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Recognizable phenotypes in CDG

  • Phenomics
  • Published:
Journal of Inherited Metabolic Disease

Abstract

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.

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References

  • 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 120:235–242

    Article  PubMed  CAS  Google Scholar 

  • 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 44:222–225

    Article  PubMed  Google Scholar 

  • Antoun H, Villeneuve N, Gelot A et al (1999) Cerebellar atrophy: an important feature of carbohydrate deficient glycoprotein syndrome type 1. Pediatr Radiol 29:194–198

    Article  PubMed  CAS  Google Scholar 

  • Artigas J, Cardo E, Pineda M et al (1998) Phosphomannomutase deficiency and normal pubertal development. J Inherit Metab Dis 21:78–79

    Article  PubMed  CAS  Google Scholar 

  • 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 262:154–164

    Article  PubMed  CAS  Google Scholar 

  • 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:2103–2108

    Article  PubMed  CAS  Google Scholar 

  • 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):107–114

    Article  PubMed  CAS  Google Scholar 

  • Bortot B, Cosentini D, Faletra F et al (2013) PMM2-CDG: phenotype and genotype in four affected family members. Gene 531:506–509

    Article  PubMed  CAS  Google Scholar 

  • 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 25:635–646

    Article  PubMed  CAS  Google Scholar 

  • 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 66:545–548

    Article  PubMed  Google Scholar 

  • Bubel S, Peters V, Klein C et al (2002) CDG (congenital disorders of glycosylation). Differential hereditary ataxia in adulthood diagnosis. Nervenarzt 73:754–760

    Article  PubMed  CAS  Google Scholar 

  • Buczkowska A, Swiezewska E, Lefeber DJ (2015) Genetic defects in dolichol metabolism. J Inherit Metab Dis 38(1):157–169

    Article  PubMed  CAS  Google Scholar 

  • Clayton PT, Winchester BG, Keir G (1992) Hypertrophic obstructive cardiomyopathy in a neonate with the carbohydrate-deficient glycoprotein syndrome. J Inherit Metab Dis 15:857–861

    Article  PubMed  CAS  Google Scholar 

  • Cossins J, Belaya K, Hicks D et al (2013) Congenital myasthenic syndromes due to mutations in ALG2 and ALG14. Brain J Neurol 136:944–956

    Article  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 

  • 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 84:481–483

    Article  PubMed  Google Scholar 

  • 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):931–940

    Article  PubMed  CAS  Google Scholar 

  • 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 26:985–988

    Article  PubMed  CAS  Google Scholar 

  • Endo T (2015) Glycobiology of α-dystroglycan and muscular dystrophy. J Biochem 157(1):1–12

    Article  PubMed  CAS  Google Scholar 

  • 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 141:695–700

    Article  PubMed  CAS  Google Scholar 

  • Erlandson A, Bjursell C, Stibler H et al (2001) Scandinavian CDG-Ia patients: genotype/phenotype correlation and geographic origin of founder mutations. Hum Genet 108:359–367

    Article  PubMed  CAS  Google Scholar 

  • Garel C, Baumann C, Besnard M et al (1998) Carbohydrate-deficient glycoprotein syndrome type I: a new cause of dysostosis multiplex. Skelet Radiol 27:43–45

    Article  CAS  Google Scholar 

  • 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 68:347–354

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 51:385–390

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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):108–114

    Article  PubMed  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

    Article  PubMed  PubMed Central  Google Scholar 

  • Honzík T, Magner M, Krijt J et al (2012) Clinical picture of S-adenosylhomocysteine hydrolase deficiency resembles phosphomannomutase 2 deficiency. Mol Genet Metab 107:611–613

    Article  PubMed  CAS  Google Scholar 

  • 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 23:162–174

    Article  PubMed  CAS  Google Scholar 

  • Işıkay S, Başpınar O, Yılmaz K (2014) A case of congenital disorder of glycosylation ia presented with recurrent pericardial effusion. Iran J Pediatr 24:652–654

    PubMed  PubMed Central  Google Scholar 

  • Jaeken J, Péanne R (2017) What is new in CDG? J Inherit Metab Dis 40(4):569–586

    Article  PubMed  CAS  Google Scholar 

  • Kasapkara ÇS, Barış Z, Kılıç M et al (2017) PMM2-CDG and sensorineural hearing loss. J Inherit Metab Dis 40:629-630

  • 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Krasnewich DM, Holt GD, Brantly M et al (1995) Abnormal synthesis of dolichol-linked oligosaccharides in carbohydrate-deficient glycoprotein syndrome. Glycobiology 5(5):503–510

