20 Congenital Disorders of Glycosylation
Jaak Jaeken
20.1 Introduction
Among the 19 identified disorders of N- and O-glycan synthesis, only two are amenable to treatment: phosphomannose isomerase deficiency (CDG-Ib) is efficiently treatable by mannose, while GDP-fucose transporter deficiency (CDG-IIc) can be partially treated by fucose. Symptomatic treatment mainly consists of antithrombotic therapy in CDG-Ia, and management of epilepsy.
218 Congenital Disorders of Glycosylation 20.2 Nomenclature
No. Disorder Definitions/Comment Gene
symbol
OMIM No.
20.1 Phosphomannomutase 2 (PMM2) deficiency (CDG-Ia)
Deficient mannose-1-phosphate and GDP-mannose
PMM2 212065
20.2 Phosphomannose isomerase (PMI) deficiency (CDG-Ib)
Deficient mannose-6-phosphate and GDP mannose
MPI 602579
20.3 Glucosyltransferase I deficiency (CDG-Ic)
Deficient Glc3Man9GlcNAc2P2dolichol and downstream metabolites
hALG6 603147 20.4 Mannosyltransferase VI deficiency
(CDG-Id)
Deficient Man6GlcNAc2P2dolichol and downstream metabolites
hALG3 601110 20.5 Dolichol-P-Man synthase I
deficiency (CDG-Ie)
Deficient Man6GlcNAc2P2dolichol and downstream metabolites
DPM1 603503
20.6 Lec 35 deficiency (CDG-If) Increased Man5GlcNAc2P2dolichol and Man9GlcNAc2
MPDU1 604041 20.7 Mannosyltransferase VIII
deficiency (CDG-Ig)
Deficient Man8GlcNAc2P2dolichol and downstream metabolites
hALG12 607143 20.8 Glucosyltransferase II deficiency
(CDG-Ih)
Deficient Glc2Man9GlcNAc2P2dolichol and downstream metabolites
hALG8 608104 20.9 Mannosyltransferase II deficiency
(CDG-Ii)
Deficient Man2GlcNAc2P2dolichol and downstream metabolites
hALG2 607906 20.10 UDP-GlcNAc: dolichol phosphate
N-acetylglucosamine-1-phosphate transferase deficiency (CDG-Ij)
Deficient GlcNAc2P2dolichol and downstream metabolites
DPAGT1 608093
20.11 Mannosyltransferase I deficiency (CDG-Ik)
Deficient Man1GlcNAc2P2dolichol and downstream metabolites
hALG1 608540 20.12 N-Acetylglucosaminyltransferase II
(GnT II) deficiency (CDG-IIa)
Accumulation of Sia1Gal1GlcNAc3Man3
protein
MGAT2 212066 20.13 Glucosidase I deficiency (CDG-IIb) Accumulation of Glc3Man9
GlcNAc2protein; presence of Glc3Man in urine
GCS1 606056
20.14 GDP-fucose transporter 1 deficiency (CDG-IIc)
Generalized fucose deficiency FUCT1 266265 20.15 β-1,4-Galactosyltransferase 1
deficiency (CDG-IId)
Accumulation of GlcNAc4Man3protein B4GALT1 607091 20.16 β-1,4-Galactosyltransferase 7
deficiency
Decrease in glycosaminoglycans B4GALT7 130070 20.17 Glucuronyltransferase/N-acetyl-d-
hexosaminyltransferase deficiency (multiple exostoses syndrome)
Decrease in glycosaminoglycans EXT1/
EXT2
133700
20.18 O-Mannosyltransferase 1 deficiency (Walker-Warburg syndrome)
Decrease in O-mannosylglycans POMT1 236670 20.19 O-Mannosyl-β-1,2-N-
acetylglucosaminyltransferase 1 deficiency (muscle-eye-brain disease)
Decrease in O-mannosylglycans POMGnT1 253280
Treatment 219 20.3 Treatment
I 20.1 Phosphomannomutase 2 deficiency
A minority of these patients present recurrent strokes (at least in part due to hyperaggregability of blood platelets). These strokes can be prevented more or less efficiently by small doses acetylsalicylic acid (∼ 1 mg/kg per day).
