41 Congenital Disorders of Glycosylation

Jaak Jaeken

41.1 Introduction – 525

41.2 Congenital Disorders of Protein N-Glycosylation – 526 41.2.1 Phosphomannomutase 2 Deficiency (CDG-Ia) – 526 41.2.2 Phosphomannose-Isomerase Deficiency (CDG-Ib) – 527 41.2.3 Glucosyltransferase I Deficiency (CDG-Ic) – 528

41.3 Congenital Disorders of Protein O-Glycosylation – 528 41.3.1 Hereditary Multiple Exostoses – 528 41.3.2 Walker-Warburg Syndrome – 529 41.3.3 Muscle-Eye-Brain Disease – 529

41.4 Newly Discovered Disorders – 529 41.4.1 COG7 Deficiency – 529 41.4.2 GM3 Synthase Deficiency – 529

References – 530 524 Chapter 41 · Congenital Disorders of Glycosylation

Synthesis of N-Glycans This complex synthesis proceeds in three stages, sche- (2) Stepwise assembly in the ER, by further addition of matically represented in . Fig. 41.1. Man and Glc of the 14-unit oligosaccharide precur- (1) Formation in the cytosol of nucleotide-linked sugars, sor, dolichol pyrophosphate-N-acetylglucosamine2- mainly guanosine diphosphate-mannose (GDP- mannose9-glucose3 (indicated by an asterix in the Man), also uridine diphosphate glucose (UDP-Glc) lower left part of . Fig. 41.1). and UDP-N-acetylglucosamine (UDP-GlcNAc), (3) Transfer of this precursor onto the nascent protein followed by attachment of GlcNAc and Man units (depicted in the left part of . Fig. 41.1), followed to dolichol phosphate, and flipping (indicated by by final processing of the glycan in the Golgi appa- circular arrows) of the nascent oligosaccharide ratus by trimming and attachment of various sugar structure into the endoplasmic reticulum (ER). units.

. Fig. 41.1. Schematic representation of the synthesis of chol pyrophosphate-N-acetylglucosamine2-mannose9-glucose3. N-glycans. ER, endoplasmic reticulum; Fru, fructose; GDP, guano- Defects are indicated by solid bars across the arrows. Modified sine diphosphate; Glc, glucose; GlcNAc, N-acetylglucosamine; after Matthijs et al [7] Man, mannose; P, phosphate; UDP, uridine diphosphate; *, doli- 525 41 41.1 · Introduction

41.1 Introduction . Fig. 41.1. Six disorders of the processing of N-glycans (CDG-II group) are known and designated CDG-IIa to Numerous proteins are glycosylated with tree or antenna- CDG-IIf. They are also listed in . Table 41.1, and the loca- like oligosaccharide structures (. Fig. 41.1), also termed tion of the CDG-IIb defect is shown in . Fig. 41.1. Five glycans, attached to the polypeptide chain. Most extracel- disorders of O-glycosylation have been identified and are lular proteins, such as serum proteins (transferrin, clotting listed in . Table 41.2. The defect of oligosaccharide-chain factors), most membrane proteins, and several intracellular processing that leads to deficiency of the mannose-6-phos- proteins (such as lysosomal enzymes), are glycoproteins. phate recognition marker of the lysosomal enzymes and The glycans are defined by their linkage to the protein: N- causes mucolipidosis II or III is discussed in 7 Chap. 39. The glycans are linked to the amide group of asparagine, and deficiencies of the lysosomal enzymes that degrade the O-glycans are linked to the hydroxyl group of serine or oligosaccharide side chains, and cause oligosaccharidoses, threonine. Synthesis of N-glycans, schematically represent- are also discussed in that chapter. ed in . Fig. 41.1, proceeds in three stages: formation of nu- Patients with CDG form a rapidly growing group, with cleotide-linked sugars, asssembly, and processing. Synthesis a very broad spectrum of clinical manifestations. Moreover, of O-glycans involves assembly but no processing, and oc- their discovery has opened new avenues in the field. In 2004, curs mainly in the Golgi apparatus. It forms a diversity of a combined N- and O-glycosylation defect was reported. It is structures such as O-xylosylglycans, O-mannosylglycans, due to the deficiency of a subunit, COG7, in a protein com- and O-N-acetylgalactosaminylglycans. plex involved in trafficking and function of the glycosylation In recent years, a series of defects of the synthesis of the machinery. Also in 2004, the first defect in lipid glycosylation oligosaccharide chains of glycoproteins, named Congenital was reported, namely the deficiency of GM3 synthase, an Disorders of Glycosylation (CDG), have been identified. enzyme involved in the synthesis of gangliosides. Twelve disorders of the assembly of N-glycans (CDG-I Because of the large number of CDGs, only the most group) are currently known, designated CDG-Ia to CDG-Il. frequently reported types will be considered in detail in this They are listed in . Table 41.1, together with the main clin- chapter: CDG-Ia, CDG-Ib, and CDG-Ic. The hereditary ically affected organs and systems, defective proteins, and multiple exostoses syndrome, Walker-Warburg syndrome, genes. The location of each enzyme defect is shown in muscle-eye-brain disease, and the newly discovered dis-

