Congenital disorder of Glycosylation, Type Ib
Synonym: CDG Syndromes, Carbohydrate-Deficient Glycoprotein Syndromes
Congenital disorder of Glycosylation, Type Ib is one of a group of disorders of abnormal glycosylation of N-linked oligosaccharides. Manifestations range from severe developmental delay and hypotonia with multiple organ system involvement to hypoglycemia and protein-losing enteropathy with normal development; the disorders most commonly begin in infancy. Thirteen different enzymes in the N-linked oligosaccharide synthetic pathway are currently recognized to be defective in individual types of CDG. CDG-Ia is the most common form reported and is characterized by cerebellar hypoplasia, facial dysmorphism, psychomotor retardation, and abnormal fat distribution. The clinical course has been divided into an infantile multisystem stage, a late-infantile and childhood ataxia-mental retardation stage, and an adult stable disability stage. (1)
What is CDG?
Congenital Disorders of Glycosylation (CDG), formerly called carbohydrate-deficient glycoprotein syndrome,are a group of inherited disorders that affect a process called glycosylation.Glycosylation is a process by which all human cells build long sugar chains that are attached to proteins. Together the proteins and their attached sugars are called glycoproteins. Glycoproteins, have many very important functions in the human body and are required for the normal growth and function of all tissues and organs.
The process or pathway which makes this glycosylation takes at least 100 steps, and specialized proteins called enzymes trigger each step. Hundreds of enzymes are used in making the sugar chains and adding them to thousands of proteins. Sometimes coordinated groups of enzymes work in a specific order to add some sugars, or cleave others from the maturing chain. In individuals born with CDG, one of the many glycosylation enzymes in the pathway malfunctions. However, the impact on the body structures and functions differs depending upon the altered enzyme. CDG is caused by a genetically inherited change or malfunction of one of these enzymes. If one of these enzymes malfunction then the cells in the body of a child or adult cannot glycosylate correctly. This incorrect glycosylation is the underlying basis of the important medical issues in individuals with CDG. (2)
Exact figures are unknown, but estimate have been mentioned it may be 1 in 5000 births.
Symptoms and Signs Type 1b:
Other symptoms may include profound hypoglycemia, failure to thrive, liver fibrosis.
Type ib id distinct from the other CDGs in tha there is a lack of significant central nervous system involvment.
Mutation of MPI; Chromosomal locus 15q22-qter
The diagnostic test for all forms of CDG is the same, serum transferrin glycoforms, also called "transferrin isoforms analysis" or "carbohydrate-deficient transferrin analysis," by isoelectric focusing (IEF) or other isoform analysis (i.e., capillary electrophoresis, GC/MS) to determine the number of sialylated N-linked oligosaccharide residues linked to serum transferrin and is available. [Stibler & Jaeken 1990, Jaeken & Carchon 2001].
Diagnosis of CDG Physician
Test Name: Carbohydrate Deficient Transferrin Test
Method: ESI-MS method superior to IEF, CE (Capillary Electrophoresis), or HPLC (High Performance Liquid Chromatography)
Laboratory: Mayo Medical Laboratories Test (82414); CPT Code 82373
Requirments: Requires: 0.1 ml of serum
Detection: Will detect all known CDG-I types, many CDG-x. Will not detect: CDG-IIb, CDG IIc, CDG-IIf. Test may need to be rerun if done less than 2 weeks of age.
There is no treatment or cure for the disorder so treatments will focus on the complications and/or manifestations. There will need to be a dietary regime that focuses on the hypoproteinemia (protein-loss). Treatment for the protein losing enteropathy is critical otherwise the condition can be fatal.
Treatment for and management of lymphedema is also available.
Congenital muscular dystrophies including Fukuyama congenital muscular dystrophy (FCMD), caused by mutations in FCMD; muscle-eye-brain (MEB) disease, caused by mutations in POMGNT1 [Yoshida et al 2001, Martin & Freeze 2003]; and Walker-Warburg syndrome, caused by mutations in POMT1 (see Congenital Muscular Dystrophies Overview).
Mar 26, 2008
Clinical Information and Studies
Alternative titles; symbolsCDG Ib; CDGIb
Gene map locus 15q22-qter
A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type Ib (CDG Ib) is caused by mutation in the gene encoding mannosephosphate isomerase (MPI; 154550). CDG Ia (212065) is caused by mutation in the gene encoding phosphomannomutase-2 (PMM2; 601785).
Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. Type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein. These disorders can be identified by a characteristic abnormal isoelectric focusing profile of plasma transferrin (Leroy, 2006).
For a discussion of the classification of CDGs, see CDG1A (212065).
CDG Ib is clinically distinct from most other CDGs by the lack of significant central nervous system involvement. The predominant symptoms are chronic diarrhea with failure to thrive and protein-losing enteropathy with coagulopathy. Some patients develop hepatic fibrosis. CDG Ib is also different from other CDGs in that it can be treated effectively with oral mannose supplementation, but can be fatal if untreated (Marquardt and Denecke, 2003). Thus, CDG Ib should be considered in the differential diagnosis of patients with unexplained hypoglycemia, chronic diarrhea, liver disease, or coagulopathy in order to allow early diagnosis and effective therapy (Vuillaumier-Barrot et al., 2002)
Pelletier et al. (1986) first described CDG Ib clinically. They observed secretory diarrhea with protein-losing enteropathy, enterocolitis cystica superficialis, intestinal lymphangiectasia, and congenital hepatic fibrosis in 4 children whose parents originated from the same northeastern province of Quebec. Jaeken et al. (1998) suggested that the patients reported by Pelletier et al. (1986) had CDG Ib. The infants, who died between the ages of 4 and 21 months, also had antithrombin III deficiency (107300), a typical feature of CDG syndromes.
Niehues et al. (1998) reported an 11-month-old boy who presented with diarrhea and vomiting. He was born at term with a normal birth weight. He developed protein-losing enteropathy, and small bowel biopsy showed lysosomal inclusion bodies and dilated rough endoplasmic reticulum filled with prominent tubular bundles. He also had recurrent thrombotic events and severe life-threatening gastrointestinal bleeding. Laboratory studies showed severe hypoproteinemia, anemia, and decreased antithrombin III (AT3; 107300). Isoelectric focusing of serum transferrin showed a pattern consistent with CDG type I. However, the patient had no psychomotor or mental retardation, which was fundamentally different from all other types of CDGs. A deficiency of phosphomannose isomerase was found, with activity in fibroblasts decreased to 7.4% of normal control values. Each parent had approximately 50% residual activity consistent with a heterozygous state. Daily oral mannose administration resulted in clinical improvement.
