During the assembly phase a lipid-linked oligosaccharide dolichylpyrophosphate-GlcNAc2Man9Glc3 is formed by addition of 2 GlcNAc residues, 9 mannoses of which the first 5 are delivered by GDP-mannose on the cytoplasmic side. GDP-mannose is synthesized from fructose 6-phosphate, an intermediate of the glycolytic pathway. After flipping the growing oligosaccharide to the luminal side of the endoplasmic reticulum 4 other mannose residues are attached, deliverd by Dol-P-Man and 3 glucose residues deliverd by Dol-P-Glc. The oligosaccharide moiety of this lipid linked oligosaccharide is then transferred to selected asparagines of the nascent proteins.

PHENOTYPE

The phosphomannomutase (PMM) deficiency (MIM 212065, 601785) is the longest and, thus, best known CDG. An estimated 300 patients are known worldwide. It has been found in more than twenty different populations from Asia, Australia, Europe, and North and South America (3, 7, 14, 19, 26, 37, 40, 64, 69, 71, 97, 109, 112, 121, 126).

The clinical picture comprises mild to severe neurological disease, mild to pronounced dysmorphy, and variable involvement of many organs. In the neonatal period and infancy, common striking features are abnormal eye movements, alternating internal strabism, and axial hypotonia. Variable feeding problems occur (anorexia, vomiting, diarrhea). Psychomotor retardation is constant and generally marked. Later, retinitis pigmentosa develops, and though less frequent, stroke-like episodes, epilepsy, and joint contractures may also develop. Walking without support is seldom achieved, but as a rule there is no psychomotor regression. Dysmorphy ranges from mild and aspecific to rather characteristic, particularly as an abnormal subcutaneous adipose tissue distribution with fat pads and nipple retraction. A minority of infants develop severe and mostly fatal organ disease, such as acute cerebral hemorrhage, cardiomyopathy with or without pericardial effusion, liver failure, or nephrotic syndrome (11, 14, 24, 25, 54, 59, 76, 77, 82, 92, 93, 149, 153). Nearly all organs show structural/morphological abnormalities, as demonstrated by radiological and histological techniques. The most important of these are olivopontocerebellar hypoplasia, decreased myelin, multivacuolar inclusions in the Schwann cells of peripheral nerves, renal cysts, liver fibrosis, lamellar inclusions in the lysosomes of the hepatocytes (but not of the Kupffer cells), and osteopenia (32, 46, 48, 98, 111, 144, 145). Mortality is about 20% in the first years of life. Adults have a stable mental retardation, variable peripheral neuropathy, and sometimes severe kyphoscoliosis and premature aging (137). Hypogonadism also occurs in females. In spite of all these handicaps, most patients have an extrovert and cheerful personality. More recently, patients with a very mild presentation have been identified. As a result, the clinical criteria have been redefined: All CDG-Ia patients showed mental retardation, hypotonia, cerebellar hypoplasia, and strabismus, but the classical hallmarks, i.e., the inverted nipples and fat pads, are not always present (50).

The glycosylation defect causes abnormalities in a large number of glycoproteins. This has been best documented with regard to serum glycoproteins (10, 13, 39, 51, 52, 55, 57, 60, 93, 134, 139, 140, 146, 151). Most glycoprotein concentrations or enzyme activities in serum are decreased (striking examples are clotting factor XI and cholinesterase); the others are increased, such as lysosomal enzyme activities (e.g., arylsulphatase A and ß-glucuronidase), or normal. Isoelectrofocusing (IEF) of serum glycoproteins shows a cathodal shift due to the deficiency of sialic acid, a negatively charged monosaccharide. This feature has been applied for diagnostic purposes (79, 135), and IEF of serum transferrin is still the most widely used screening test for CDG. In PMM deficiency and in the other defects of N-glycan assembly, a so-called type 1 pattern is obtained, characterized by a decrease of anodal fractions and an increase of disialo- and asialotransferrin (Figure 2). The reduction in GDP-mannose level reduces the dolichol pyrophosphate-linked oligosaccharide pool. Entire sugar chains are missing from the glycoproteins, leaving glycosylation sites unoccupied and thus resulting in a general hypoglycosylation. This pattern is opposed to the type 2 pattern that also shows an increase of the threesialo- and monosialofractions, most likely because of the incorporation of truncated or monoantennary sugar chains. It is seen in defects of the N-glycan processing (see below). It has to be noted that the transferrin IEF test can be normal in well documented PMM deficiency (47). On the other hand, an abnormal pattern does not always imply CDG; a transferrin protein variant or an artifact must always be considered first (Figure 2). Hypoglycosylation of a brain glycoprotein (ß-trace protein) has also been reported (124). Remarkably, a normal glycosylation pattern is found in the fetus (28 In terms of the biochemical defect, a decisive contribution to its elucidation was the finding that serum transferrin from CDG-Ia patients lacks one or both of the two glycans (156, 163). This suggested a defect in an early glycosylation step and eventually led to the discovery of the enzymatic defect 15 years after the clinical report of the index patients (31, 65, 154). In affected patients, the PMM defect is associated with a decrease of mannose 1-phosphate, GDP-mannose, GDP-fucose, and dolichyl-phosphomannose in their fibroblasts and a decrease of mannose levels in their serum (42, 43). However, the substrate mannose 6-phosphate is not increased. It was subsequently shown that two different PMM isozymes exist in human tissues and that only PMM2 is deficient in these patients (105, 106). In most patients, very low activities (<5% of mean normal activity) have been found in liver, leukocytes, fibroblasts, or lymphoblasts. Remarkably, in some patients significantly higher activities (up to 25% of the normal activity) have been recorded in fibroblasts or lymphoblasts versus leukocytes (50). PMM1 and PMM2 have different expression patterns in human tissues. It is noteworthy that the latter is only weakly expressed in brain, which is one of the most severely affected organs in CDG-Ia (122). The three-dimensional structure of PMM2 is still unknown, but the protein belongs to the haloacid dehalogenase superfamily of proteins, which are characterized by the conservation of three different motifs that are probably involved in the catalytic activity (6). The reaction mechanism of the enzyme involves the phosphorylation of the first aspartate in an extremely conserved DXDXT/V sequence that is close to the amino-terminus of the enzyme (Asp-12) and is also found in a series of other phosphatases and phosphomutases (31).