. Table 41.1. Genetic N-glycosylation disorders

Name Main clinically affected organs and systems Defective protein Defective gene

CDG-I CDG-Ia Nervous system, fat tissue, other organs1 Phosphomannomutase 2 PMM2 CDG-Ib Intestine, liver Phosphomannose isomerase MPI CDG-Ic Nervous system Glucosyltransferase I hALG6 CDG-Id Nervous system Mannosyltransferase VI hALG3 CDG-Ie Nervous system Dolichol-P-Man synthase I DPM1 CDG-If Nervous system, skin Lec35 Lec35 CDG-Ig Nervous system Mannosyltransferase VIII hALG12 CDG-Ih Intestine, liver Glucosyltransferase II hALG8 CDG-Ii Nervous system, eyes, liver Mannosyltransferase II hALG2 CDG-Ij Nervous system UDP-GlcNAc: dolichol phosphate DPAGT1 N-acetylglucosamine 1-phosphate transferase CDG-Ik Nervous system, liver Mannosyltransferase I hALG1 CDG-Il Nervous system, liver Mannosyltransferase VII/IX hALG9

CDG-II CDG-IIa Nervous system, skeleton, intestine, N-acetylglucosaminyltransferase II MGAT2 immune system, dysmorphism CDG-IIb Nervous system, dysmorphism Glucosidase I GLS1 CDG-IIc Nervous system, immune system, dysmorphism GDP-fucose transporter 1 FUCT1 CDG-IId Nervous system, skeletal muscles E-1,4-galactosyltransferase 1 B4GALT1 CDG-IIe2 Nervous system, liver, skeleton Conserved oligomeric Golgi complex, COG7 subunit 7 CDG-IIf Megathrombocytopenia, neutropenia CMP-sialic acid transporter SLC35A1

1 Eyes, heart, liver, kidneys, skeleton, gonads, immune system. 2 Preliminary assignment. 526 Chapter 41 · Congenital Disorders of Glycosylation

. Table 41.2. Genetic O-glycosylation disorders

Name Main clinically affected Defective protein Defective gene organs and systems

Defects in O-xylosylglycan synthesis

Multiple exostoses syndrome Cartilage Glucuronyltransferase/N-acetyl-D- EXT1/EXT2 hexosaminyltransferase

Progeroid variant of Ehlers-Danlos Generalized rapid aging β-1,4-Galactosyltransferase 7 B4GALT7 syndrome

Defects in O-mannosylglycan synthesis

Walker-Warburg syndrome O-mannosyltransferase 1 POMT1

Muscle-eye-brain disease Brain, eyes, skeletal muscles O-mannosyl-β-1,2-N-acetylglucos- POMGnT1 aminyltransferase 1

Defect in O-N-acetylgalactosaminylglycan synthesis

Familial tumoral calcinosis Skin, subcutaneous tissues, ppGaNTase-T31 GALNT3 kidneys

