Congenital Disorder of Glycosylation IId (CDG-IId) - A New Entity: Clinical Presentation with Dandy-Walker Malformation and Myopathy

Abstract

A 1.5-year-old boy with macrocephaly due to a Dandy-Walker malformation presented with progressive hydrocephalus, extensive muscular hypotonia, transient cholestatic syndrome, extensive coagulation abnormalities and elevated creatine kinase indicating myopathy. Diagnostic work-up indicated a congenital disorder of glycosylation (CDG, formerly carbohydrate deficient glycoprotein syndrome). The serum transferrin pattern obtained by automated isoelectric focusing (IEF) showed an hitherto unreported pattern with strongly elevated tri-, di-, mono- and asialotransferrin bands, increasing in this order together with markedly decreased tetrasialotransferrin. Investigation of two additional glycoproteins, α₁-antitrypsin and α₁-antichymotrypsin, confirmed a generalised defect of glycosylation. All known glycosylation defects could be ruled out by enzymatic analyses in either leukocytes or fibroblasts or by the results obtained by IEF. SDS-electrophoresis demonstrated a marked difference in the molecular weight of transferrin, suggesting the lack of parts or of all oligosaccharide chains. The defect could be delineated to a deficiency of β-1,4-galactosyltransferase (E.C.2.4.1.38) due to a homozygous insertion (1031 - 1032 insC). Details of the biochemical and molecular findings will be described elsewhere.

Key words

Congenital Disorders of Glycosylation - CDG - Isoelectric Focusing - Transferrin - α₁-Antitrypsin - α₁-Antichymotrypsin - Myopathy - Dandy-Walker Malformation