Jaeken et al. (1998) reported 3 patients with CDG type I who had a marked deficiency of phosphomannose isomerase with normal PMM2 (601785). One of the patients had been reported by Niehues et al. (1998). The clinical presentation of PMI (MPI)-deficient CDG disease was distinctive in its hepatic-intestinal presentation. One of the 3 patients was the offspring of unrelated Lebanese parents. He had chronic diarrhea beginning at the age of 3 months and hypoglycemia with convulsions, coma, and apnea. There was no dysmorphism. The liver was enlarged and showed fibrosis of the portal spaces and microvesicular steatosis on biopsy. Generalized edema secondary to hypoalbuminemia developed by age 10 months and he was treated with Diazoxide. Histology of duodenal biopsies showed partial villus atrophy with hypercellularity and only rare and discrete lymphangiectasias. The patient suffered from frequent bacterial as well as viral gastroenteritis. At the age of 26 months, the abdomen was large with pronounced collateral circulation, numerous disseminated angiomas, and persisting hepatomegaly. Tube feeding by gastrostomy was necessary. Neurologic examination and psychomotor development were normal. The patient was last seen at the age of 2 years with persisting protein-losing enteropathy. He died at the age of 4 years.
De Lonlay et al. (1999) reported a 3-month-old girl who presented with hyperinsulinemic hypoglycemia, severe vomiting and diarrhea, congenital hepatic fibrosis, and coagulation factor deficiencies. Mannose therapy led to dramatic clinical improvement and normalization of several biochemical abnormalities.
Babovic-Vuksanovic et al. (1999) reported a 2.5-year-old girl with CDG Ib who presented with severe and persistent hypoglycemia and subsequently developed protein-losing enteropathy, liver disease, and coagulopathy.
De Lonlay et al. (2001) reported the clinical, biologic, and molecular analysis of 26 patients with CDG I, including 20 CDG Ia, 2 CDG Ib, 1 CDG Ic, and 3 CDG Ix (212067) patients detected by Western blotting and isoelectric focusing of serum transferrin. The 2 patients with CDG Ib had severe liver disease, protein-losing enteropathy, and hyperinsulinemic hypoglycemia, but no neurologic involvement.
Niehues et al. (1998) found that oral administration of mannose was effective therapy for CDG Ib. Mannose treatment corrected the clinical phenotype as well as the hypoglycosylation of serum glycoproteins.
Jaeken et al. (1998) provided a diagram of mannose metabolism. The defect in PMI deficiency involves the conversion of fructose-6-phosphate to mannose-6-phosphate. Hexokinase phosphorylates mannose to mannose-6-phosphate. A logical consequence of this fact is that PMI deficiency, unlike PMM deficiency, should be treatable by administration of mannose supplements. This appeared to be the case in the patient reported by Niehues et al. (1998) and Freeze et al. (1997).
Schollen et al. (2000) noted that hexokinase provides an alternative pathway for the synthesis of mannose-6-phosphate from mannose. Whereas the dietary intake of mannose is minimal and probably not enough for normal glycosylation, oral mannose supplementation promotes this alternative pathway and has been successful in treating several cases of CDG Ib (Babovic-Vuksanovic et al., 1999; de Lonlay et al., 1999).
Niehues et al. (1998) identified a heterozygous mutation in the MPI gene (154550.0001) in a patient with CDG Ib. Subsequently, Schollen et al. (2000) identified a second MPI mutation (154550.0004) in this patient, confirming compound heterozygosity and autosomal recessive inheritance.
Vuillaumier-Barrot et al. (2002) found that the protein-losing enteropathy-hepatic fibrosis syndrome described in the Saguenay-Lac Saint-Jean region of Quebec, reported by Pelletier et al. (1986), is caused by an arg295-to-his mutation in the MPI gene (R295H; 154550.0005), and is therefore a form of CDG Ib.
McKusick - updated : 1/31/2003
Michael J. Wright - updated : 1/31/2001
Victor A. McKusick - updated : 9/25/2000
Hudson H. Freeze - updated : 2/17/2000
Hudson H. Freeze - reviewed : 2/17/2000
Victor A. McKusick : 4/28/1998
Kniffin - reorganized : 6/26/2007
Cassandra L. Kniffin - updated : 6/22/2007
Marla J. F. O'Neill - updated : 10/30/2006
tkritzer : 6/3/2004
tkritzer : 5/24/2004
|GLYCOGEN STORAGE DISEASE Ib|
Alternative titles; symbolsGSD1B
A number sign (#) is used with this entry because of evidence that type Ib glycogen storage disease can result from mutation in the glucose-6-phosphate transporter gene (602671).
Senior and Loridan (1968) proposed the existence of a second type of von Gierke disease in which, although glucose-6-phosphatase activity is present on in vitro assay, glucose is not liberated from glucose-6-phosphate in vivo. They referred to this as 'functional deficiency of G6P.' They pointed out that some mutants in Neurospora show impaired enzyme function in the intact fungus despite normal activity in homogenates. Arion et al. (1975) concluded that G6Pase activity requires 2 components of the microsomal membrane: (1) a glucose-6-phosphate specific transport system that shuttles G6P from the cytoplasm to the lumen of the endoplasmic reticulum (a G6P translocase), and (2) an enzyme, glucose-6-phosphate phosphohydrolase, bound to the luminal surface of the membrane. Narisawa et al. (1978) described a patient who appeared to have a defect in the transport system. In liver without detergent, enzyme activity was very low but normal activity was obtained by addition of detergent. Kuzuya et al. (1983) reported a 25-year-old patient. Protuberant abdomen and diarrhea were noted at age 1 or 2 years, and short stature and hepatomegaly at age 4 years. At age 18, yellowish-red spots appeared on her legs and hypertension was detected. At age 20, she was 138 cm tall. Eruptive xanthoma and hyperlipidemia were present. Liver scintography suggested the presence of adenomas.