1 UDP-N-acetyl-α-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3.

orders will also be briefly discussed. For recent reviews CDG should be considered particularly in multi-organ 7 [1–7], and for recent reports not covered by these reviews disease with neurological involvement. Isoelectrofocusing 7 [8–10]. of serum transferrin is still the screening method of choice X CDG should be considered a possible diagnosis in any but it is important to realize that it is able to detect only a unexplained clinical condition. The rationale for this rec- limited number of CDGs, namely N-glycosylation disorders ommendation is twofold: Firstly, the extremely broad clini- associated with sialic acid deficiency. The (partial) defi- cal spectrum covered by the some 25 known CDGs and, ciency of sialic acid in these forms of CDG causes one of secondly, since about 1% of the human genome is involved two main types of cathodal shift (. Fig. 41.2 and Sect. 41.2.1). in glycosylation, it is more than probable that the majority A type 1 pattern indicates an assembly disorder and CDG-Ia of CDGs have still to be discovered. We predict that these and CDG-Ib should be considered first. If these are ex- will also include diseases due to defects in organ-specific cluded the next step is dolichol-linked glycan analysis which glycosylation (brain-CDG, kidney-CDG, etc). Also, as has will usually locate the site of the defect. A type 2 pattern already been shown for hereditary multiple exostoses, indicates a disorder of processing; protein-linked glycan Walker-Warburg syndrome and others, there is no doubt analysis should then be performed in an attempt to identify that known diseases with unknown etiology will continue the defective step. to be identified as CDGs.

41.2 Congenital Disorders of Protein N-Glycosylation

41.2.1 Phosphomannomutase 2 Deficiency (CDG-Ia)

Clinical Presentation CDG-Ia is by far the most frequent CDG with at least 550 patients known worldwide. The symptomatology can be recognized shortly after birth. The nervous system is affected in all patients, and most other organs are involved in a variable way. The neurological picture comprises alternat- . Fig. 41.2a–d. Serum transferrin isoelectrofocusing patterns. ing internal strabismus and other abnormal eye movements, a normal pattern; b type 1 pattern; c and d type 2 patterns; 0, 2, 4 indi- axial hypotonia, psychomotor retardation (IQ typically be- cate the number of sialic acid residues tween 40 and 60), ataxia and hyporeflexia. After infancy, 527 41 41.2 · Congenital Disorders of Protein N-Glycosylation