References

• 1 Adamowicz M, Pronicka E. Carbohydrate deficient glycoprotein syndrome - Like transferrin isoelectric focusing pattern in untreated fructosaemia.  Eur J Pediatr. 1996;  155 347-348
• 2 Altland K, Hackler R, Knoche W. Double one-dimensional electrophoresis of human serum transferrin: A new high-resolution screening method for genetically determined variation.  Hum Genet. 1980;  54 221-231
• 3 Barkovich J. Neuroimaging manifestations and classification of congenital muscular dystrophies.  AJNR Am J Neuroradiol. 1998;  19 1389-1396
• 4 Burda P, Borsig L, de Rijk-van Andel J, Wevers R, Jaeken J, Carchon H. et al . A novel carbohydrate-deficient glycoprotein syndrome characterized by a deficiency in glucosylation of the dolichol-linked oligosaccharide.  J Clin Invest. 1998;  102 647-652
• 5 Charlwood J, Clayton P, Keir G, Mian N, Winchester B. Defective galactosylation of serum transferrin in galactosemia.  Glycobiology. 1998;  8 351-357
• 6 Chitayat D. Dandy-Walker malformation syndromes: reply to Fiumara et al.  Am J Med Genet. 1996;  63 413
• 7 Cormand B, Pihko H, Bayes M, Valanne L, Santavuori P, Talim B. et al . Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease.  Neurology. 2001;  56 993-994
• 8 de Jong G, van Eijk H G. Microheterogeneity of human serum transferrin: A biological phenomenon studied by isoelectric focusing in immobilized pH gradients.  Electrophoresis. 1998;  9 589-598
• 9 de Koning T J, Dorland L, van Diggelen O P, Boonman A MC, de Jong G J, van Noort W L. et al . A novel disorder of N-glycosylation due to phosphomannose isomerase deficiency.  Biochem Biophys Res Commun. 1998;  245 38-42
• 10 de Praeter C M, Gerwig G J, Bause E, Nuytinck L K, Vliegenthart J FG, Breuer W. et al . A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency.  Am J Hum Genet. 2000;  66 1744-1756
• 11 de Zegher F, Jaeken J. Endocrinology of the carbohydrate-deficient glycoprotein syndrome type 1 from birth through adolescence.  Pediatr Res. 1995;  37 395-401
• 12 Fiumara A, Barone R, Nigro F, Sorge G, Pavone L. Familial Dandy-Walker variant in CDG syndrome.  Am J Med Genet. 1996;  63 412
• 13 Hackler R, Arndt T, Peters V, Assmann B, Hoffmann G F, Steinmetz A. Automated isoelectric focusing of serum isotransferrins for laboratory diagnosis of carbohydrate deficient glycoprotein syndrome using the PhastSystem™.  Scand J Clin Lab Invest. 1998;  58 (Suppl 228) 66-67
• 14 Hagberg B A, Blennow G, Kristiansson B, Stibler H. Carbohydrate-deficient glycoprotein syndromes: Peculiar group of new disorders.  Pediatr Neurol. 1993;  9 255-262
• 15 Hayashi Y K, Ogawa M, Tagawa K, Noguchi S, Ishihara T, Nonaka I. et al . Selective deficiency of α-dystroglycan in Fukuyama-type congenital muscular dystrophy.  Neurology. 2001;  57 115-121
• 16 Holzbach U, Hanefeld F, Helms G, Hänicke W, Frahm J. Localized proton magnetic resonance spectroscopy of cerebral abnormalities in children with carbohydrate-deficient glycoprotein syndrome.  Acta Paediatr. 1995;  84 781-786
• 17 Imbach T, Schenk B, Schollen E, Burda P, Stutz A, Grünewald S. et al . Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorders of glycosylation type Ie.  J Clin Invest. 2000;  105 233-239
• 18 Jaeken J, Carchon H, Stibler H. The carbohydrate-deficient glycoprotein syndromes: pre-golgi and golgi disorders?.  Glycobiol. 1993;  3 423-428
• 19 Jaeken J, Schachter H, Carchon H, De Cock P, Coddeville B, Spik G. Carbohydrate deficient glycoprotein syndrome type II: A deficiency in Golgi localised N-acetyl-glucosaminyltransferase II.  Arch Dis Child. 1994;  71 123-127
• 20 Jaeken J, Artigas J, Barone R, Fiumara A, de Koning T J, Poll-The B T. et al . Phosphomannomutase deficiency is the main cause of carbohydrate-deficient glycoprotein syndrome with type I isoelectrofocusing pattern of serum sialotransferrins.  J Inher Metab Dis. 1997;  20 447-449
• 21 Jaeken J, Matthijs G, Saudubray J-M, Dionisi-Vici C, Bertini E, de Lonlay P. et al . Phosphomannose isomerase deficiency: a carbohydrate-deficient glycoprotein syndrome with hepatic-intestinal presentation.  Am J Hum Genet. 1998;  62 1535-1539
• 22 Jaeken J, Carchon H. What's new in congenital disorders of glycosylation?.  Eur J Pediatr Neurol. 2000;  4 163-167
• 23 Keir G, Winchester B G, Clayton P. Carbohydrate-deficient glycoprotein syndromes: inborn errors of protein glycosylation.  Ann Clin Biochem. 1999;  36 20-36
• 24 Kim S, Westphal V, Srikrishna G, Mehta D P, Peterson S, Filiano J. et al . Dolichol phosphate mannose synthase (DPM1) mutations define congenital disorder of glycosylation Ie (CDG-Ie).  J Clin Invest. 2000;  105 191-198
• 25 Kolble N, Wisser J, Kurmanavicius J, Boltshauser E, Stallmach T, Huch A. et al . Dandy-Walker malformation: prenatal diagnosis and outcome.  Prenat Diagn. 2000;  20 318-327
• 26 Körner C, Knauer R, Holzbach U, Hanefeld F, Lehle L, von Figura K. Carbohydrate-deficient glycoprotein syndrome type V: deficiency of dolichyl-P-Glc:Man₉GlcNAc₂-PP-dolichyl glucosyltransferase.  Proc Natl Acad Sci USA. 1998;  95 13200-13205
• 27 Körner C, Knauer R, Stephani U, Marquardt T, Lehle L, von Figura K. Carbohydrate deficient glycoprotein syndrome type IV: deficiency of dolichyl-P-Man : Man₅GlcNAc₂-PP-dolichyl mannosyltransferase.  EMBO J. 1999;  18 6816-6822
• 28 Krasnewich D, Gahl W A. Carbohydrate-deficient glycoprotein syndrome.  Adv Pediatr. 1997;  44 109-140
• 29 Lübke T, Marquardt T, von Figura K, Körner C. A new type of carbohydrate-deficient glycoprotein syndrome due to a decreased import of GDP-fucose into the golgi.  J Biol Chem. 1999;  274 25986-25989
• 30 Lübke T, Marquardt T, Etzioni A, Hartmann E, von Figura K, Körner C. Complementation cloning identifies CDG-IIc, a new type of congenital disorders of glycosylation, as a GDP-fucose transporter deficiency.  Nature Genet. 2001;  28 73-76
• 31 Niehues R, Hasilik M, Alton G, Körner C, Schiebe-Sukumar M, Koch H G. et al . Carbohydrate-deficient glycoprotein syndrome type Ib - Phosphomannose isomerase deficiency and mannose therapy.  J Clin Invest. 1998;  101 1414-1420
• 32 Noll B, Hackler R, Pelzer M, Pelzer S, Nusser P, Maisch B. et al . Semi-automated rapid isoelectric focusing of apolipoproteins C from human plasma using PhastSystem^TM and immunofixation.  Clin Chem Lab Med. 1999;  37 643-648
• 33 Participants, “First International Workshop on CDGS”, Leuven, Belgium, November 12 - 13, 1999 . Carbohydrate-deficient glycoprotein syndromes become congenital disorders of glycosylation: An updated nomenclature for CDG.  Glycoconj J. 1999;  16 669-671
• 34 Stibler H, Holzbach U, Kristiansson B. Isoforms and levels of transferrin, antithrombin, α₁-antitrypsin and thyroxine-binding globulin in 48 patients with carbohydrate-deficient glycoprotein syndrome type I.  Scand J Clin Lab Invest. 1998;  58 55-61
• 35 Van Schaftingen E, Jaeken J. Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I.  FEBS Lett. 1995;  377 318-320
• 36 Yamashita K, Ideo H, Ohkura T, Fukushima K, Yuasa I, Ohno K. et al . Sugar chains of serum transferrin from patients with carbohydrate deficient glycoprotein syndrome. Evidence of asparagine-N-linked oligosaccharide transfer deficiency.  J Biol Chem. 1993;  268 5783-5789