Recurrent infections and neutropenia have been recognized as distinctive features of GSD Ib. Corbeel et al. (1983) provided a 6-year follow-up on the hematologic effects of termino-lateral portacaval anastomosis. Granulocyte counts returned to normal and recurrent infections ceased after the shunt. Platelet dysfunction, evident before surgery, was also corrected. Marked hypochromic anemia, probably caused by sequestration of iron in the spleen and resistant to therapy, was a persistent feature in this patient. The mechanism of the granulocyte defect in this disorder was discussed. Roe et al. (1986) observed Crohn disease in 2 unrelated boys with GSD Ib. Their neutrophils showed severe chronic neutropenia and markedly deficient chemotactic response, whereas the leukocytes were normal in 4 patients with GSD Ia (232200). Thus, chronic inflammatory bowel disease (IBD) appears to be an integral part of GSD Ib and the abnormality of leukocytes is probably involved in the pathogenesis of the IBD. Oral lesions and perianal abscesses are common in this disorder (Ambruso et al., 1985). Ueno et al. (1986) found that neutrophils were defective in both motility and respiratory burst, whereas monocytes showed a defect only in respiratory burst. Bashan et al. (1988) showed that the rate of 2-deoxyglucose transport into GSD Ib polymorphonuclear leukocytes was 30% of that into cells of normal controls. Transport was normal in GSD Ib lymphocytes and in GSD Ia polymorphonuclear leukocytes and lymphocytes. The striking limitation of glucose transport across the cell membrane of polymorphonuclear leukocytes probably accounts for the impairment of leukocyte function that is characteristic of GSD Ib but not GSD Ia. Schroten et al. (1991) used granulocyte colony-stimulating factor (CSF3; 138970) to treat successfully the neutropenia in 2 patients with GSD Ib associated with recurrent bacterial infections. Roe et al. (1992) administered granulocyte-macrophage colony stimulating factor (CSF2; 138960) to the 2 adolescent boys whom they had reported in 1986 (Roe et al., 1986). They observed a prompt increase in neutrophil counts to normal, complete relief from abdominal symptoms, and an increase in appetite, energy, and weight, and a feeling of well being. There was radiologic evidence of bowel healing and a decrease in the erythrocyte sedimentation rate. Both patients remained free of oral and anal lesions over a period of 10 and 12 months of treatment. One patient was switched to G-CSF (CSF3) because of a presumed allergic reaction to GM-CSF. In a multicenter study in the United States and Canada, Talente et al. (1994) identified 5 patients with GSD type Ib who were 18 years of age or older. Severe recurrent bacterial infections and gingivitis were present. One patient, a 22-year-old college student, was described in detail. She had severe recurrent stomatitis, recurrent otitis media and externa, perianal and perirectal abscesses, and, at the age of 12 years, 2 brain abscesses due to Staphylococcus aureus. At 18 years of age, she was as tall as an 8-year-old and had not undergone any pubertal changes.
In a patient with GSD Ib, Heyne and Henke-Wolter (1989) found a change in the oligosaccharide side chains of the alpha-1-antitrypsin (107400) glycoprotein suggesting effects of the limited availability of glucose or glucose derivatives for the synthesis of N-glycosidic glycoproteins. Kikuchi et al. (1990) found secondary amyloidosis in a 12-year-old girl with GSD Ib.
In 14 children (aged 4 to 16 years) with GSD Ia and GSD Ib, Lee et al. (1996) found that the use of uncooked cornstarch loads resulted in satisfactory glycemia lasting only a median of 4.25 hours (range 2.5 to 6).
In studies of 5 patients with GSD Ib, Kuijpers et al. (2003) found neutrophils in the circulation that showed signs of apoptosis with increased caspase activity, condensed nuclei, and perinuclear clustering of mitochondria to which the proapoptotic BCL2 member BAX (600040) had translocated already. Granulocyte colony-stimulating factor (GCSF; 138970) added to in vitro cultures did not rescue the GSD Ib neutrophils from apoptosis as occurred with GCSF-treated control neutrophils. Moreover, the 2 GSD Ib patients on GCSF treatment did not show significantly lower levels of apoptotic neutrophils in the bloodstream. Kuijpers et al. (2003) studied neutrophils from children with infections (active pneumonia or septicemia) or with other neutropenic syndromes (Shwachman-Diamond syndrome; 260400), but to date had not observed circulating apoptotic neutrophils in these patients.
Annabi et al. (1998) reported linkage of the GSD Ib locus to genetic markers spanning a 3-cM region on 11q23. The region is located between D11S939 centromerically and D11S4129 telomerically and includes the IL10R (146933), ATP1G1 (601814), and ALL1 (159555) genes. The authors studied 8 consanguineous families and 1 nonconsanguineous family of various ethnic origins. The assignment to chromosome 11 was confirmed by Kure et al. (1998), who showed that the translocase gene that is mutated in this disorder maps to chromosome 11 by study of somatic cell hybrids.
In 2 female patients with GSD Ib, Gerin et al. (1997) found 2 point mutations in the glucose-6-phosphate translocase gene (602671.0001 and 602671.0002). Kure et al. (1998) identified 3 additional mutations, one of which, W118R (602671.0003), may be unusually frequent among Japanese patients with GSD Ib.
Kure et al. (2000) proposed that GSD Ib without neutropenia could be due to glucose-6-phosphate translocase mutations with residual transporter activity based on finding biallelic mutations with normal liver microsomal GTPase activity in 2 Japanese patients; see 602671.0015 and 602671.0016.
Chou and Mansfield (1999) reviewed the molecular genetics of type I glycogen storage diseases.
Krasikov - updated : 3/4/2004
Victor A. McKusick - updated : 9/8/2003
Proteins that traverse the secretory pathway of eukaryotic cells can be covalently modified with carbohydrates, which are important for their stability and folding, and which mediate diverse recognition events in growth and development (1). Defects in the attachment of carbohydrate to protein give rise to mental and psychomotor retardation, dysmorphism, and blood coagulation defects (2, 3). These symptoms, referred to as CDG (for congenital disorders of glycosylation, or, until recently, for carbohydrate-deficient glycoprotein syndrome), are caused by mutations that affect the pathway for N-glycosylation.