No efficient treatment is known for this disease (97), although correction of the glycosylation defect in vitro by supplementation of mannose or deprivation of glucose has been reported (90, 115, 116, 117).

GENOTYPE

The PMM2 protein is encoded by the PMM2 gene, located on chromosome 16p13 (105). The gene is relatively small and the coding region is composed of 8 exons. The open reading frame (ORF) of 738 nucleotides predicts a protein of 246 amino acids. The paralogous PMM1 gene on chromosome 22q13 is not implicated in disease (106, 133). Both the human PMM1 and the human PMM2 gene were identified on the basis of the similarity of EST sequences from the IMAGE consortium with the sequence of yeast Sec53 (104). Mutation analysis of PMM2 in CDG-Ia patients revealed a plethora of mainly missense mutations (102). A thorough screening of the exons and flanking intron sequences of the PMM2 gene essentially detected all mutations in CDG-Ia cases (15, 64, 102, 107). The mutational spectrum comprises one particularly frequent mutation R141H, which has been identified in all Caucasian populations, and a few mutations that show a founder effect in distinct populations. Figure 3 presents the frequency and regional distribution of these mutations. In Scandinavian countries, R141H and F119L together make up 72% of all mutations (15, 85, 86). As a result, the most common genotype is F119L/R141H. In contrast, the genotypes are much more heterogenous in other European countries, e.g., Spain, Portugal, France, or Italy (102). There is a clear discrepancy between the frequency of the most prevalent PMM2 mutation, R141H, and its occurrence in CDG-Ia. On the basis of the observed carrier frequency, approximately 1/20000 homozygotes for R141H are expected under Hardy-Weinberg equilibrium (132). Thus, one would expect to find the homozygous R141H/R141H genotype in 45% to 60% of the CDG-Ia patients. Not a single has been found and this is statistically significant. The lack of homozygotes for R141H cannot be explained by genetic drift or nonrandom mating, but it is easily explained by the severity of the mutation: The enzymatic activity of recombinant R141H protein is virtually zero (86, 123). Therefore, homozygosity for R141H is probably incompatible with life. The disease frequency is given by the frequency of compound heterozygotes for R141H and another mutation as well as the occurrence of combinations of the other mutations. The frequency of the other mutations is estimated to be between 1/300 and 1/400, depending on the population. The combined data allowed us to give a rough estimate of the frequency of the disease: It could be as high as 1/20000. Because the R141H mutation is genetically lethal, it should disappear unless the loss of alleles is compensated by new mutations or by a heterozygous advantage. Remarkably, the common R141H mutation is associated with the same haplotype in most cases (132). The mutational event must have occurred at least 200 generations ago (132). This implies a heterozygous advantage for this mutation, whereby the coefficient for fitness is 1.06 in favor of the mutated allele. Because this effect is small, pinpointing the selective pressure that maintains this mutation in the gene pool will be difficult.