I 20.2 Phosphomannose isomerase deficiency
Oral mannose, 1 g/kg BW per day, divided into five doses per day. The clinical symptoms disappear rapidly, but it takes several months for the serum trans- ferrin pattern to improve or normalize.
I 20.14 GDP-fucose transporter deficiency
Oral fucose, 150 mg/kg BW, five times a day, abolishes or prevents infections and normalizes neutrophil counts in some patients (depending on genotype).
Dangers/Pitfalls
• 20.2 Higher mannose doses can induce osmotic diarrhea
• 20.14 Higher fucose doses can induce autoimmune neutropenia
20.4 Alternative Therapies/Experimental Trials None
20.5 Follow-up/Monitoring
I 20.2 Phosphomannose isomerase deficiency
• Clinical monitoring: 3–6 monthly
• Biochemical monitoring: serum transaminases, albumin, transferrin iso- electrofocusing, clotting factor XI: according to clinical and biochemical data.
I 20.14 GDP-fucose transporter deficiency
• Clinical monitoring: 3–6 monthly
• Biochemical monitoring: leukocytosis and formula: weekly until normaliza- tion; thereafter 3–6 monthly.
220 References References
1. Harms HK, Zimmer KP, Kurnik K, Bertele-Harms RM, Weidinger S, Reiter K (2002) Oral mannose therapy persistently corrects the severe clinical symptoms and biochemical abnormalities of phosphomannose isomerase deficiency. Acta Paediatr 91:1065–1072 2. Hidalgo A, Ma S, Peired AJ, Weiss LA, Cunningham-Rundles C, Frenette PS (2003)
Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the GDP- fucose transporter gene. Blood 101:1705–1712
3. Jaeken J, Matthijs G, Saudubray JM, Dionisi-Vici C, Bertini E, Lonlay P de, Henri H, Car- chon H, Schollen E, Van Schaftingen E (1998) Phosphomannose isomerase deficiency:
a carbohydrate-deficient glycoprotein syndrome with hepatic-intestinal presentation.
Am J Hum Genet 62:1535–1539
4. Koning TJ de, Dorland J, Diggelen OP van, Boonman AMC, Jong GJ de, Noort WL van, De Schrijver JD, Duran M, Berg IET van den, Gerwig GJ, Berger R, Poll-The BT (1998) A novel disorder of N-glycosylation due to phosphomannose isomerase deficiency.
Biochem Biophys Res Commun 245:38–42
5. Lonlay P de, Cuer M, Vuillaumier-Barrot S, Beaune G, Castelnau P, Kretz M, Durand G, Saudubray JM, Seta N (1999) Hyperinsulinemic hypoglycemia as a presenting sign in phosphomannose isomerase deficiency: a new manifestation of carbohydrate-deficient glycoprotein syndrome treatable with mannose. J Pediatr 135:379–383
6. Lühn K, Marquardt T, Harms E, Vestweber D (2001) Discontinuation of fucose therapy in LAD II causes rapid loss of selectin ligands and rise of leukocyte counts. Blood 97:330–332
7. Marquardt T, Lühn K, Srikrishna G, Freeze HH, Harms E, Vestweber D (1999) Correction of leukocyte adhesion deficiency type II with oral fucose. Blood 94:3976–3985
8. Niehues R, Hasilik M, Alton G, Körner C, Schiebe-Sukumar M, Koch HG, Zimmer KP, Wu R, Harms E, Reiter K, Figura K von, Freeze HH, Harms HK, Marquardt T (1998) Carbohydrate-deficient glycoprotein syndrome type Ib: phosphomannose isomerase deficiency and mannose therapy. J Clin Invest 101:1414–1420
9. Sturla L, Puglielli L, Tonetti M, Berninsone P, Hirschberg CB, De Flora A, Etzioni A (2001) Impairment of the Golgi GDP-l-fucose transport and unresponsiveness to fucose replacement therapy in LAD II patients. Pediatr Res 49:537–542