In this pathway (Figure 1), a branched saccharide of 14 sugars is built up on the polyisoprenoid carrier lipid dolichyl pyrophosphate (PP-Dol), then transferred to asparagines in the sequence Asn-X-Ser/Thr (where X is any amino acid except proline). Synthesis of the lipid-linked oligosaccharide (LLO) is carried out by enzymes in the membrane of the endoplasmic reticulum (ER) that act in a specific order, each transferring a specific sugar to the nascent glycolipid (4, 5). Two N-acetylglucosamines (GlcNAc's) and 5 mannoses (Man) are transferred from the sugar nucleotides UDP-GlcNAc and GDP-Man at the cytoplasmic face of the membrane, after which the Man5GlcNAc2-PP-Dol formed is flipped into the lumen of the ER, where 4 mannoses and 3 glucoses are added from dolichol-phosphate-mannose (Dol-P-Man) and Dol-P-glucose. The oligosaccharide is then attached to protein by oligosaccharyltransferase, a complex of at least 8 proteins (6). After transfer, the 3 glucoses and 1 mannose are trimmed from the oligosaccharide, and once the glycoprotein is transported to the Golgi apparatus, further mannoses can be removed and other sugars added to the residual oligosaccharide, generating diverse structures.
Many steps in Glc3Man9GlcNAc2-PP-Dol assembly have been defined genetically using yeast asparagine-linked glycosylation (alg) mutants, an approach pioneered by Huffaker and Robbins (7). Mutations in LLO assembly lead to formation of incomplete oligosaccharides, which are poor oligosaccharyltransferase substrates; asparagines that normally are glycosylated may remain unmodified, yielding glycoproteins with fewer carbohydrate chains. In the diagnosis of CDG, hypoglycosylation is inferred from altered isoelectric focusing patterns of transferrin (2).
The CDGs defined so far can be divided into 2 types, depending on whether they impair LLO assembly and transfer (CDG-I) or whether they affect trimming of the protein-bound oligosaccharide or the addition of sugars to it (CDG-II). (A new nomenclature for CDGs has been proposed by the participants in the First International Workshop on CDGs [Leuven, Belgium, November 12–13, 1999] and is followed here.) Two of the type I CDGs arise from deficiencies in the supply of mannose for glycosyl transfer reactions because of defects in the formation of Man-6-P from fructose-6-P by phosphomannose isomerase (PMI) (CDG-Ib, formerly Type Ib) or in the conversion of Man-6-P to Man-1-P by phosphomannomutase (PMM) (CDG-Ia, formerly Type Ia) (3). A third CDG-I (CDG-Ic, originally Type V) is caused by a defect in the transfer of glucose to Man9GlcNAc2-PP-Dol by the hAlg6 protein (8, 9).
Two reports in this issue (10, 11) and 1 elsewhere (12) describe new CDGs, types Id and Ie, in which LLO assembly is blocked at Man5GlcNAc2-PP-Dol. Fibroblasts from CDG-Ie patients (10, 11) have low activity of Dol-P-Man synthase, which transfers mannose from GDP-Man to Dol-P to generate the donor of the luminally added mannoses. The human enzyme has 3 subunits (13, 14). Dpm1 is catalytic (15). Dpm2 and Dpm3 are small proteins; Dpm2 promotes binding of Dol-P to the enzyme. CDG-Ie patients have a point mutation in Dpm1, and the mutant enzyme's Km for GDP-Man is 6-fold higher than normal. In CDG-Id cells, Dol-P-Man synthase is normal, and transfer of mannose from Dol-P-Man to the LLO is affected by a missense mutation in the hALG3 gene (12).
Of the new CDGs, type Id specifically affects N-glycosylation. However, the Dol-P-Man synthase deficiency that leads to CDG-Ie can have further biochemical consequences: Dol-P-Man donates the mannoses found in glycosylphosphatidylinositol (GPI) membrane anchors, the mannose attached through C-linkage to certain tryptophans, and the mannose in O-linked glycoproteins (16–18). A defect in GPI assembly leads to the disease paroxysmal nocturnal hemoglobinuria (PNH; 16), but it is not clear whether deficiencies in GPI synthesis or in O- or C-mannosylation contribute to the pathology of CDG-Ie; these patients apparently do not exhibit PNH symptoms, and the clinical features of CDG-Id and -Ie are similar. However, CDG-I cells always retain residual activity of an affected enzyme, which presumably permits them to glycosylate proteins and attach GPI anchors to them above a threshold level necessary for viability. It is possible that when GDP-Man and Dol-P-Man are in limited supply, they are used more efficiently in other pathways, so that GPI anchoring occurs but N-glycosylation is incomplete (19).
Deficiencies in mannose-containing precursors in CDG-Ia, -Ib, and -Ie might be predicted to be bypassed if the cells are supplemented with mannose. Indeed, the LLO defect in PMI-defective (CDG-Ib) and PMM-defective (CDG-Ia) fibroblasts can be corrected by supplying mannose in their medium, but study results differ on whether this is possible in CDG-Ie cells. PMI deficiency can also be bypassed in the patient: oral mannose therapy has been used successfully to treat CDG-Ib (3).
Additional types of CDG-I could arise from defects at other steps in assembly of the LLO, in its translocation across the membrane, or in its transfer to asparagine. The challenge now is to determine the structures and biochemical activities of the enzymes involved, and the mechanism of Man5GlcNAc2-PP-Dol translocation. A further issue is whether CDG-I symptoms are due to hypoglycosylation of a few specific proteins. If so, the roles of these glycoproteins in, for example, the nervous system, are of great interest. Because the progress made in identifying the genes mutated in the CDG-I subtypes has relied on work done in yeast, these studies are an excellent example of how basic research with a model organism can help us understand human genetic disease.
Congenital disorders of glycosylation (CDG), formerly known as carbohydrate-deficient glycoprotein syndromes, lead to diseases with variable clinical pictures. We report the delineation of a novel type of CDG identified in 2 children presenting with severe developmental delay, seizures, and dysmorphic features. We detected hypoglycosylation on serum transferrin and cerebrospinal fluid β-trace protein. Lipid-linked oligosaccharides in the endoplasmic reticulum of patient fibroblasts showed an accumulation of the dolichyl pyrophosphate Man5GlcNAc2 structure, compatible with the reduced dolichol-phosphate-mannose synthase (DolP-Man synthase) activity detected in these patients. Accordingly, 2 mutant alleles of the DolP-Man synthase DPM1 gene, 1 with a 274C>G transversion, the other with a 628delC deletion, were detected in both siblings. Complementation analysis using DPM1-null murine Thy1-deficient cells confirmed the detrimental effect of both mutations on the enzymatic activity. Furthermore, mannose supplementation failed to improve the glycosylation status of DPM1-deficient fibroblast cells, thus precluding a possible therapeutic application of mannose in the patients. Because DPM1 deficiency, like other subtypes of CDG-I, impairs the assembly of N-glycans, this novel glycosylation defect was named CDG-Ie.