PHENOTYPE

Although the basic defect is in the enzyme just preceding phosphomannomutase, the clinical picture of CDG-Ib (MIM 154550, 602579) is markedly different from that of CDG-Ia. At least 12 patients, belonging to nine families, have been diagnosed. The majority showed a hepatic-intestinal disease with liver fibrosis and protein-losing enteropathy, which in some was associated with coagulation disturbances and/or hyperinsulinemic hypoglycemia (2, 9, 36, 73, 110, 150). In one family with three affected siblings, the main feature was prolonged episodic vomiting, sometimes associated with diarrhea (34, 35). One patient had only transient liver disease (73), and another subject was a clinically normal woman whose affected sibling died at age 5 (87, 119). Symptoms started between 2 and 12 months, and there was no, or only transient, neurological involvement. Three patients have died. There is a report from 1986 on four infants who most probably suffered from the same disease and who died between 4 and 21 months (120). We speculate that many patients with this disorder are not recognized as such. What led to the diagnosis of CDG in these patients? The observation of a profound deficiency of antithrombin III, a common feature of CDG, was the primary reason that we, and other investigators, performed the transferrin assay and diagnosed CDG-Ib. The blood biochemical abnormalities are similar to those found in PMM2 deficiency. Contrary to PMM2 deficiency, incorporation of [2-3H]-mannose in fibroblasts into newly synthesized glycoproteins is increased (73, 110). Phosphomannose isomerase (PMI) deficiency is noted in leukocytes, fibroblasts, and liver. PMI is widely distributed in human tissues, and the molecule contains zinc. The use of metal chelators should thus be avoided in sample preparation and measurement of the enzyme (72). The clinical differences between PMI and PMM2 deficiency, in particular with regard to the neurological manifestations, are intriguing. Several explanations have been provided (72). One of these is that brain hexokinase, which can convert mannose to mannose 6-phosphate thus bypassing PMI, has a rather high affinity for mannose, whereas glucokinase, the major hexokinase present in hepatocytes, has a very low affinity for mannose and is thus less efficient in phosphorylating this substrate. PMI deficiency is the only known CDG for which an efficient treatment is available, namely oral D-mannose administration. The ability to directly convert mannose to mannose 6-phosphate by hexokinases made this possible. Doses of 100-150 mg/kg three to six times per day are effective, but the biochemical parameters normalize only after several months of treatment (9, 36, 110). Screening for this potentially lethal disorder is worthwhile because this treatment exists.

GENOTYPE

Based on its similarity to yeast, the human mannose 6-phosphate isomerase (MPI), or PMI, cDNA sequence was originally cloned by Proudfoot et al (125). The gene is composed of eight exons, spans only 5 kb (131), and is located on chromosome 15 (152). The protein contains 423 amino acids, and the structure (of the Candida albicans ortholog) of the protein has been published (29). To date, 12 different mutations have been found in nine families (36, 73, 110, 131). Ten of the 12 mutations are missense mutations, mostly affecting amino acids conserved among human, mouse, and C. albicans PMI. These amino acids may be important for the structural integrity or catalytic activity of the enzyme. Only mutation Y255C (36) affects a semiconserved position. M51, D131, M138, and S102 are structurally close to the active site of the enzyme. R152, R219, G250, and Y255 are positioned in the helical domain, and I398 and R418 are in the C-terminal domain. In the first patient with CDG-Ib, as described by Niehues et al (110), a missense mutation, R219Q, was originally identified at the cDNA level. The second mutation, an insertion of C in exon 3 (c. 166-167insC), escaped identification until the patient's DNA was sequenced at the genomic level (131). This frameshift mutation results in a premature stop after codon 62 and therefore must result in an inactive protein. Apparently, the mRNA is unstable. In another patient who was compound heterozygous for the IVS5-1G>C splice mutation and had a missense mutation (R418H), the second allele was also overrepresented at the mRNA level (131). Mutation analysis on genomic DNA is clearly an asset for the identification of mutations that affect the stability or splicing of the mRNA. In CDG-Ib, three patients were homozygous for the mutations M51T, D131N, and R152Q, respectively (131). The presence of homozygous patients is expected for a rare recessive disease.

PHENOTYPE

About 30 patients, only half of which have been reported, with CDG-Ic (MIM 603147, 604566) are known to the authors (22, 49, 53, 61, 62, 88). The clinical presentation is mainly neurological but milder than in PMM2 deficiency. It comprises moderate psychomotor retardation, pronounced axial hypotonia, strabismus, epilepsy, and in a few patients, ataxia. There is no important cerebellar hypoplasia, no peripheral neuropathy, and inconstant retinitis pigmentosa. Serum transaminases can be increased during infections. Hypoalbuminemia and proteinuria, features of CDG-Ia, are absent. A number of serum glycoproteins are decreased, and levels of factor XI and apolipoprotein B are particularly low. IEF of serum transferrin shows a type 1 pattern. Lipid-linked oligosaccharide analysis in fibroblasts reveals an accumulation of dolichylpyrophosphate-linked Man9GlcNAc2, owing to a deficiency of dolichyl-P-Glc: Man9GlcNAc2-pyrophosphate-dolichyl glucosyltransferase (ALG6). This is the first CDG whose basic defect was elucidated on the basis of yeast genetics (22, 88). Noteworthy, the first CDG-Ic patients were also compiled as a group, preselected based on clinical examination (49). However, it is now clear that the clinical presentation is less homogeneous than originally described (22).