    Article  PubMed  CAS  Google Scholar 

  • 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 40:179–181

    PubMed  Google Scholar 

  • 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 101:253–257

    Article  PubMed  CAS  Google Scholar 

  • 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 92:166–171

    Article  PubMed  CAS  Google Scholar 

  • 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):195–207

    Article  PubMed  CAS  Google Scholar 

  • 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):657–672

    Article  PubMed  CAS  Google Scholar 

  • 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 9:207

    Article  PubMed  PubMed Central  Google Scholar 

  • 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–CR472

    Google Scholar 

  • 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 39:713–723

    Article  PubMed  CAS  Google Scholar 

  • 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 164:223–226

    Article  PubMed  Google Scholar 

  • Panneerselvam K, Freeze HH (1996) Mannose corrects altered N-glycosylation in carbohydrate-deficient glycoprotein syndrome fibroblasts. J Clin invest. 97:1478-87

  • Pavone L, Fiumara A, Barone R et al (1996) Olivopontocerebellar atrophy leading to recognition of carbohydrate-deficient glycoprotein syndrome type I. J Neurol 243:700–705

    Article  PubMed  CAS  Google Scholar 

  • 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 1:117–123

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 2:16–19

    Article  PubMed  CAS  Google Scholar 

  • Resende C, Carvalho C, Alegria A et al (2014) Congenital disorders of glycosylation with neonatal presentation. BMJ Case Rep

  • 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):261–269

    Article  PubMed  CAS  Google Scholar 

  • 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 19:1413–1424

    Article  PubMed  CAS  Google Scholar 

  • 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 46:287–288

    Article  PubMed  CAS  Google Scholar 

  • 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 33:827–830

    Article  PubMed  Google Scholar 

  • Senderek J, Müller JS, Dusl M et al (2011) Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. Am J Hum Genet 88:162–172

    Article  PubMed  PubMed Central  CAS  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 

  • 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 130:533–535

    Article  PubMed  CAS  Google Scholar 

  • 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):843–851

    Article  PubMed  Google Scholar 

  • 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 108:241–246

    Article  PubMed  Google Scholar 

  • 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 24:198–207

    Article  PubMed  CAS  Google Scholar 

  • Thompson DA, Lyons RJ, Russell-Eggitt I et al (2013) Retinal characteristics of the congenital disorder of glycosylation PMM2-CDG. J Inherit Metab Dis 36:1039–1047

    Article  PubMed  CAS  Google Scholar 

  • 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–S44

    Article  PubMed  CAS  Google Scholar 

  • Truin G, Guillard M, Lefeber DJ et al (2008) Pericardial and abdominal fluid accumulation in congenital disorder of glycosylation type Ia. Mol Genet Metab 94:481–484

    Article  PubMed  CAS  Google Scholar 

  • 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 125:715–716

    PubMed  CAS  Google Scholar 

  • van de Kamp JM, Lefeber DJ, Ruijter GJG et al (2007) Congenital disorder of glycosylation type Ia presenting with hydrops fetalis. J Med Genet 44:277–280

    Article  PubMed  CAS  Google Scholar 

  • 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 2:239–244

    Article  CAS  Google Scholar 

  • 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 254:1356–1358

    Article  PubMed  CAS  Google Scholar 

  • Vleugels W, Haeuptle MA, Ng BG et al (2009a) RFT1 deficiency in three novel CDG patients. Hum Mutat 30:1428–1434

    Article  PubMed  CAS  Google Scholar 

  • 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):910–917

    Article  PubMed  CAS  Google Scholar 

  • Wolthuis DFGJ, van Asbeck EV, Kozicz T, Morava E (2013) Abnormal fat distribution in PMM2-CDG. Mol Genet Metab 110:411–413

    Article  PubMed  CAS  Google Scholar 

  • 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 22:144–150

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

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.

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Authors and Affiliations

  1. Medical Genetics Branch National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Carlos R. Ferreira

  2. Division of Genetics and Metabolism, Children’s National Medical Center, Washington, DC, USA

    Carlos R. Ferreira

  3. Metabolic Center, Department of Pediatrics, University Hospitals Leuven, Herestraat 49, B-3000, Leuven, Belgium

    Ruqaia Altassan, Jaak Jaeken & Eva Morava

  4. Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium

    Ruqaia Altassan, Jaak Jaeken & Eva Morava

  5. UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Lisboa, Portugal

    Dorinda Marques-Da-Silva & Rita Francisco

  6. Portuguese Association for CDG, Lisboa, Portugal

    Dorinda Marques-Da-Silva & Rita Francisco

  7. Department of Clinical Genomics, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA

    Eva Morava

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  1. Carlos R. Ferreira
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  2. Ruqaia Altassan
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  3. Dorinda Marques-Da-Silva
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  4. Rita Francisco
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  5. Jaak Jaeken
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  6. Eva Morava
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Correspondence to Eva Morava.

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

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Ferreira, C.R., Altassan, R., Marques-Da-Silva, D. et al. Recognizable phenotypes in CDG. J Inherit Metab Dis 41, 541–553 (2018). https://doi.org/10.1007/s10545-018-0156-5

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