The detection of hypoglycosylation of proteins based on rapid assays such as isoelectric focusing of serum transferrin has led to the identification of several novel defects of N-linked glycosylation. The related diseases have been classified as congenital disorders of glycosylation (CDG), formerly known as carbohydrate-deficient glycoprotein syndromes (1, 2). In keeping with the importance of oligosaccharides for glycoprotein functions (3), defective glycosylation leads to various clinical presentations, such as dysmorphism, encephalopathy, coagulation disorders, and other organ dysfunctions.
To date, 5 types of CDG have been characterized at the biochemical and genetic level. The currently established subtypes of CDG-I are caused by deficiencies in various compounds. CDG-Ia is caused by a defect in the PMM2 gene and a resulting deficiency in phosphomannomutase (4). The PMI gene is responsible for CDG-Ib and its characteristic deficiency in phosphomannose isomerase (5, 6). CDG-Ic is linked to the ALG6 gene and a deficiency in Man9GlcNAc2-PP-Dol–dependent α1,3-glucosyltransferase (PP-Dol = dolichyl pyrophosphate) (7–9), and CDG-Id is caused by a defect in ALG3 and a resulting deficiency in Man5GlcNAc2-PP-Dol–dependent α1,3-mannosyltransferase (10). All of these defects lead to incomplete biosynthesis of lipid-linked Glc3Man9GlcNAc2 in the endoplasmic reticulum (ER) and subsequent hypoglycosylation of nascent proteins. By contrast, deficiency of the Golgi-localized N-acetylglucosaminyltransferase-II enzyme in CDG-IIa leads to defective maturation of complex-type N-linked glycans (11).
The assembly of lipid-linked oligosaccharides takes place at the membrane of the ER. First, Man5GlcNAc2-PP-Dol is assembled at the cytoplasmic side of the membrane; UDP-GlcNAc and GDP-Man serve as sugar donors. After the flipping of the oligomannose core into the luminal side of the ER, 4 mannose residues and 3 glucose residues are added using dolichol-phosphate-mannose (DolP-Man) and dolichol-phosphate-glucose (DolP-Glc), respectively, as donor substrates (Figure 1) (12). DolP-Man is synthesized from GDP-Man and DolP by DolP-Man synthase. The human enzyme consists of 2 subunits encoded by 2 genes, DPM1 (13, 14) and DPM2 (15). Cell lines with impaired DolP-Man synthase activity exhibit altered N-linked protein glycosylation; glycosylphosphatidylinositol-anchor (GPI-anchor) biosynthesis (16) and C-linked protein mannosylation (17) are also affected. Herein we describe the identification of DolP-Man synthase deficiency caused by mutations in the DPM1 gene as the primary cause for a novel type of CDG, which we call CDG-Ie.
Patient cells. Primary fibroblasts isolated from a skin biopsy were grown in DMEM/F12 with high glucose levels (Life Technologies Inc., Paisley, Scotland) supplemented with 10% FCS. Alternatively, cells were cultured in medium supplemented with 5 mM α-D-mannose (Sigma-Aldrich Co., Buchs, Switzerland) for 15 days.
PMM and PMI assays. PMM and PMI activities were measured in enucleated fibroblast cell lysates using the assays of Van Schaftingen and Jaeken (18).
Isoelectric focusing and Western blot. Isoelectric focusing separation of serum transferrin was performed as described previously (19). Proteins from 100-μL cerebrospinal fluid samples were precipitated with ethanol and then resuspended in Laemmli buffer (20). Proteins were separated under reducing conditions by SDS-PAGE. After transfer to nitrocellulose, β-trace protein was detected using an anti–β-trace protein monoclonal antibody (provided by H.S. Conradt, Gesellschaft für Biotechnologische Forschung mblt, Braunschweig, Germany) (21).
Analysis of lipid-linked oligosaccharides. Fibroblast cells grown to 90% confluence on 530-cm2 plates were washed with PBS and then incubated for 90 minutes at 37°C in minimal Eagle's medium (Life Technologies Inc.) supplemented with 5% dialyzed FCS. After this initial incubation period, cells were labeled by the addition of 175 μCi [3H]mannose (Amersham Pharmacia Biotech, Freiburg, Germany) for 1 hour at 37°C. Cells were then washed twice with ice-cold PBS and scraped off in 10 mL methanol and 0.1 mM Tris, pH 7.4 (8:3 vol/vol). After the addition of 10.9 mL chloroform and extensive mixing of the samples, cells were collected by centrifugation at 5,300 g for 5 minutes. Lipid-linked oligosaccharides were extracted as described previously (8) and were analyzed by HPLC (22).
DolP-Man synthase assay. Fibroblasts grown on a 530-cm2 plate were trypsinized and washed twice in ice-cold PBS. Cells were lysed on ice in 50 mM HEPES (pH 7.4), 25 mM KCl, 5 mM MgCl2, 5 mM MnCl2, and 0.2% Triton X-100 for 15 minutes; nuclei were removed by centrifugation. DolP-Man synthase activity was assayed using 30 μL of cell lysate in 100 μL of the same buffer, with the addition of 40 μg/mL DolP (Sigma-Aldrich Co.) and 17 μM GDP-[14C]mannose (Amersham Pharmacia Biotech). Reaction mixtures were incubated for 0, 5, and 15 minutes at 37°C. DolP-Man was isolated by organic extraction (23), and the radioactivity was measured in a beta counter (Beckman Coulter Inc., Fullerton, California, USA).
RT-PCR. Extraction of total RNA from patient and control fibroblasts (2 × 107) was performed by the procedure of Chomczynski and Sacchi (24). Eight micrograms of total RNA and 100 units of Moloney murine leukemia virus reverse transcriptase (New England Biolabs Inc., Beverly, Massachusetts, USA) were used for reverse transcription. The reaction mixture (100 μL total volume) was incubated for 2 hours at 37°C. DPM1 cDNA (13) was amplified by PCR using the primer pair 5′-CATGGCCTCCTTGGAAGTCAG-3′ and 5′-ACCAGGCTTCTTTCATGTTTAACC-3′, with 8 μL reverse transcription product as template. The cycling conditions were 35 cycles at 94°C for 45 seconds, 56°C for 30 seconds, and 72°C for 1 minute, preceded by 6 cycles performed at higher annealing temperatures (twice at 65°C, twice at 63°C, twice at 60°C).
