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

Abstract

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.

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Fig. 1

Abbreviations

AF:

Alpha-fetoprotein

AP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

AT:

Antithrombin

CDG:

Congenital disorder(s) of glycosylation

CK:

Creatine kinase

ER:

Endoplasmic reticulum

ERGIC:

Endoplasmic reticulum-Golgi intermediate compartment

γ-GT:

Gamma-glutamyl transferase

IEF:

Isoelectrofocusing

PT:

Prothrombin time

PTT:

Partial thromboplastin time

TA:

Transaminases

References

  • AlSubhi S, AlHashem A, AlAzami A et al (2015) Further delineation of the ALG9-CDG phenotype. JIMD Rep 27:107–112

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 93:444–449

    CAS  Article  PubMed  Google Scholar 

  • 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 109:433–442

    CAS  Article  PubMed  Google Scholar 

  • Babovic-Vuksanovic D, Patterson MC, Schwenk WF et al (1999) Severe hypoglycemia as a presenting symptom of carbohydrate-deficient glycoprotein syndrome. J Pediatr 135:775–781

    CAS  Article  PubMed  Google Scholar 

  • 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 30:107

    CAS  Article  PubMed  Google Scholar 

  • Blomme B, Van Steenkiste C, Callewaert N, Van Vlierberghe H (2009) Alteration of protein glycosylation in liver diseases. J Hepatol 50:592–603

    CAS  Article  PubMed  Google Scholar 

  • 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 298:9962–9971

    Article  Google Scholar 

  • 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 444:50–53

    CAS  Article  PubMed  Google Scholar 

  • 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 38:282–287

    Article  PubMed  Google Scholar 

  • 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 245:38–42

    Article  PubMed  Google Scholar 

  • 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 1792:841–843

    Article  PubMed  Google Scholar 

  • 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 38:14–19

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 147:847–850

    Article  PubMed  Google Scholar 

  • 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 339:755–760

    CAS  Article  PubMed  Google Scholar 

  • Ferro JM, Viana P, Santos P (2016) Management of neurologic manifestations in patients with liver disease. Curr Treat Options Neurol 18:37

    Article  PubMed  Google Scholar 

  • 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 103:3764–3769

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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 75:146–150

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Freeze HH, Chong JX, Bamshad MJ, Ng BG (2014) Solving glycosylation disorders: fundamental approaches reveal complicated pathways. Am J Hum Genet 94:161–175

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Fung CW, Matthijs G, Sturiale L et al (2012) COG5-CDG with a mild neurohepatic presentation. JIMD Rep 3:67–70

    CAS  Article  PubMed  Google Scholar 

  • 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 13:535–542

    CAS  Article  PubMed  Google Scholar 

  • Grünewald S (2009) The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia). Biochim Biophys Acta 1792:827–834

    Article  PubMed  Google Scholar 

  • 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 26:49–54

    Article  PubMed  Google Scholar 

  • Hendriksz CJ, McClean P, Henderson MJ et al (2001) Successful treatment of carbohydrate deficient glycoprotein syndrome type 1b with oral mannose. Arch Dis Child 85:339–340

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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) 69:358–365

    Article  Google Scholar 

  • Höck M, Wegleiter K, Ralser E et al (2015) ALG8-CDG: novel patients and review of the literature. Orphanet J Rare Dis 10:73–80

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 607–622

    Chapter  Google Scholar 

  • 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 375:1–71

    CAS  PubMed  Google Scholar 

  • 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 62:1535–1539

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 98:322–330

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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 98:310–321

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Jansen EJR, Timal S, Ryan M et al (2016c) ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation. Nat Commun 7:11600

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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–e283

    Article  PubMed  Google Scholar 

  • 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 37:510–512

    CAS  Article  PubMed  Google Scholar 

  • 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 85:236–239

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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 87:455–460

    CAS  Article  PubMed  Google Scholar 

  • 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 40:32–34

    CAS  Article  PubMed  Google Scholar 

  • 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:2748–2754

    Article  PubMed  Google Scholar 

  • 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 5:220–224

    Article  PubMed  Google Scholar 

  • 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 93:40–43

    CAS  Article  Google Scholar 

  • 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 147:851–853

    Article  PubMed  Google Scholar 

  • 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 9:207

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 39:765–780

    CAS  Article  PubMed  Google Scholar 

  • Morava E (2014) Galactose supplementation in phosphoglucomutase-1 deficiency; review and outlook for a novel treatable CDG. Mol Genet Metab 112:275–279

