenital disorders of glycosylation (CDG): a review. J Inherit Metab Dis 39:765–780CrossRefPubMedGoogle Scholar
  46. Morava E (2014) Galactose supplementation in phosphoglucomutase-1 deficiency; review and outlook for a novel treatable CDG. Mol Genet Metab 112:275–279CrossRefPubMedPubMedCentralGoogle Scholar
  47. Morava E, Zeevaert R, Korsch E et al (2007) A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia. Eur J Hum Genet 15:638–665CrossRefPubMedGoogle Scholar
  48. Morava E, Vodopiutz J, Lefeber DJ et al (2012) Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations. Pediatrics 130:e1034–e1039CrossRefPubMedGoogle Scholar
  49. Morava E, Tiemes V, Thiel C et al (2016) ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavior and limb anomalies. J Inherit Metab Dis 39:713–723CrossRefPubMedGoogle Scholar
  50. Ng BG, Kranz C, Hagebeuk EEO et al (2007) Molecular and clinical characterization of a Moroccan Cog7 deficient patient. Mol Genet Metab 91:201–204CrossRefPubMedPubMedCentralGoogle Scholar
  51. Ng BG, Sharma V, Sun L et al (2011) Identification of the first COG-CDG patient of Indian origin. Mol Genet Metab 102:364–367CrossRefPubMedGoogle Scholar
  52. Ng BG, Shiryaev SA, Rymen D et al (2016) ALG1-CDG: clinical and molecular characterization of 39 unreported patients. Hum Mutat 37:653–660CrossRefPubMedPubMedCentralGoogle Scholar
  53. Niehues R, Hasilik M, Alton G et al (1998) Carbohydrate-deficient glycoprotein syndrome type Ib. phosphomannose isomerase deficiency and mannose therapy. J Clin Invest 101:1414–1420CrossRefPubMedPubMedCentralGoogle Scholar
  54. Ono H, Sakura N, Yamashita K, Yuasa I, Ohno K (2003) Novel nonsense mutation (R194X) in the PMM2 gene in a Japanese patient with congenital disorder of glycosylation type Ia. Brain Dev 27:525–528CrossRefGoogle Scholar
  55. Panneerselvam K, Freeze HH (1996) Mannose enters mammalian cells using a specific transporter that is insensitive to glucose. J Biol Chem 271:9417–9421CrossRefPubMedGoogle Scholar
  56. Reynders E, Foulquier F, Leão Teles E et al (2009) Golgi function and dysfunction in the first COG4-deficient CDG type II patient. Hum Mol Genet 18:3244–3256CrossRefPubMedPubMedCentralGoogle Scholar
  57. Rohlfing A-K, Rust S, Reunert J et al (2014) ALG1-CDG: a new case with early fatal outcome. Gene 534:345–351CrossRefPubMedGoogle Scholar
  58. Rymen D, Winter J, Van Hasselt PM et al (2015) Key features and clinical variability of COG6-CDG. Mol Genet Metabol 116:163–170CrossRefGoogle Scholar
  59. Schollen E, Frank CG, Keldermans L et al (2004) Clinical and molecular features of three patients with congenital disorders of glycosylation type Ih (CDG-Ih) (ALG8 deficiency). J Med Genet 41:550–556CrossRefPubMedPubMedCentralGoogle Scholar
  60. 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
  61. Shanti B, Silink M, Bhattacharya K et al (2009) Congenital disorder of glycosylation type Ia: heterogeneity in the clinical presentation from multivisceral failure to hyperinsulinaemic hypoglycaemia as leading symptoms in three infants with phosphomannomutase deficiency. J Inherit Metab Dis 32:S241–S251CrossRefPubMedGoogle Scholar
  62. Sorte H, Mørkrid L, Rødningen O et al (2012) Severe ALG8-CDG (CDG-Ih) associated with homozygosity for two novel missense mutations detected by exome sequencing of candidate genes. Eur J Med Genet 55:196–202CrossRefPubMedGoogle Scholar
  63. Spaapen LJM, Bakker JA, Van Der Meer SB et al (2005) Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder. J Inherit Metab Dis 28:707–714CrossRefPubMedGoogle Scholar
  64. Sparks SE, Krasnewich DM (2014) Congenital disorders of N-linked glycosylation. pathway overview. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K (eds) eneReviews®. University of Washington, Seattle, pp 1993–2016Google Scholar
  65. Sun L, Eklund EA, Chung WK, Wang C, Cohen J, Freeze HH (2005) Congenital disorder of glycosylation Id presenting with hyperinsulinemic hypoglycemia and islet cell hyperplasia. J Clin Endocrinol Metab 90:4371–4375CrossRefPubMedGoogle Scholar
  66. Tegtmeyer LC, Rust S, van Scherpenzeel M et al (2014) Multiple phenotypes in phosphoglucomutase 1 deficiency. N Eng J Med 370:533–542CrossRefGoogle Scholar
  67. Vesela K, Honzik T, Hansikova H et al (2009) A new case of ALG8 deficiency (CDG Ih). J Inherit Metab Dis 32:259–264CrossRefGoogle Scholar
  68. Vleugels W, Keldermans L, Jaeken J et al (2009) Quality control of glycoproteins bearing truncated glycans in an ALG9-defective (CDG-IL) patient. Glycobiology 19:910–917CrossRefPubMedGoogle Scholar
  69. Weinstein M, Schollen, Matthijs G et al (2005) CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features. Am J Med Genet 136A:194–197CrossRefGoogle Scholar
  70. Westphal V, Kjaergaard S, Davis JÁ, Peterson SM, Skovby F, Freeze HH (2001) Genetic and metabolic analysis of the first adult with congenital disorder of glycosylation type Ib: long-term outcome and effects of mannose supplementation. Mol Genet Metabol 73:77–85CrossRefGoogle Scholar
  71. Wong SY, Beamer LJ, Gadomski T et al (2016) Defining the phenotype and assessing severity in phosphoglucomutase-1 deficiency. J Pediatr 175:130–136CrossRefPubMedGoogle Scholar
  72. Wu X, Steet RA, Bohorov O et al (2004) Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder. Nat Med 10:518–523CrossRefPubMedGoogle Scholar
  73. Zeevaert R, Foulquier F, Cheillan D et al (2009) A new mutation in COG7 extends the spectrum of COG subunit deficiencies. Eur J Med Genet 52:303–305CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM 2017

Authors and Affiliations

  • D. Marques-da-Silva
    • 1
    • 2
    • 3
  • V. dos Reis Ferreira
    • 2
    • 3
  • M. Monticelli
    • 1
    • 4
  • P. Janeiro
    • 5
  • P. A. Videira
    • 1
    • 2
    • 3
  • P. Witters
    • 3
    • 6
  • J. Jaeken
    • 3
    • 6
    Email author
  • D. Cassiman
    • 3
    • 6
    Email author
  1. 1.UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e TecnologiaUniversidade NOVA de LisboaLisboaPortugal
  2. 2.Portuguese Association for CDGLisboaPortugal
  3. 3.CDG & Allies – Professionals and Patient Associations International Network (CDG & Allies – PPAIN)CaparicaPortugal
  4. 4.Dipartimento di BiologiaUniversità degli Studi di Napoli “Federico II”NapoliItaly
  5. 5.Departamento de PediatriaUnidade de Doenças Metabólicas, CHLN, Hospital de Sta. MariaLisboaPortugal
  6. 6.Center for Metabolic DiseasesUZ and KU LeuvenLeuvenBelgium

Personalised recommendations