symptoms include retinitis pigmentosa, often stroke-like made by isoelectrofocusing and immunofixation of serum episodes, and sometimes epilepsy. As a rule there is no re- transferrin [18] (. Fig. 41.2). Normal serum transferrin is gression. During the first year(s) of life, there are variable mainly composed of tetrasialotransferrin and small amounts feeding problems (anorexia, vomiting, diarrhea) that can of mono-, di-, tri-, penta- and hexasialotransferrins. The result in severe failure to thrive. Other features are a vari- partial deficiency of sialic acid (a negatively charged and able dysmorphism, which may include large, hypoplastic/ end-standing sugar) in CDG causes a cathodal shift. Two dysplastic ears, abnormal subcutaneous adipose-tissue dis- main types of cathodal shift can be recognized. Type 1 is tribution (fat pads, orange peel skin), inverted nipples, and characterized by an increase of both disialo- and asialotrans- mild to moderate hepatomegaly, skeletal abnormalities and ferrin and a decrease of tetra-, penta- and hexasialotransfer- hypogonadism. Some infants develop a pericardial effu- rins; in type 2 there is also an increase of the tri- and/or sion and/or cardiomyopathy. At the other end of the clini- monosialotransferrin bands. In PMM2 deficiency, a type 1 cal spectrum are patients with a very mild phenotype (no pattern is found. A type 1 pattern is also seen in the second- dysmorphic features, slight psychomotor retardation). Pa- ary glycosylation disorders, chronic alcoholism and hered- tients often have an extraverted and happy appearance. itary fructose intolerance. A shift due to a transferrin pro- Neurological investigations reveal (olivoponto) cerebellar tein variant has first to be excluded (by isoelectrofocusing hypoplasia, variable cerebral hypoplasia and peripheral after neuraminidase treatment, studying another glycopro- neuropathy. Liver pathology is characterized by fibrosis tein and investigating the parents). The carbohydrate-defi- and steatosis, and electron microscopy shows myelin-like cient transferrin (CDT) assay is also useful for the diagnosis lysosomal inclusions in hepatocytes but not in Kupffer cells of sialic acid-deficient CDG. It quantifies the total sialic [11–16]. acid-deficient serum transferrin. A draw-back is a non-neg- ligible number of false-positive results. Recently, capillary Metabolic Derangement zone electrophoresis of total serum has been introduced for Phosphomannomutase (PMM) catalyzes the second com- the diagnosis of CDG [19]. mitted step in the synthesis of guanosine diphosphate (GDP) In addition to the above-mentioned serum glycoprotein mannose, namely the conversion of mannose-6-phosphate abnormalities, laboratory findings include elevation of se- into mannose-1-phosphate, which occurs in the cytosol rum transaminase levels, hypoalbuminemia, hypocholeste- (. Fig. 41.1). CDG-Ia is due to the deficiency of PMM2, the rolemia, and tubular proteinuria. To confirm the diagnosis, principal isozyme of PMM. Since GDP-mannose is the do- the activity of PMM should be measured in leukocytes or nor of the mannose units used in the ER to assemble the fibroblasts. dolichol-pyrophosphate oligosaccharide precursor, the defect causes hypoglycosylation, and hence deficiency and/or Treatment and Prognosis dysfunction of numerous glycoproteins, including serum No effective treatment is available. The promising finding proteins (such as thyroxin-binding globulin, haptoglobin, that mannose is able to correct glycosylation in fibroblasts clotting factor XI, antithrombin, cholinesterase etc.), lyso- with PMM deficiency [20] could not be substantiated in somal enzymes and membranous glycoproteins. patients [21]. There is a substantially increased mortality (~20%) in the first years of life due to severe infection or Genetics vital organ involvement (liver, cardiac or renal insuffi- PMM deficiency is inherited as an autosomal-recessive trait ciency). due to mutations of the PMM2 gene on chromosome 16p13. At least 60 mutations (mainly missense) have been identified. The most frequent mutation causes a R141H substitu- 41.2.2 Phosphomannose-Isomerase tion which, remarkably, has not yet been found in the ho- Deficiency (CDG-Ib) mozygous state, pointing to a lethal condition [17]. The frequency of this mutation in the normal Belgian popula- Clinical Presentation tion is as high as 1/50. The incidence of PMM deficiency is Three groups independently reported this CDG first in not known; in Sweden it has been estimated at 1:40,000. 1998 [22–24]. Some 20 patients have been described. Most Prenatal testing should only be offered in families with have presented with hepatic-intestinal disease without no- a documented PMM deficiency and mutations in the table dysmorphism, and with or without only minor neuro- PMM2 gene. It cannot be performed by any assay that de- logical involvement. Symptoms started between the ages of termines the glycosylation of proteins since this has been 1 and 11 months. One patient had recurrent vomiting and found to be normal in the foetus [7]. liver disease that disappeared after the introduction of solid food at the age of 3 months. A healthy adult has been re- Diagnostic Tests ported who had transient feeding problems in childhood. The diagnosis of congenital disorders of N-glycosylation in In the other patients, symptoms persisted and consisted of general (and of PMM deficiency in particular) is usually various combinations of recurrent vomiting, abdominal 528 Chapter 41 · Congenital Disorders of Glycosylation