GENOTYPE

The ALG6 gene is much larger than the PMM2 or MPI genes, and this hampers molecular diagnostics. The gene has 14 exons and spans 55 kb. It is located on chromosome 1p22.3 (62). The ORF of 1521 bp predicts a protein of 507 amino acids, with an identity of 32% to Saccharomyces cerevisiae alg6p (61). In the original publication, all four patients from a related family were homozygous for the A333V mutation (61). This mutation has also been identified in other patients, and haplotype analysis revealed a founder effect for this mutation. In seven additional patients from six families, apart from A333V, two other mutant alleles were identified: IVS3+5 G>A and the combination of F304S and S478P (62). The detrimental effect of the A333V, the splice mutant, and the S478P mutations was confirmed by the lack of complementation of alg6 yeast mutants. Interestingly, none of the missense mutations completely abolished the activity, indicating the important function of ALG6 for N-linked glycosylation of proteins. However, the clinical presentation in another CDG-Ic patient (originally described as CDG type V) is very similar to the above, even though the patient was homozygous for a 3 bp deletion (dell299) in combination with the F304S variant (53, 88). The dell 299 mutation was also observed in other patient (157). F304S is most likely a frequent polymorphism. Again, the detection of a mutation in a splicing donor site underlined the importance of analyzing the gene sequence at the genomic level.

phenotype

Four patients with CDG-Id have been described, two boys and two girls. The patients were described by Stibler et al. (1), Denecke et al. (2), Schollen et al. (3), and Sun et al. (4). They share a phenotype of microcephaly, dysmorphic features, severe/absent psychomotor retardation and seizrues. Three of them have optic atrophy. The fourth patient is described with vision impairment and decreased amplitudes on ERG. The most severely affected patient is patient KR (4), a girl with prenatal diagnosis of short femurs, agenesis of corpus callosum, Dandy Walker malformation, bilateral hydroureteronephrosis and oligohydramnios. Other clinical features after birth include abnormal fat distribution, hypotonia, a small ASD, hyperinsulinemic hypoglycaemia and lethargy. She died at the age of 19 days because of urosepsis. The patient described by Stibler et al.(1) presented also with spastic tetraparesis and coloboma of the iris, whereas the patient described by Denecke et al. (2) presented with arthrogryposis multiplex, abnormal eye movements, strabism, dysplastic nails and recurrent vomiting because of pyloric hypertrophy. Muscle biopsy showed moderate fibrosis and hypertrophy of type 2c muscle. Cerebral atrophy was found on MRI of the brain. The patient described by Schollen et al. (3) had some characteristics of arthrogryposis with clubfeet, ulnar deviation of the fingers and overriding second fingers. She also presented with hypotonia and scoliosis.

Genotype

In 1999, the lipid-linked oligosaccharide analysis revealed an accumulation of the dolichylpyro-phosphate-Man5GIcNAc2 precursor in fibroblasts of the first patient, described by Stibler et al (1). Subsequently, the basic defect in this child was identified as a deficiency of the ER mannosyltransferase that attaches a mannosylresidue from dolicholphosphomannose to Man5GlcNAc2-pyrophosphate-dolichol(dolichyl-P-Man:Man5GlcNAc2-pyrophosphate-dolichylmannosyltransferase) encoded by the ALG3 gene.

Four point mutations have been described in the ALG3 gene. All patients described so far were homozygous for the disease causing mutation: c.353 G>A (G118D), c.512 G>A (R171Q), c.796 C>T (R266C) and a silent point mutation in exon 1 (c. 165 C>T) causing a deletion (c.160-196del) in the transcript, because of the activiation of a cryptic splice site. The resulting frameshift generates a stop codon after amino acid 64 (5).

1. Stibler H, Stephani U, Kutsch U. 1995. Carbohydrate-deficient glycoprotein syndrome: a fourth subtype. Neuropediatrics 26:235-37
2. Denecke J, Kranz C, Von Kleist-Retzow JC, Bosse K, Herkenrath P, Debus O, Harms E, Marquardt T. Congenital disorder of glycosylation type Id: clinical phenotype, molecular analysis, and glycosylation of fetal proteins. Ped Res 2005; 58: 248-253.
3. SchollenE, Grünewald S, Keldermans L, Albrecht B, Körner C, Matthijs G. CDG-Id caused by homozygosity for an ALG3 mutation due to segmental maternal isodisomy UPD3 (q21.3-qter). Eur J Med Genet 2005; 48:153-158.
4. Sun L, Eklund EA, Chung WK, Wang C, Cohen J, Freeze HH. Congenital disorders of glycosylation Id (CDG-Id) presenting with hyperinsulinemic hypoglycemia and islet cell hyperplasia. J Clin Endocrin Metab 2005; 90: 4371-4375.
5. 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 Mut 2004; 23: 477-486.
6. 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-dolilchyl mannosyltransferase. The EMBO journal 1999; 18: 6816-6822.

