Congenital disorders of glycosylation type I

Congenital disorders of glycosylation (CDG) are a group of disorders caused by defects in various genes for N-glycan biosynthesis. CDG type I is defined by mutations in genes encoding enzymes which involves disrupted synthesis of the lipid linked oligosaccharide precursor and its transfer to polypeptide chain of protein, affecting N-glycan assembly in cytosol and endoplasmic reticulum. An increasing number of disorders have been discovered, with many subtypes identified. PMM2-CDG is the most common form, with over 800 patients diagnosed mostly in Europe. Almost all type present in infancy. These diseases demonstrate a broad range of clinical manifestation, associated with developmental delay, psychomotor retardation, hypotonia, seizures, hepatomegaly, microcephaly, and pericardial effusion.

Inherited metabolic disease

nt06015  N-Glycan biosynthesis

(CDG-Ia) PMM2 [HSA:5373] [KO:K17497]
(CDG-Ib) MPI [HSA:4351] [KO:K01809]
(CDG-Ic) ALG6 [HSA:29929] [KO:K03848]
(CDG-Id) ALG3 [HSA:10195] [KO:K03845]
(CDG-Ie) DPM1 [HSA:8813] [KO:K00721]
(CDG-If) MPDU1 [HSA:9526] [KO:K09660]
(CDG-Ig) ALG12 [HSA:79087] [KO:K03847]
(CDG-Ih) ALG8 [HSA:79053] [KO:K03849]
(CDG-Ii) ALG2 [HSA:85365] [KO:K03843]
(CDG-Ij) DPAGT1, ALG7 [HSA:1798] [KO:K01001]
(CDG-Ik) ALG1 [HSA:56052] [KO:K03842]
(CDG-IL) ALG9 [HSA:79796] [KO:K03846]
(CDG-Im) DOLK [HSA:22845] [KO:K00902]
(CDG-In) RFT1 [HSA:91869] [KO:K06316]
(CDG-Io) DPM3 [HSA:54344] [KO:K09659]
(CDG-Ip) ALG11 [HSA:440138] [KO:K03844]
(CDG-Iq) SRD5A3 [HSA:79644] [KO:K12345]
(CDG-Ir) DDOST [HSA:1650] [KO:K12670]
(CDG-Is) ALG13 [HSA:79868] [KO:K07432]
(CDG-It) PGM1 [HSA:5236] [KO:K01835]
(CDG-Iu) DPM2 [HSA:8818] [KO:K09658]
(CDG-Iv) NGLY1 [HSA:55768] [KO:K01456]
(CDG-Iw) STT3A [HSA:3703] [KO:K07151]
(CDG-Ix) STT3B [HSA:201595] [KO:K07151]
(CDG-Iy) SSR4 [HSA:6748] [KO:K04571]
(CDG-Iz) CAD [HSA:790] [KO:K11540]
(CDG-Iaa) NUS1 [HSA:116150] [KO:K19177]
(CDG-Ibb) DHDDS [HSA:79947] [KO:K11778]
(CDG-Icc) MAGT1 [HSA:84061] [KO:K19478]

PMID:16511948

Sparks SE

Inherited disorders of glycosylation.

Mol Genet Metab 87:1-7 (2006)
DOI:10.1016/j.ymgme.2005.11.004

PMID:12756558

Marquardt T, Denecke J

Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies.

Eur J Pediatr 162:359-79 (2003)
DOI:10.1007/s00431-002-1136-0

PMID:12905014 (CDG type Ia)

Neumann LM, von Moers A, Kunze J, Blankenstein O, Marquardt T

Congenital disorder of glycosylation type 1a in a macrosomic 16-month-old boy with an atypical phenotype and homozygosity of the N216I mutation.

Eur J Pediatr 162:710-3 (2003)
DOI:10.1007/s00431-003-1278-8

PMID:12414827 (CDG type Ib)

Vuillaumier-Barrot S, Le Bizec C, de Lonlay P, Barnier A, Mitchell G, Pelletier V, Prevost C, Saudubray JM, Durand G, Seta N

Protein losing enteropathy-hepatic fibrosis syndrome in Saguenay-Lac St-Jean, Quebec is a congenital disorder of glycosylation type Ib.

J Med Genet 39:849-51 (2002)
DOI:10.1136/jmg.39.11.849

PMID:10359825 (CDG type Ic)

Imbach T, Burda P, Kuhnert P, Wevers RA, Aebi M, Berger EG, Hennet T

A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic.

Proc Natl Acad Sci U S A 96:6982-7 (1999)
DOI:10.1073/pnas.96.12.6982

PMID:15108280 (CDG type Id)

Denecke J, Kranz C, Kemming D, Koch HG, Marquardt T

An activated 5' cryptic splice site in the human ALG3 gene generates a premature termination codon insensitive to nonsense-mediated mRNA decay in a new case of congenital disorder of glycosylation type Id (CDG-Id).