pain, protein-losing enteropathy, recurrent thromboses, Metabolic Derangement gastrointestinal bleeding, liver disease and symptoms of Glucosyltransferase I deficiency is a defect in the attach- (hyperinsulinemic or normoinsulinemic) hypoglycemia. In ment in the ER of the first of three glucose molecules to the 1985, four infants from Quebec were reported with a simi- dolichol-linked mannose9-N-acetylglucosamine2 interme- lar syndrome who retrospectively were shown most prob- diate (. Fig. 41.1). It causes hypoglycosylation of serum ably to have the same disease [25]. glycoproteins, because non-glucosylated oligosaccharides are a sub-optimal substrate for the oligosaccharyltrans- Metabolic Derangement ferase and are, therefore, transferred to proteins with a Phosphomannose-isomerase (PMI) catalyzes the first com- reduced efficiency. For an unknown reason, the blood mitted step in the synthesis of GDP-mannose, namely the glycoproteins are unusually low (particularly factor XI and conversion of fructose-6-phosphate into mannose-6-phos- coagulation inhibitors, such as antithrombin and protein phate (. Fig. 41.1). Hence the blood biochemical abnor- C). The reason the clinical picture in these patients is much malities are indistinguishable from those found in PMM2 milder that that of PMM deficient patients may be because deficiency. Since the substrate of PMI, fructose-6-phos- a deficiency in glucosylation of the dolichol-linked oligosac- phate, is efficiently metabolized in the glycolytic pathway, it charides does not affect the biosynthesis of GDP-mannose does not accumulate intracellularly. and, hence, does not affect the biosynthesis of compounds such as GDP-fucose or the biosynthesis of glycosylphos- Genetics phatidylinositol-anchored glycoproteins. Inheritance of PMI deficiency is autosomal recessive. The gene has been localised to chromosome 15q22. Several mu- Genetics tations have been identified. Prenatal diagnosis is only pos- Inheritance of this glucosyltransferase deficiency is auto- sible if the molecular defect is known in the proband [7]. somal recessive. The gene maps to chromosome 1p22.3. A333V is a common mutation. Prenatal diagnosis is only Diagnostic Tests reliable if the molecular defect is known in the proband Serum transferrin isoelectrofocusing shows a type 1 pat- [7]. tern. The diagnosis is confirmed by finding a decreased X activity of PMI in leukocytes or fibroblasts and/or (a) Diagnostic Tests mutation(s) in the corresponding gene. This disease illustrates that, even in cases of mild psychomotor retardation without any specific dysmorphic fea- Treatment and Prognosis tures, isoelectrofocusing of serum sialotransferrins should PMI deficiency is the most rewarding CDG to diagnose be performed. When a type 1 pattern is found, PMM and because, so far, it is the only one known that can be effi- PMI deficiency must be considered first. If these enzymes ciently treated. Mannose is the therapeutic agent [24]. Hex- show normal activities, the next step is the analysis of the okinases phosphorylate mannose to mannose 6-phosphate, dolichol-linked oligosaccharides in fibroblasts. If the major thus bypassing the defect. An oral dose of 1 g mannose/kg fraction of these oligosaccharides consists of nine mannose body weight per day (divided in 5 doses) is used. The clini- and two N-acetylglucosamine residues without the three cal symptoms usually disappear rapidly but it takes several glucose residues that are normally present, this specific glu- months before the transferrin isoelectrofocusing pattern cosyltransferase activity should be measured in fibroblasts improves significantly. Nevertheless, several patients with (which is only undertaken by very few laboratories). If proven PMI deficiency, including one receiving mannose deficient activity is found then this should be followed by treatment, have died. mutation analysis.

Treatment and Prognosis 41.2.3 Glucosyltransferase I Deficiency No efficient treatment is available. The long-term outcome (CDG-Ic) is unknown since all reported patients have been children.

Clinical Presentation CDG-Ic is the second most common N-glycosylation dis- 41.3 Congenital Disorders order with more than 30 patients identified since its de- of Protein O-Glycosylation scription in 1998 [26]. Clinical features in common with CDG-Ia are hypotonia, strabismus and seizures, but psy- 41.3.1 Hereditary Multiple Exostoses chomotor retardation is milder, there is less dysmorphism, and usually no retinitis pigmentosa or cerebellar hypopla- Hereditary multiple exostoses is an autosomal dominant sia. A few patients have had protein-losing enteropathy, a disease with a prevalence of 1/50 000, and characterized by consistent feature in CDG-Ib and CDG-Ih [27]. the formation on the ends of long bones of cartilage-capped 529 41 41.4 · Newly Discovered Disorders