Genomic PCR. The human DPM1 cDNA sequence (GenBank accession D86198) was used to screen the available databases using the basic local alignment search tool (BLAST) algorithm (25). One human genomic sequence from a BAC contig on chromosome 20q13 (accession AL334553) was found to include the DPM1 gene. Exon and intron boundaries were determined by alignment of the genomic sequence with the cDNA sequence. The regions including exons 3 and 8 of the human DPM1 gene were amplified with the primers 5′-TGCTTTAAAGTTCTAACAAGTGCAA-3′ and 5′- AGCAGGTGTGAGGGGTTAGA-3′, and 5′-ACCAATGGCCAGTGAAAGTT-3′ and 5′-AAACCTTACTGCTCCTTTACCA-3′, respectively.
DNA sequencing. PCR fragments were purified using GENECLEAN (Bio 101 Inc., Carlsbad, California, USA) or QIAquick (QIAGEN Gmblt, Hilden, Germany) DNA purification kits. Sequencing was performed by a combination of cycle sequencing using the ThermoSequenase fluorescent-labeled primer cycle sequencing kit with 7-deaza dGTP, and solid phase sequencing using the AutoRead Sequencing Kit (both from Amersham Pharmacia Biotech). The sequences were analyzed on an ALF DNA sequencer (Amersham Pharmacia Biotech).
Cloning of human DPM1 cDNA and site-directed mutagenesis. DPM1 cDNA was amplified by PCR as described above using 100 ng of the human T-cell cDNA library as template (26), and 4 units of Klentaq polymerase (Sigma-Aldrich Co.). The resulting 840-bp fragment was subcloned into the SmaI site of pBluescript II SK+ (Stratagene, La Jolla, California, USA). Site-directed mutagenesis was performed using 100 ng of the resulting plasmid (pBS-DPM1wt) as template, and 4 units of Klentaq polymerase. The primers applied to introduce the 274C>G mutation were 5′-CATGGCCTCCTTGGAAGTCAG-3′, 5′-CCCAACTTTTTCTCTCCTGGTCTTAG-3′, 5′-TCTAAGACCAGGAGAGAAAAAGTTG-3′, and 5′-ACCAGGCTTCTTTCATGTTTAACC-3′. The primers used to introduce the 628delC deletion were 5′-CATGGCCTCCTTGGAAGTCAG-3′, 5′-TCTGAAGACGTAGCCTTTAGAAACAC-3′, 5′-TCTTCAGATGGAGATGATTGTTCG-3′, and 5′-ACCAGGCTTCTTTCATGTTTAACC-3′. Twenty PCR cycles were carried out at 94°C for 45 seconds, 52°C for 30 seconds, and 68°C for 60 seconds. The PCR products were gel purified, and the corresponding fragments were mixed and used as template for a second PCR that used the full-length primers to obtain the 2 DPM1 fragments with the designed mutations. The accuracy of the obtained fragments was confirmed by sequencing. The DPM1 cDNA sequence and the 2 mutant variants were directionally subcloned into the BamHI-XhoI sites of the mammalian expression vector pcDNA3.1+ (Invitrogen, Corp. Carlsbad, California, USA).
Transfection of BW5147 cells. The mouse BW5147 Thy1-null cells of complementation class E (Thy1-E cells; 27) were generously provided by Robert Hyman (The Salk Institute, San Diego, California, USA), and were cultured in DMEM supplemented with 10% FCS. For transfection, 20 μg of plasmid DNA was mixed with 107 cells resuspended in cold PBS. Cells were electroporated with a Gene Pulser (Bio-Rad, Hercules, California, USA) set at 250 V and 960 μF. After a 10-minute resting period on ice, cells were resuspended in cell medium and incubated at 37°C for 3 days.
Flow cytometry. FITC-labeled antibodies to mouse Thy1.1 and human CD59 were purchased from PharMingen (San Diego, California, USA). Before addition of anti-Thy1.1 antibody, BW5147 cells were incubated with anti-CD16/CD32 antibody for 10 minutes on ice to block Fc receptor–mediated antibody binding. Cells were washed twice with PBS and 1% FCS and then incubated with diluted (1:100) antibodies for 15 minutes on ice. After rinsing cells once in PBS and 1% FCS, fluorescence was analyzed on a FACScan flow cytometer equipped with CellQUEST software (Becton Dickinson, Franklin Lakes, New Jersey, USA).
Two siblings (a boy 3 years and 4 months of age, and his younger sister aged 19 months) were hospitalized after repeated seizure episodes. They were born at term after an uneventful pregnancy. In both children, weight, length, and head circumference was normal at birth, but microcephaly developed in early childhood. Hypertelorism, gothic palate, small hands with dysplastic nails, and knee contractures were observed. Notably, nipples were not inverted as is found in CDG type Ia. Because of a failure to thrive, the younger child received nasogastric feeding. Her early childhood was complicated by recurrent infections. Severe epilepsy started in the girl at the age of 5 weeks, and in her brother at the age of 6 months. Both children were hypotonic and showed a severe global developmental delay. There was no visual fixation, and they were unable to interact socially. Electroencephalogram was severely abnormal with bilateral epileptiform changes. Magnetic resonance imaging of the brain revealed widening of the frontotemporal lobe and the ventricular system but normal pons and cerebellum. A very low flash electroretinogram suggested early retinopathy in the baby girl. Both children showed recurrent moderately elevated transaminases and creatine kinase, and signs of mild coagulopathy (Table 1).
Isoelectric focusing of serum transferrin showed decreased tetrasialotransferrin and increased disialotransferrin and asialotransferrin levels, suggesting a possible lack of entire N-glycan chains (Figure 2a). The hypoglycosylation phenotype was also detected in cerebrospinal fluid, as shown by the presence of hypoglycosylated β-trace protein (Figure 2b). These patterns were reminiscent of the distribution observed in CDG types Ia, Ib, and Ic.
However, PMM and PMI activity levels were found to be normal in the patients' fibroblasts (data not shown). We investigated the profile of dolichol-bound oligosaccharides in the ER to detect a possible defect in the assembly of the oligomannose core. This analysis revealed an accumulation of the Man5GlcNAc2-PP-Dol precursor structure in both patients (Figure 3). This accumulation was indicative of decreased availability of DolP-Man, the substrate for mannosyltransferases that act in the lumen of the ER (see Figure 1). Alternatively, a block at the level of the Man5GlcNAc2-PP-Dol–dependent mannosyltransferase would yield a phenotype similar to that observed in the Saccharomyces cerevisiae alg3 yeast mutant, which lacks this mannosyltransferase activity (28, 29).