Hum Mutat 23:477-86 (2004)
DOI:10.1002/humu.20026

PMID:12736397 (CDG type Ig)

Zdebska E, Bader-Meunier B, Schischmanoff PO, Dupre T, Seta N, Tchernia G, Koscielak J, Delaunay J

Abnormal glycosylation of red cell membrane band 3 in the congenital disorder of glycosylation Ig.

Pediatr Res 54:224-9 (2003)
DOI:10.1203/01.PDR.0000072327.55955.F7

PMID:15235028 (CDG type Ih)

Schollen E, Frank CG, Keldermans L, Reyntjens R, Grubenmann CE, Clayton PT, Winchester BG, Smeitink J, Wevers RA, Aebi M, Hennet T, Matthijs G

Clinical and molecular features of three patients with congenital disorders of glycosylation type Ih (CDG-Ih) (ALG8 deficiency).

J Med Genet 41:550-6 (2004)
DOI:10.1136/jmg.2003.016923

PMID:12684507 (CDG type Ii)

Thiel C, Schwarz M, Peng J, Grzmil M, Hasilik M, Braulke T, Kohlschutter A, von Figura K, Lehle L, Korner C.

A new type of congenital disorders of glycosylation (CDG-Ii) provides new insights into the early steps of dolichol-linked oligosaccharide biosynthesis.

J Biol Chem 278:22498-505 (2003)
DOI:10.1074/jbc.M302850200

PMID:12872255 (CDG type Ij)

Wu X, Rush JS, Karaoglu D, Krasnewich D, Lubinsky MS, Waechter CJ, Gilmore R, Freeze HH

Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1 Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation Type Ij.

Hum Mutat 22:144-50 (2003)
DOI:10.1002/humu.10239

PMID:17273964 (CDG type Im)

Kranz C, Jungeblut C, Denecke J, Erlekotte A, Sohlbach C, Debus V, Kehl HG, Harms E, Reith A, Reichel S, Grobe H, Hammersen G, Schwarzer U, Marquardt T

A defect in dolichol phosphate biosynthesis causes a new inherited disorder with death in early infancy.

Am J Hum Genet 80:433-40 (2007)
DOI:10.1086/512130

PMID:18313027 (CDG type In)

Haeuptle MA, Pujol FM, Neupert C, Winchester B, Kastaniotis AJ, Aebi M, Hennet T

Human RFT1 deficiency leads to a disorder of N-linked glycosylation.

Am J Hum Genet 82:600-6 (2008)
DOI:10.1016/j.ajhg.2007.12.021

PMID:19576565 (CDG type Io)

Lefeber DJ, Schonberger J, Morava E, Guillard M, Huyben KM, Verrijp K, Grafakou O, Evangeliou A, Preijers FW, Manta P, Yildiz J, Grunewald S, Spilioti M, van den Elzen C, Klein D, Hess D, Ashida H, Hofsteenge J, Maeda Y, van den Heuvel L, Lammens M, Lehle L, Wevers RA

Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies.

Am J Hum Genet 85:76-86 (2009)
DOI:10.1016/j.ajhg.2009.06.006

PMID:20080937 (CDG type Ip)

Rind N, Schmeiser V, Thiel C, Absmanner B, Lubbehusen J, Hocks J, Apeshiotis N, Wilichowski E, Lehle L, Korner C

A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase hALG11 leads to congenital disorder of glycosylation-Ip.

Hum Mol Genet 19:1413-24 (2010)
DOI:10.1093/hmg/ddq016

PMID:20637498 (CDG type Iq)

Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, Lehle L, Hombauer H, Adamowicz M, Swiezewska E, De Brouwer AP, Blumel P, Sykut-Cegielska J, Houliston S, Swistun D, Ali BR, Dobyns WB, Babovic-Vuksanovic D, van Bokhoven H, Wevers RA, Raetz CR, Freeze HH, Morava E, Al-Gazali L, Gleeson JG

SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder.

Cell 142:203-17 (2010)
DOI:10.1016/j.cell.2010.06.001

PMID:22305527 (CDG type Ir)

Jones MA, Ng BG, Bhide S, Chin E, Rhodenizer D, He P, Losfeld ME, He M, Raymond K, Berry G, Freeze HH, Hegde MR

DDOST mutations identified by whole-exome sequencing are implicated in congenital disorders of glycosylation.

Am J Hum Genet 90:363-8 (2012)
DOI:10.1016/j.ajhg.2011.12.024

PMID:22492991 (CDG type Is)

Timal S, Hoischen A, Lehle L, Adamowicz M, Huijben K, Sykut-Cegielska J, Paprocka J, Jamroz E, van Spronsen FJ, Korner C, Gilissen C, Rodenburg RJ, Eidhof I, Van den Heuvel L, Thiel C, Wevers RA, Morava E, Veltman J, Lefeber DJ

Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing.