tumors, known as osteochondromas [28]. These are often burg syndrome but less severe, and with longer survival present at birth but usually not diagnosed before early [30]. The defect is in protein O-mannosyl-E-1,2-N-acetyl- childhood. Their growth slows at adolescence and stops in glucosaminyltransferase 1, catalyzing the second step in the adulthood. A small percentage of these lesions are subject synthesis of the O-mannosylglycan core [33]. The disease is to malignant degeneration. Complications may arise from autosomal recessive and due to mutations in POMGnT1, compression of peripheral nerves and blood vessels. located on chromosome 1p34-p33. The basic defect resides in a Golgi-localised protein complex, termed exostosin-1/exostosin-2 (EXT1/EXT2), which adds d-glucuronic and N-acetylglucosamine units 41.4 Newly Discovered Disorders in the synthesis of heparan sulfate (. Fig. 39.1). It has been hypothesized that mutations in these glycosyltransferases 41.4.1 COG7 Deficiency impair the synthesis of a glycosaminoglycan that exerts a tumor-suppression function. This would explain the higher COG7 deficiency was identified in two siblings born risk of affected individuals to develop chondrosarcomas small for gestational age and with perinatal asphyxia. They and osteosarcomas. had dysmorphic features, particularly of the face, ence- Fifty mutations in the EXT1 gene, localized on chromo- phalopathy, and cholestatic liver disease. Both died, at 5 some 8q24.1, and 25 mutations in EXT2, on chromosome and 10 weeks, respectively. There was a mild to moderate 11p11-p12, have been identified [29]. Mutations in the two increase of lysosomal enzyme activities in plasma. There genes are responsible for over 70% of the cases of hereditary was a type 2 pattern on serum transferrin isoelectrofocus- multiple exostoses. Prenatal diagnosis can be performed by ing [34]. mutation analysis. Studies of fibroblast glycoproteins showed a partial N- and O-glycosylation defect caused by a decreased trans- port of CMP-sialic acid and UDP-galactose into the Golgi, 41.3.2 Walker-Warburg Syndrome and a reduced activity of two glycosyltransferases involved in the galactosylation and sialylation of O-glycans. The lo- Walker-Warburg Syndrome is one of some 25 neuronal mi- calization of the 8-subunit conserved oligomeric Golgi gration disorders known in humans. It is characterized by (COG) complex, involved in trafficking and function of brain and eye dysgenesis associated with congenital muscu- the glycosylation machinery, was found to be abnormal: on lar dystrophy. Male patients often have testicular defects. indirect immunofluorescence there was diffuse cytoplas- Psychomotor development is absent. The brain lesions con- mic staining instead of Golgi staining of COG5, COG6 and sist of »cobblestone« lissencephaly, agenesis of the corpus COG8. The basic defect was eventually localised to the callosum, cerebellar hypoplasia, hydrocephaly and some- COG7 subunit, and a homozygous intronic mutation was times encephalocoele [30]. The disease usually runs a fatal found in COG7, located on chromosome 16p [10]. course before the age of one year, and only symptomatic treatment is available. The metabolic derangement is an aberrant glycosyla- 41.4.2 GM3 Synthase Deficiency tion of D-dystroglycan, an external membrane protein ex- pressed in muscle, brain and other tissues [31]. Most gly- This first identified glycolipid glycosylation disorder was cans of this heavily glycosylated protein seem to be O-linked detected in an Old Order Amish pedigree [9]. The first via mannose, and they control the interaction with extracel- symptoms consisted of poor feeding and irritability appear- lular matrix proteins. Disrupted glycosylation of D-dystro- ing between 2 weeks and 3 months of age. Epilepsy devel- glycan (and probably other glycoproteins) results in loss of oped within the first year (grand mal and other presenta- this interaction and hence in progressive muscle degenera- tions) and was difficult to control. Moreover, the patients tion and abnormal neuronal migration (overmigration) in showed profound developmental stagnation with regres- the brain. In about 20% of the patients this disrupted glyco- sion. On brain magnetic resonance imaging there was dif- sylation is due to a defective O-mannosyltransferase-1, fuse atrophy at an older age. which catalyzes the first step in the synthesis of the O-man- The metabolic derangement was identified as a defect nosylglycan core. It is caused by mutations in the gene of lactosylceramide α-2,3 sialyltransferase (also called GM3 POMT1, located on chromosome 9q34.1 [32]. synthase) which can be measured in plasma or fibroblasts. The defect causes accumulation of lactosylceramide associated with a decrease of the gangliosides of the GM3 and 41.3.3 Muscle-Eye-Brain Disease GD3 series. A homozygous mutation was found in SIAT9, localized on chromosome 2p11.2. Muscle-eye-brain disease is a neuronal migration/congenital muscular dystrophy syndrome similar to Walker-War- 530 Chapter 41 · Congenital Disorders of Glycosylation