The coding sequences of the 3 candidate genes (DPM1, DPM2, and the ALG3 mannosyltransferase gene) were investigated in the patients. Whereas human DPM1 and DPM2 cDNA have been cloned previously, the human gene orthologous to the ALG3 mannosyltransferase gene was not known as such, although its cDNA had been isolated and specified as encoding a Not56-like protein (GenBank accession Y09022). The sequences of the DPM2 and ALG3 mannosyltransferase cDNA of the patients revealed no abnormality (not shown). However, based on cDNA analysis, 2 mutant DPM1 alleles were identified in the patients. The 2 siblings and their mother were found to be heterozygous for a C→G transversion at position 274, resulting in arginine-to-glycine substitution (R92G). The 2 children were also heterozygous for an allele with a C deletion at position 628 that was also detected in the father. The mutation resulted in a premature stop of the translation at position 640 (codon 213) (Figure 4).
Comparison of Dpm1 protein sequences from several species indicated that the arginine residue at position 92 was semiconserved. This was found in Caenorhabditis briggsiae and Schizosaccharomyces pombe, but not in Saccharomyces cerevisiae, Trypanosoma brucei, or Ustilago maydis (14). It is worth noting that the species in which the R92 residue is conserved contain a class of DolP-Man synthase constituted of 2 subunits, Dpm1 and Dpm2.
The genomic structure of the DPM1 gene was elucidated to confirm the presence of the mutations at the genomic level. The genomic organization of DPM1 had been only partially characterized, with the first 3 exons revealed (13). To complete the task, we first searched GenBank for possible genomic sequences that would include the DPM1 gene. In fact, a contig sequence (accession AL334553) on chromosome 20q13 was found to contain the entire DPM1 gene, which spans 23.6 kbp. The DPM1 gene was split in 9 exons (Figure 5). Examination of the exon-intron boundaries showed that the 274C>G mutation was in exon 3 and the 628delC deletion was in the middle of exon 8, thereby excluding possible splicing artifacts. Sequencing of exons 3 and 8 in the CDG patients and their parents confirmed the mutations found at the cDNA level (data not shown).
DolP-Man synthase activity was measured in fibroblasts from the CDG patients and from healthy control subjects. An activity of 11.8 pmol/min per mg protein was found in control cells, and a residual activity of 0.7 pmol/min per mg protein was detected in the CDG cells. Although DolP-Man synthase activity in the CDG fibroblasts was decreased to 6% of the normal level, the remaining activity was significantly above the detection limit of the assay, indicating that the 2 mutations identified in the DPM1 gene of CDG patients did not completely inactivate the enzyme. To determine the impact of each mutation on DolP-Man synthase activity, we engineered DPM1 expression vectors that expressed either the wild-type cDNA, the 274C>G mutation, or the 628delC deletion. The constructs were transfected into mouse BW5147 Thy1-E cells (27), which are deficient in DolP-Man synthase activity due to inactive Dpm1 enzyme (13). Restoration of Thy1 expression was analyzed by flow cytometry 3 days after transfection. Cells transfected with a construct expressing wild-type DPM1 reacted positively for Thy1 staining, whereas cells transfected with an empty vector remained Thy1-negative (Figure 6). A small population of Thy1-positive cells was detected after transfection with the DPM1 gene containing the 274C>G substitution, indicating that this mutation does not abolish DolP-Man activity. By contrast, the transfection of Thy1-E cells with the vector including the DPM1 gene with the 628delC deletion failed to restore Thy1 expression at all (Figure 6); this is compatible with the observation that a deletion of the 24 COOH-terminal amino acids also abolished DolP-Man synthase activity (15).
Depletion of GDP-Man caused by deficiencies in PMM and PMI, and the resulting protein hypoglycosylation can be improved in vitro by supplementing with 1–2 mM mannose in the cell culture medium (30, 31). To evaluate whether the DolP-Man synthase deficiency detected in CDG patients can be overcome by mannose addition, we cultured the CDG fibroblasts in the presence or absence of 5 mM α-D-mannose for a period of 15 days. The dolichol-bound oligosaccharides were then analyzed in both cell populations. At the same time, we analyzed the levels of the GPI-anchored protein CD59 at the surface of CDG fibroblasts before and after mannose supplementation. Identical lipid-linked oligosaccharide profiles were detected in cells cultured with or without the addition of mannose (Figure 7a). Similarly, after mannose supplementation, the CD59 levels measured on DPM1-deficient CDG fibroblasts remained unchanged, at 40% of the amount normally found on fibroblast cells (Figure 7b).
We have identified a novel type of CDG caused by a deficiency in DolP-Man synthase activity. The shortage of DolP-Man affects the biosynthesis of the lipid-linked Glc3Man9GlcNAc2 substrate for N-linked protein glycosylation, and results in a suboptimal N-glycosylation of nascent glycoproteins and suboptimal biosynthesis of GPI-anchored proteins. Because DolP-Man deficiency causes hypoglycosylation of proteins similar to that encountered in CDG-I, we propose to classify this novel ER-associated defect as CDG-Ie. Clinically, apart from the psychomotor retardation and the marked hypotonia, these patients are quite different from CDG-Ia patients. By contrast, CDG-Ie patients show striking similarities with the patients reported by Stibler et al. and defined as CDG type IV (32). The molecular basis of the defect underlying the glycosylation deficiency in these type IV patients has not been disclosed yet, but we speculate that it may be either identical to the defect presented here or otherwise related to an alteration at the level of DolP-Man availability or incorporation into oligosaccharides.
DolP-Man serves as donor substrate in the process of N-linked protein glycosylation, GPI-core biosynthesis, and C-glycosylation of proteins (17). Therefore, a limitation in the DolP-Man pool can possibly affect the formation of different types of glycoproteins. Indeed, we detected decreased levels of the GPI-anchored CD59 protein at the surface of CDG-Ie fibroblasts. Similarly, the shortage of mannose-1-phosphate caused by both PMM and PMI deficiencies may also affect the same pathways, because GDP-Man is the substrate for DolP-Man synthesis. However, analysis of CD59 levels on fibroblasts of several CDG-Ia and -Ib patients revealed normal levels (data not shown). Because GDP-Man not only serves as a substrate for DolP-Man synthesis, the differences in the biochemical and clinical representation of CDG-Ia and CDG-Ib vs. CDG-Ie can be understood on this basis. In addition, it is important to note that all mutations that cause the clinical picture of CDG are missense mutations allowing for some residual activity of the affected protein. The extent of this residual activity strongly affects the clinical picture of the CDG patients.