Phenotype

Seven patients have been described in literature with CDG-Ie, four girls and three boys. The patients were described by Imbach et al. (1), Kim et al (2), García-Silva et al. (3) and Dancourt et al. (4).
The patient share a phenotype of severe developmental delay, hypotonia, (acquired) microcephaly, seizures and dysmorphic features. Six patients have poor to absent visual fixation. Two of them have cortical blindness, two fo them retinopathy and one optic nerve atrophy. Strabism has been described in four patients and nystagmus in three. three patients present with cerebellar ataxia and tremor and four patients with failure to thrive. Feeding problems are present in three patients. Other clinical features include hepatomegaly (3 pt), neonatic apnoeic spells (2 pt), recurrent infections (2pt), polyneuropathy (1pt), bulemia and obesity (1pt). Transaminases are elevated in three patients, CK is elevated in five patients and hyperammoniemia is present in only one patient. On MRI of the brain, five patients showed eelayed myelinisation and five atrophy of some part of the brain (two frontal lobe, two (ponto)cerebellar and one cerebral atrophy). Transitory hypodensities in basal ganglia and abnormal signal in the nucleus dentatus have been described each in a diferrent patient.

Genotype

IEF of serum transferrin showed a type 1 pattern with only little or no increase of asialotransferrin. Analysis of the lipid-linked oligosaccharides in the ER of fibroblasts revealed an accumulation of dolichylpyrophosphate-Man5GlcNAc2 instead of Glc3Man9GlcNAc2, due to a reduced activity of dolichol-phosphate-mannose synthase (DPM1).

Five different mutations in DPM1 have been described, two missense point mutations, two deletions and one intronic splice mutation. Four patients are homozygousfor the disease causing mutation, the others are compound heterozygous. Four patients carry the mutation c.274 C>G(R92G) in exon 3, one in a homozygous way and three in a heterozygous way together with either 628delC in exon 8 (premature stop in codon 213) (2pts) or 331-343del (13bp deletion) in exon 4 with loss of 150 amino acids. Another patient was found to be homozygous for the point mutation c.742 T>C (S248P) and two siblings were homozygous for an intronic mutation causing exon skipping of exon 5 (IVS4-5 T>A).

1. Imbach T, Schenk  B, Schollen E, Burda P, Stutz A, Grünewald S, Bailie NM, King MD, Jaeken J, Matthijs G, Berger EG, Aebi M, Hennet T. Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie. J Clin Invest 2000; 105: 233-239.
2. Kim S, Westphal V, Srikrishna G, Mehta DP, Peterson S, Filiano J, Karnes PS, Patterson MC, Freeze HH. Dolichol phosphate mannose synthase (DPM1) mutations define congenital disorder of glycosylation Ie (CDG-Ie). J Clin Invest 2000; 105: 191-198.                                                               3. García-Silva MT, Matthijs G, Schollen E, Cabrera JC, Sanchez del Pozo J, Martí Herreros M, Simón R, Maties M, Martín Hernandez E, Hennet T, Briones P. Congenital disorder of glycosylation (CDG) type Ie. A new patient. J Inherit Metab Dis 2004; 27: 591-600
4. Dancourt J, Vuillaumier-Barrot S, Ogier de Baulny H, Sfaello I, Barnier A, Le Bizec C, Dupre T, Durand G, Seta N, Moore SEH. A new intronic mutation in the DPM1 gene is associated with a milder form of CDG-Ie in two french siblings. Ped Res 2006; 59: 835-839.

phenotype

CDG-If has been identified in four unrelated patients, two girls and two boys. Schenk et al.(1) described 3 unrelated patients. An additional patient was described by Kranz et al (2).  The four patients share a phenotype of severe psychomotor retardation, seizures and an ichtyosis like/ scaling skin disorder. Patient 'S' died at the age of 10 months because of apnoe during seizures. He presented with severe feeding difficulties, oxygen dependency and growth retardation. Dysmorphic features include a large anterior fontanel, bilateral parietal bossing and thin lips. Additional features were wild pericardial effusion and bilateral small cortical renal cysts. Laboratory findings showed mild persistent thrombocytopenia and periodic elevation of CPK's. Patient 'L' presented with hypertonia at the age of 5 months. Besides the already mentioned psychomotor retardation, seizures and ichtyosis like skin disorder, she also had growth retardation at the age of 16 years. Electronmicroscopy of a liver biopsy revealed lamellar lysosomal inclusions.Transient growth hormone and IGF-I deficiency was detected. A sibling died at the age of 2 months with similar disease. Patient 'A' had no growth problems. At the age of 10 years his developmental age was about 2.5 years. The additional patient described by Kranz et L. presented with failure to thrive, impaired vision (amaurosis), strabism and nystagmus. On MRI generalized cerebral atrophy was detected. ATIII was reduced (50%).

genotype

Five  different mutations have been described in the MPDU1 gene (17p12-13): four point mutations and one deletion. This gene is known to be involved in the utilisation of dol-P-Man and dol-P-Glc. This leads to the synthesis of inbomplete and poorly transferred precursor oligosaccharides lacking both mannose and glucose residues. Man9GlcNAc2 and Man5GlcNAc2 are the major LLO's detected, but complete Glc3Man9GlcNAc2 was also detected. the CHO homologue of MPDU1 is Lec 35.