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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 15:638–665

    CAS  Article  PubMed  Google Scholar 

  • Morava E, Vodopiutz J, Lefeber DJ et al (2012) Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations. Pediatrics 130:e1034–e1039

    Article  PubMed  Google Scholar 

  • 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 39:713–723

    CAS  Article  PubMed  Google Scholar 

  • Ng BG, Kranz C, Hagebeuk EEO et al (2007) Molecular and clinical characterization of a Moroccan Cog7 deficient patient. Mol Genet Metab 91:201–204

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Ng BG, Sharma V, Sun L et al (2011) Identification of the first COG-CDG patient of Indian origin. Mol Genet Metab 102:364–367

    CAS  Article  PubMed  Google Scholar 

  • Ng BG, Shiryaev SA, Rymen D et al (2016) ALG1-CDG: clinical and molecular characterization of 39 unreported patients. Hum Mutat 37:653–660

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Niehues R, Hasilik M, Alton G et al (1998) Carbohydrate-deficient glycoprotein syndrome type Ib. phosphomannose isomerase deficiency and mannose therapy. J Clin Invest 101:1414–1420

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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 27:525–528

    Article  Google Scholar 

  • Panneerselvam K, Freeze HH (1996) Mannose enters mammalian cells using a specific transporter that is insensitive to glucose. J Biol Chem 271:9417–9421

    CAS  Article  PubMed  Google Scholar 

  • 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 18:3244–3256

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Rohlfing A-K, Rust S, Reunert J et al (2014) ALG1-CDG: a new case with early fatal outcome. Gene 534:345–351

    CAS  Article  PubMed  Google Scholar 

  • Rymen D, Winter J, Van Hasselt PM et al (2015) Key features and clinical variability of COG6-CDG. Mol Genet Metabol 116:163–170

    CAS  Article  Google Scholar 

  • 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 41:550–556

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Serrano M, de Diego V, Muchart J et al (2015) Phosphomannomutase deficiency (PMM2-CDG): ataxia and cerebellar assessment. Orphanet J Rare Dis 10:138

    Article  PubMed  PubMed Central  Google Scholar 

  • 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–S251

    Article  PubMed  Google Scholar 

  • 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 55:196–202

    Article  PubMed  Google Scholar 

  • 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 28:707–714

    CAS  Article  PubMed  Google Scholar 

  • 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 1993–2016

    Google Scholar 

  • 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 90:4371–4375

    CAS  Article  PubMed  Google Scholar 

  • Tegtmeyer LC, Rust S, van Scherpenzeel M et al (2014) Multiple phenotypes in phosphoglucomutase 1 deficiency. N Eng J Med 370:533–542

    CAS  Article  Google Scholar 

  • Vesela K, Honzik T, Hansikova H et al (2009) A new case of ALG8 deficiency (CDG Ih). J Inherit Metab Dis 32:259–264

    CAS  Article  Google Scholar 

  • Vleugels W, Keldermans L, Jaeken J et al (2009) Quality control of glycoproteins bearing truncated glycans in an ALG9-defective (CDG-IL) patient. Glycobiology 19:910–917

    CAS  Article  PubMed  Google Scholar 

  • 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:194–197

    Article  Google Scholar 

  • 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 73:77–85

    CAS  Article  Google Scholar 

  • Wong SY, Beamer LJ, Gadomski T et al (2016) Defining the phenotype and assessing severity in phosphoglucomutase-1 deficiency. J Pediatr 175:130–136

    CAS  Article  PubMed  Google Scholar 

  • Wu X, Steet RA, Bohorov O et al (2004) Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder. Nat Med 10:518–523

    CAS  Article  PubMed  Google Scholar 

  • 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 52:303–305

    Article  PubMed  Google Scholar 

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Acknowledgements

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 (http://www.diogosampaio.pt/), who helped design Fig. 1 of this publication.

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Correspondence to J. Jaeken or D. Cassiman.

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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.

Funding

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.

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Communicated by: Eva Morava

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Marques-da-Silva, D., dos Reis Ferreira, V., Monticelli, M. et al. Liver involvement in congenital disorders of glycosylation (CDG). A systematic review of the literature. J Inherit Metab Dis 40, 195–207 (2017). https://doi.org/10.1007/s10545-016-0012-4

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Keywords

  • Liver Involvement
  • Cutis Laxa
  • Ductal Plate Malformation
  • Conserve Oligomeric Golgi
  • PMM2 Gene