References 22. de Koning TJ, Dorland L, van Diggelen OP et al (1998) A novel disorder of N-glycosylation due to phosphomannose isomerase defi- 1. Aebi M, Hennet T (2001) Congenital disorders of glycosylation: ciency. Biochem Biophys Res Commun 245:38-42 genetic model systems lead the way. Trends Cell Biol 11:136-141 23. Jaeken J, Matthijs G, Saudubray J-M et al (1998) Phosphomannose 2. Freeze HH (2002) Human disorders in N-glycosylation and animal isomerase deficiency: a carbohydrate-deficient glycoprotein syn- models. Biochim Biophys Acta 1573:388-393 drome with hepatic-intestinal presentation. Am J Hum Genet 3. Jaeken J (2003) Komrower lecture: Congenital disorders of glyco- 62:1535-1539 sylation (CDG): it’s all in it! J Inherit Metab Dis 26:99-118 24. Niehues R, Hasilik M, Alton G et al (1998) Carbohydrate-deficient 4. Lowe JB, Marth JD (2003) A genetic approach to mammalian glycan glycoprotein syndrome type Ib: phosphomannose isomerase defi- function. Annu Rev Biochem 72:643-691 ciency and mannose therapy. J Clin Invest 101:1414-1420 5. Marquardt T, Denecke J (2003) Congenital disorders of glycosyla- 25. Pelletier VA, Galeano N, Brochu P et al (1985) Secretory diarrhea tion: review of their molecular bases, clinical presentations and with protein-losing enteropathy, enterocolitis cystica superficialis, specific therapies. Eur J Pediatr 162:359-379 intestinal lymphangiectasia and congenital hepatic fibrosis: a new 6. Jaeken J, Carchon H (2004) Congenital disorders of glycosylation: syndrome. J Pediatr 108:61-65 a booming chapter of pediatrics. Curr Opin Pediatr 16:434-439 26. Burda P, Borsig L, de Rijk-van Andel J et al (1998) A novel carbo- 7. Matthijs G, Schollen E, Van Schaftingen E (2004) The prenatal diag- hydrate-deficient glycoprotein syndrome characterized by a de- nosis of congenital disorders of glycosylation (CDG). Prenat Diagn ficiency in glucosylation in the dolichol-linked oligosaccharide. 24:114-116 J Clin Invest 102:647-652 8. Frank CG, Grubenmann CE, Eyaid W, Berger EG, Aebi M, Hennet T 27. Grünewald S, Imbach T, Huijben K et al (2000) Clinical and biochem- (2004) Identification and functional analysis of a defect in the hu- ical characteristics of congenital disorder of glycosylation type Ic, man ALG9 gene: definition of congenital disorders of glycosylation the first recognized endoplasmic reticulum defect in N-glycan syn- type Il. Am J Hum Genet 75:146-150 thesis. Ann Neurol 47:776-781 9. Simpson MA, Cross H, Proukakis C et al (2004) Infantile onset symp- 28. Wicklund CL, Pauli RM, Johnston D, Hecht JT (1995) Natural history tomatic epilepsy syndrome caused by a homozygous loss-of-func- study of hereditary multiple exostoses. Am J Med Genet 55:43-46 tion mutation of GM3 synthase. Nat Genet 36:1225-1229 29. Wuyts W, Van Hul W (2000) Molecular basis of multiple exostoses: 10. Wu X, Steet RA, Bohorov O et al (2004) Mutation of the COG com- mutations in the EXT1 and EXT2 genes. Hum Mutat 15:220-227 plex subunit gene COG7 