Three patients are homozygous for a missense point mutation. Patient S is homozygous for c.218G>A (G73E), patient A is homozygous for c.356 T>C (L119P) and the patient described by Kranz et al. is homozygous for c.211 T>C (L74S). Patient L is compound heterozygous for the following mutations: c. 2 C>T (M1T) of maternal origin and c.511delC of paternal origin, leading to a frameshift with a premature stopcodon at position 213.

1.  Schenk B, Imbach T, Frank CG, Grubenmann CE, Raymond GV, Hurvitz H, Raas-Rotchild A, Luder AS, Jaeken J, Berger EG, Matthijs G, Hennet T, Aebi M. MPDU1 mutations undderlie a novel human congenital disorder fo glycosylation, designated type If. J Clin Invest 2001; 108: 16871695
2. Kranz C, Denecke J, Lehrmn MA, Ray S, Kienz P, Kreissel G, Sagi D, Peter-Katalinic J, Freeze HH, Schmid T, Jackowski-Dohrmann S, Harms E, Marquardt T. A mutation in the human MPDU1 gene causes congenital disorder of glycosylation type If (CDG-If). J Clin Invest 2001; 108: 1613-1619.

genotype

Until now 6 patients with CDG-Ig have been described (1,2,3,4,5,6). Three of them are girls and three of them are boys. Three patients are American, two european, one is Indian and one Tunesian. All patients presented with facial abnormalities, hypotonia, global delay and failure to thrive. The boys all presented with genital hypoplasia. Subcutaneous fat pads and inverted nipples were both described in two patients. other presenting symptoms included microcephaly (3/6), feeding problems (2/6) and convulsions (2/6). Laboratory findings showed hypogammaglobulinemia in 5 patients. Other laboratory findings were: low blood clotting factor XI (3/6), low cholesterol (2/6), low ATIII (2/6) and low protein C (2/6).

genotype

Due to a deficiency in dolichyl-P-mannose: Man7GlcNAc2 (alfa-1,6-) mannosyltransferase there is an accumulation of dolichyl pyrophosphate linked Man7GlcNAc2. The defect is located on the ALG12 gene. Ten different mutations have been described in 7 different exons. Two patients are homozygous for the disease causing mutation: c.241 G>A (A81T) in exon 3  and c. 424 T>G (F142V) in exon 4. The other patients are compound heterozygous for the following sets of mutations: c.824 G>A (S275N)/c.29delG, c.688 T>G (Y230D)/c.931 C>T (R311C), c.473 T>C (L158P)/c.1242 C>G (Y414X) and c.200 C>T (T67M)/c.437G>A (R146Q).  The described mutations include 9 point mutations (eight missense and one nonsense) and one deletion. The c.29delG mutation leads to a frameshift and a premature stop codon after amino acid 19 (1,2,3,4,5,6).


1.  Grubenmann CE, Frank CG, Kjaergaard S, Berger EG, Aebi M, Hennet T. ALG12 mannosyltransferase defect in congenital disorder or glycosylation type Ig. Hum. Mol Genet 2002; 11: 2331-2339. 

2. Chantret I, Dupré T, Delenda C, Bucher S, Dancourt J, Barnier A, Charollais A, Heron D, Bader-Meunier B, Danos O, Seta N, Durand G, Oriol R, Codogno P, Moore SEH. Congenital disorders of glycosylation type Ig is defined by a deficiency in dolichyl-P-mannose: Man7GlcNAc2-PP-dolichyl mannosyltransferase. J Biol Chem 2002; 277: 25815-25822.                                     

3. Thiel C, Schwarz M, Hasilik M, Grieben U, Hanefeld F, Lehle L, von Figura K, Körner C. Deficiency of dolichyl-P-Man: Man7GlcNAc2-PP-dolichyl mannosyltranferase causes congenital disorder of glycosylation type Ig. Biochem J 2002; 367: 195-201.                          

4. Zdebska E, Bader-Meunier B, Schischmanoff PO, Dupré T, Seta N, Tchernia G, Koscielak J, Delauny J. Abnormal glycosylation of red cell membrane band 3 in the congenital disorder of glycosylation Ig. Ped Res 2003; 54: 224-229.                                                                                            

5. Di Rocco M, Hennet T, Grubenmann CE, Pagliardini S, Allegri AEM, Frank CG, Aebi M, Vignola S, Jaeken J. Congenital disorder of glycosylation (CDG) Ig: report on a patient and review of the literature. J Inherit Metab 2005; 28: 1162-1164. 