Hum Mol Genet 21:4151-61 (2012)
DOI:10.1093/hmg/dds123

PMID:23109149 (CDG type Iu)

Barone R, Aiello C, Race V, Morava E, Foulquier F, Riemersma M, Passarelli C, Concolino D, Carella M, Santorelli F, Vleugels W, Mercuri E, Garozzo D, Sturiale L, Messina S, Jaeken J, Fiumara A, Wevers RA, Bertini E, Matthijs G, Lefeber DJ

DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy.

Ann Neurol 72:550-8 (2012)
DOI:10.1002/ana.23632

PMID:23842455 (CDG type Iw, Ix)

Shrimal S, Ng BG, Losfeld ME, Gilmore R, Freeze HH

Mutations in STT3A and STT3B cause two congenital disorders of glycosylation.

Hum Mol Genet 22:4638-45 (2013)
DOI:10.1093/hmg/ddt312

PMID:17716641 (marker)

Marklova E, Albahri Z

Screening and diagnosis of congenital disorders of glycosylation.

Clin Chim Acta 385:6-20 (2007)
DOI:10.1016/j.cca.2007.07.002

PMID:17523137 (marker)

Sanz-Nebot V, Balaguer E, Benavente F, Neususs C, Barbosa J

Characterization of transferrin glycoforms in human serum by CE-UV and CE-ESI-MS.

Electrophoresis 28:1949-57 (2007)
DOI:10.1002/elps.200600648

PMID:19862844

Haeuptle MA, Hennet T

Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides.

Hum Mutat 30:1628-41 (2009)
DOI:10.1002/humu.21126

PMID:24218363 (CDG type Iy)

Losfeld ME, Ng BG, Kircher M, Buckingham KJ, Turner EH, Eroshkin A, Smith JD, Shendure J, Nickerson DA, Bamshad MJ, Freeze HH

A new congenital disorder of glycosylation caused by a mutation in SSR4, the signal sequence receptor 4 protein of the TRAP complex.

Hum Mol Genet 23:1602-5 (2014)
DOI:10.1093/hmg/ddt550

PMID:28007989 (CDG type Iz)

Koch J, Mayr JA, Alhaddad B, Rauscher C, Bierau J, Kovacs-Nagy R, Coene KL, Bader I, Holzhacker M, Prokisch H, Venselaar H, Wevers RA, Distelmaier F, Polster T, Leiz S, Betzler C, Strom TM, Sperl W, Meitinger T, Wortmann SB, Haack TB

CAD mutations and uridine-responsive epileptic encephalopathy.

Brain 140:279-286 (2017)
DOI:10.1093/brain/aww300

PMID:25066056 (CDG type Iaa)

Park EJ, Grabinska KA, Guan Z, Stranecky V, Hartmannova H, Hodanova K, Baresova V, Sovova J, Jozsef L, Ondruskova N, Hansikova H, Honzik T, Zeman J, Hulkova H, Wen R, Kmoch S, Sessa WC

Mutation of Nogo-B receptor, a subunit of cis-prenyltransferase, causes a congenital disorder of glycosylation.

Cell Metab 20:448-57 (2014)
DOI:10.1016/j.cmet.2014.06.016

PMID:24499211

Tegtmeyer LC, Rust S, van Scherpenzeel M, Ng BG, Losfeld ME, Timal S, Raymond K, He P, Ichikawa M, Veltman J, Huijben K, Shin YS, Sharma V, Adamowicz M, Lammens M, Reunert J, Witten A, Schrapers E, Matthijs G, Jaeken J, Rymen D, Stojkovic T, Laforet P, Petit F, Aumaitre O, Czarnowska E, Piraud M, Podskarbi T, Stanley CA, Matalon R, Burda P, Seyyedi S, Debus V, Socha P, Sykut-Cegielska J, van Spronsen F, de Meirleir L, Vajro P, DeClue T, Ficicioglu C, Wada Y, Wevers RA, Vanderschaeghe D, Callewaert N, Fingerhut R, van Schaftingen E, Freeze HH, Morava E, Lefeber DJ, Marquardt T

Multiple phenotypes in phosphoglucomutase 1 deficiency.

N Engl J Med 370:533-42 (2014)
DOI:10.1056/NEJMoa1206605

PMID:27343064

Sabry S, Vuillaumier-Barrot S, Mintet E, Fasseu M, Valayannopoulos V, Heron D, Dorison N, Mignot C, Seta N, Chantret I, Dupre T, Moore SE

A case of fatal Type I congenital disorders of glycosylation (CDG I) associated with low dehydrodolichol diphosphate synthase (DHDDS) activity.

Orphanet J Rare Dis 11:84 (2016)
DOI:10.1186/s13023-016-0468-1

PMID:31036665

Blommaert E, Peanne R, Cherepanova NA, Rymen D, Staels F, Jaeken J, Race V, Keldermans L, Souche E, Corveleyn A, Sparkes R, Bhattacharya K, Devalck C, Schrijvers R, Foulquier F, Gilmore R, Matthijs G

Mutations in MAGT1 lead to a glycosylation disorder with a variable phenotype.

Proc Natl Acad Sci U S A 116:9865-9870 (2019)
DOI:10.1073/pnas.1817815116