causes a lethal congenital disorder. Nat 30. Cormand B, Pikho H, Bayes M et al (2001) Clinical and genetic dis- Med 10:518-523 tinction between Walker-Warburg syndrome and muscle-eye- 11. Jaeken J, Vanderschueren-Lodeweyckx M, Casaer P et al (1980) Fa- brain disease. Neurology 56:1059-1069 milial psychomotor retardation with markedly fluctuating serum 31. Muntoni F, Brockington M, Blake DJ, Torelli S, Brown SC (2002) Defec- proteins, FSH and GH levels, partial TBG-deficiency, increased se- tive glycosylation in muscular dystrophy. Lancet 360:1419-1421 rum arylsulphatase A and increased CSF protein: a new syndrome? 32. Beltrán-Valero de Bernabé D, Currier S, Steinbrecher A et al (2002) X POMT1 Pediatr Res 14:179 Mutations in the O-mannosyltransferase gene give rise to 12. Jaeken J, Stibler H, Hagberg B (1991) The carbohydrate-deficient the severe neuronal migration disorder Walker-Warburg syndrome. glycoprotein syndrome: a new inherited multisystemic disease Am J Hum Genet 71:1033-1043 with severe nervous system involvement. Acta Paediatr Scand 33. Yoshida A, Kobayashi K, Manya H et al (2001) Muscular dystrophy >Suppl@ 375:1-71 and neuronal migration disorder caused by mutations in a glyco- 13. Van Schaftingen E, Jaeken J (1995) Phosphomannomutase defi- syltransferase, POMGnT1. Dev Cell 1:717-724 ciency is a cause of carbohydrate-deficient glycoprotein syndrome 34. Spaapen LJM, Bakker JA, van der Meer SB et al (2005) Fatal outcome type I. FEBS Lett 377:318-320 in sibs with a newly recognized multiple glycosylation disorder in- 14. Jaeken J, Besley G, Buist N et al (1996) Phosphomannomutase de- volving O-and N-glycosylation. J Inherit Metab Dis 28:707-714 ficiency is the major cause of carbohydrate-deficient glycoprotein syndrome type I. J Inherit Metab Dis 19>Suppl 1@:6 15. de Zegher F, Jaeken J (1995) Endocrinology of the carbohydrate- deficient glycoprotein syndrome type 1 from birth through adolescence. Pediatr Res 37:395-401 16. Van Geet C, Jaeken J (1993) A unique pattern of coagulation abnormalities in carbohydrate-deficient glycoprotein syndrome. Pediatr Res 33:540-541 17. Matthijs G, Schollen E, Van Schaftingen E, Cassiman J-J, Jaeken J (1998) Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1 A. Am J Hum Genet 62:542-550 18. Jaeken J, van Eijk HG, van der Heul C et al (1984) Sialic acid-deficient serum and cerebrospinal fluid transferrin in a newly recognized genetic syndrome. Clin Chim Acta 144:245-247 19. Carchon H, Chevigné R, Falmagne JB, Jaeken J (2004) Diagnosis of congenital disorders of glycosylation by capillary zone electrophoresis of serum transferrin. Clin Chem 50:101-111 20. Panneerselvam K, Freeze HH (1996) Mannose corrects altered N-glycosylation in carbohydrate-deficient glycoprotein syndrome fibroblasts. J Clin Invest 97:1478-1487 21. Kjaergaard S, Kristiansson B, Stibler H et al (1998) Failure of short- term mannose therapy of patients with carbohydrate-deficient glycoprotein syndrome type I A. Acta Paediatr 87:884-888