6. Eklund EA, Newell JW, Sun L, Seo NS, Alper G, Willert J, Freeze HH. Molecular and clinical description of the first US patients with congenital disorder of glycosylation Ig. Mol Genet Metab 2005; 84: 25-31.

fenotype

Five patients with CDG-Ih have been described (1,2): two girls and three boys. One of them was previously described by Charlwood et al. in 1997 (3) and one by Chantret et al. in 2003 (4). The clinical spectrum includes mild to severe hepato-intestinal problems and dysmorphic features. All of them show hypoalbuminemia and oedema due to protein losing. In two of the patients the diagnosis of protein losing entheropathy was confirmed. Other clinical features include ascites (3/5), diarrhea (3/5), vomiting (2/5), hepatomegaly 2/5), renal tubulopathy (2/5), nephrotic syndrome (1/5) and renal cysts (1/5). Except for hypotonia, no obvious central nervous system defects were described in the four first patients, who had cardio-respiratory problems and died at the age of 3 days, 3 months (2 patients) and 16 months. The patient described by Eklund et al. in 2005 presented with prominent central nervous system involvement including seizures, elevated protein in CSF, decelerated head growth and volume loss and leukoencephalopathy on MRI of the brain. This patient also developed cataract. Of course neurological symptoms can be masked by the early death (before the age of 3 months) of 3 patients.

genotype

Due to a deficiency in dolichyl-P-glucose: Glc1Man9GlcNAc2 (alfa-1,3-) glycosyltransferase, there is an accumulation of dolichylpyrophosphate linked Glc1Man9GlcNAc2. The defect is located on the ALG8 gene. Six different mutations have been described. One patient is homozygous, the others are compound heterozygous. The described mutations include two splice mutations, two missense point mutation, one deletion and one insertion. The c.396 insA and 413 delC mutations in exon 4 in patient MP, cause both severe truncations with premature stopcodons after amino acid 134 and 155 respectively (4). Patient GB0243 and his affected sibling are compound heterozygous for the splice mutation c.96-2 A>C in intron 1 and the tranversion c.139 A>G (p.T47P) in exon2 (1). The combination of a heterozygous splice muation (c.672+4 A>G in intron 6) and a missense muatation (c.824 G>A (p.G275D) in exon8) is present in patient NL 00097 (1). The c.139 A>G mutation is present in three patients: two times heterozygous and one time homozygous (1,2). 

1. 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 disorder of glycosylation type Ih (CDG-Ih) (ALG8 deficiency). J Med Genet 2004; 41: 550-556.

2. Eklund EA, Sun L, Westphal V, Northrop JL, Freeze HH, Scaglia FS. Congenital disorder of glycosylation (CDG)-Ih patient with a severe hepato-intestinal phenotype and evolving central neurvous system pathology. J Pediatr 2005; 147: 847-850.

3. Charlwood J, Clayton P, Johnson A, Keir G, Mian N, Winchester B. A case of carbohydrate-deficient glycoprotein syndrome type 1 (CDGS1) with normal phosphomannomutase activity. J Inher Metab Dis 1997; 20: 817-827.

4. Chantret I, Dancourt J, Dupré T, Delenda C, Bucher S, Vuillaumier-Barrot S, Ogier de Baulny H, Peletan C, Danos O, Seta N, Durand G, Oriol R, Codogno P, Moore SEH. A deficiency in Dolicyl-P-glucose: Glc1Man9GlcNAc2-PP-dolichyl alfa3-glucosyltransferase defines a new subtype of congenital disorders of glycosylation. J Biol Chem 2003; 11: 9962-9971.

fenotype

Thiel et al. (1) described the first patient with CDG-Ii. The patient is a girl who developed in the first year of life bilateral colobomas, unilateral cataract, poor vision and irregular nystagmus. Infantile spasms and hypsarrythmia appeared at the age of 4 months. MRI of the brain showed retarded myelinisation. Mental and motor development were both severly delayed and tendon reflexes were brisk. She also presented with a coccygeal dimple, a faint cardiac murmur and borderline enlargement of the liver. Laboratory investigations showed a prolonged aPTT and a strongly reduced blood clotting factor ...

genotype

The alfa-1,3-mannosyltransferase elongating Man1GlcNAc2-PP dolichol is encoded by ALG2. Defects in this enzyme cause an accumulation of Man1GlcNAc2-PP-dolichol and Man2GlcNAc2-PP-dolichol. The only patient described is compound heterozygous for c.393 G>T (K131N) and c.1040 delG both in exon2. The deletion 1040G causes a frameshift after amino acid 346 and a premature translation stop after amino acid 372 (1).

1. Thiel C, Schwarz M, Peng J, Grzmil M, Hasilik M, Braulke T, Kohlschütter A, von Figura K, Lehle L, Körner 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 2003; 278: 22498-22505.

fenotype

The first patient with CDG-Ij is described by Wu et al. in 2003 (1). She presented with intractable seizures, mental retardation, microcephaly, hypotonia, dysmorphia and strabismus (exotropia). Dysmorphic features included micrognathia, fifth finger clinodactyly, single flexion creases and skin dimples on the upper thighs. At six years her linguistic ability is minimal. It should be noted that the pregnancy occured after treatment with clomifene and maternal hypothyroidism was treated with substitution therapy.

genotype

The deficiency in UDP-GlcNAc: dolichol phosphate N-acetyl-glucosamine-1-phosphate transferase (GPT) encoded by DPAGT1 in this patient is caused by two compound heterozygous mutations: a missense mutation c.660 A>G (Y170C) in exon6 and a complex splice mutation. The maternal allele counts for only about 12% of the normal mature mRNA, while the rest shows a complex exon skipping pattern resulting in a frameshift and encoding a truncated, non-functional GPT protein (1).

1. Wu X, Rush JS, Karaoglu D, Krasnewich D, Lubinsky MS, Waechter CJ, Gilmore R, Freeze HH. Deficiency of UDP-GlcNAc: dolichol phosphate N-acetlyglucosamine-1 phosphate transferase (DPAGT1) causes a novel congenital disorder of glycosylation type Ij. Hum Mut 2003; 22: 144-150.

fenotype

The four known patients with CDG-Ik are described by Kranz et al. (1), Schwarz et al. (3) and Grubenmann et al. (3) in 2004. CDG-Ik is a severe and rapidly progressing type of CDG. All patients presented with intractable seizures. Three patients died at an early age: 2 weeks, 11 weeks and 10 months. Three of them are reported to have coagulation disturbances. The first patient (PB) was hte most affected one and presented with hydrops fetalis and hepatosplenomegaly at 30 weeks of gestation and hypogonadism, cardiomyopathy, areflexia, contractures and dysmorphic features after birth. The secon (GM) and third patient (NK) patient share microcephaly and cerebral atrophy. Other presenting symptoms in the second patient were nephrotic syndrome, aggamaglobulinemia, and respiratory failure. NK had periods of unexplained fever and no visual fixation. No cerebral atrorphy or dysmorphy was seen in the patient described by Grubenman et al. (FR), but he shared hypotonia and visual problems with GM. Other presenting symptoms of FR were psychomotor retardation and liver dysfunction.

genotype

CDG-Ik is caused by a deficiency in ALG1 encoded beta-1,4-mannosyltransferase which adds the first mannose residue to the lipid linked oligosaccharides. Due to this deficiency there is an accumulation of the LLO's GlcNAc1 and GlcNAc2. All four patients share the missense muations c.733 C>T (S258L). Two patients (PB and GM) are homozygous for this mutation. They are the most severly affected patients with death at 2 and 11 weeks of age. The other two patients are compound heterozygous for this mutation together with c. 1025 C>A (E342P) (NK) and with c.450 C>G (S150R) and c.1287 T>A (D429E) (FR).

1. Schwarz M, Thiel C, Lübbehusen J, Dorland B, de Koning T, von Figura K, Lehle L, Körner C. Deficiency of GDP-Man:GlcNAc2-PP-Dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik. Am J Hum Genet 2004; 74: 472-481.

2. Kranz C, Denecke J, Lehle L, Sohlbach K, Jeske S, Meinhardt F, Rossi R, Gudowius S, Marquardt T. Congenital disorder of glycosylation type Ik (CDG-Ik): a defect in mannosyltransferase I. Am J Hum Genet 2004; 74: 545-551.

3. Grubenmann CE, Frank CG, Hülsmeier AJ, Schollen E, Matthijs G, Mayayapek E, Berger EG, Aebi M, Hennet T. Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik. Hum Mol Genet 2004; 13: 535-542.

fenotype

Two patients are described with CDG-IL (1,2). The two girls presented with psychomotor retardation, hypotonia, seizures and hepatomegaly. The first child (1) had also microcephaly and bronchial asthma. Presenting symptoms of the second child (2) include failure to thrive, inverted nipples, strabismus, cystic renal disase, pericardial effusion, delayed myelinisation and brain atrophy.

genotype

Due to a deficiency in ALG9 encoded alfa-1,2-mannosyltranferase there is an accumulation of the LLO's MAn8GlcNAc2 and Man6GlcNAc2. Both patients are homozygous for a disease causing missense mutation: c.860 A>G (Y286C)(1) and c.1567 G>A (E523K)(2).

(2) An infant with a novel mutation in hte ALG9 gene and additional phenotypic features. Weinstein M, Schollen E, Matthijs G, Neupert C, Hennet T, Grubenmann CE, Frank CG. Aebi M, Clarke JT, Griffiths A, Seargeant L, Poplawski N. Am J Med Genet A 2005,136:194-197.

(1) Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL. Frank CG, Grubenmann CE, Eyaid W, Berger EG, Aebi M, Hennet T. Am J Genet 2004; 75: 146-150