In this respect it is interesting to note that in this first described case of CDG-Ie, the combination of a severe deletion with a missense mutation is observed: the deletion 628delC causes a complete inactivation of the protein (Figure 6) (15), whereas 274C>G seems to be a mild mutation. It may well be that, analogous to the PMM2 mutations in CDG-Ia (33), homozygosity for the severe 628delC mutation is lethal. This fits with the observation of a relatively mild mutation in combination with a deletion, yielding an inactive enzyme. It is possible that homozygosity for the 274C>G mutation may leave enough DolP-Man synthase activity to prevent a shortage of DolP-Man with pathological consequences.
The form of CDG caused by PMI deficiency (CDG-Ib) can be successfully treated with oral mannose (5). Because DolP-Man synthase activity was not completely lost in the CDG-Ie fibroblasts, we thought that an elevation of the cellular mannose pool might force the defective enzyme to produce more DolP-Man. However, our data showed that the addition of mannose had no effect on the hypoglycosylation phenotype of CDG-Ie cells. It is probable that an excess of intracellular mannose does not lead to the high pool of GDP-Man required for increasing the synthesis of DolP-Man. It is possible that a conversion of GDP-Man to GDP-fucose (34) lowers the GDP-Man pool in mannose-fed cells. In any case, considering the severe symptomatology, it is unlikely that supplementation therapy would improve the condition of CDG-Ie patients.
We thank Emile van Schaftingen for measuring the PMM and PMI activity in fibroblast cells, Bob Hyman and Andreas Conzelmann for kindly providing us with BW5147 cells, and Bea Berger for assisting with cell cultivation. This work was supported by the Swiss National Science Foundation (grant 3100-46836.96 to E.G. Berger and T. Hennet, and grants 3100-040350.94 and 31-57082.99 to M. Aebi) and by grant G.0243.98 from the Fund for Scientific Research–Flanders to G. Matthijs.
|Patricie Burda's present
address is: Howard Hughes Medical Institute, Division of Cellular and
Molecular Medicine, University of California–San Diego, 9500 Gilman
Drive, La Jolla, California 92093, USA.
Timo Imbach and Barbara Schenk contributed equally to this work.
Clinical Information and Studies
Using heparin therapy to reverse protein-losing enteropathy in a patient with CDG-Ib.
Department of Internal Medicine, Erasmus University Medical Center, Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
BACKGROUND: A 22-year-old female presented with edema, diarrhea, hypoalbuminemia and pancytopenia. She had previously been diagnosed with congenital disorder of glycosylation type Ib, and had a history of congenital hepatic fibrosis, portal hypertension and esophageal varices. In the past she had refused mannose therapy because of associated diarrhea and abdominal pain.
INVESTIGATIONS: Laboratory examinations, abdominal ultrasonography, bacterial and viral cultures of blood, urine and stools, double-balloon enteroscopy and fecal excretion test using 51Cr-labeled albumin.
DIAGNOSIS: Protein-losing enteropathy.
MANAGEMENT: Infusion of albumin followed by intravenous and subcutaneous therapy with unfractionated heparin.
Laboratory diagnosis of congenital disorders of glycosylation type I by analysis of transferrin glycoforms.
Mol Diagn Ther. 2007
Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Congenital disorders of glycosylation (CDG) are being recognized as a rapidly growing and complex group of disorders. The pathophysiology results from depressed synthesis or remodeling of oligosaccharide moieties of glycoproteins. The ultimate result is the formation of abnormal glycoproteins affecting their structure and metabolic functions. The most thoroughly studied subset of CDG are the type I defects affecting N-glycosylation. Causal mutations occur in at least 12 different genes which encode primarily monosaccharide transferases necessary for N-glycosylation in the endoplasmic reticulum. The broad clinical presentation of these glycosylation defects challenge clinicians to test for these defects in a variety of clinical settings. The first described CDG was a phosphomannomutase deficiency (CDG-Ia). The original method used to define the glycosylation defect was isoelectric focusing (IEF) of transferrin. More recently, the use of other charge separation methods and electrospray-mass spectrometry (ESI-MS) has proven valuable in detecting type I CDG defects. By mass resolution, the under-glycosylation of transferrin is characterized as the total absence of one or both N-linked oligosaccharide. Beyond providing a new understanding of the structure of transferrin in type I CDG patients, it is adaptable to high throughput serum analysis. The use of transferrin under-glycosylation to detect the type I CDG provides limited insight into the specific site of the defect in oligosaccharide assembly since its value is constrained to observation of the final product of glycoprotein synthesis. New analytical targets and tools are converging with the clinical need for diagnosis of CDG. Defining the biosynthetic sites responsible for specific CDG phenotypes is in progress, and ten more type I defects have been putatively identified. This review discusses current methods, such as IEF and targeted proteomics using mass spectrometry, that are used routinely to test for type I CDG disorders, along with some newer approaches to define the defective synthetic sites responsible for the type I CDG defects. All diagnostic endeavors are followed by the quest for a reliable treatment. The isolated success of CDG-Ib treatment will be described with the hope that this may expand to other type I CDG disorders.
PMID: 17963418 [PubMed - indexed for MEDLINE]
Congenital disorders of N-glycosylation including diseases associated with O- as well as N-glycosylation defects.
Pediatr Res. 2006 Dec
Diagnosis of congenital disorders of glycosylation type-I using protein chip technology.
Proteomics. 2006 Apr
The congenital disorders of glycosylation: a multifaceted group of syndromes.
NeuroRx. 2006 Apr
Department of Cell and Molecular Biology, Lund University, Lund, Sweden.
The congenital disorders of glycosylation (CDG) are a rapidly expanding group of metabolic syndromes with a wide symptomatology and severity. They all stem from deficient N-glycosylation of proteins. To date the group contains 18 different subtypes: 12 of Type I (disrupted synthesis of the lipid-linked oligosaccharide precursor) and 6 of Type II (malfunctioning trimming/processing of the protein-bound oligosaccharide). Main features of CDG involve psychomotor retardation; ataxia; seizures; retinopathy; liver fibrosis; coagulopathies; failure to thrive; dysmorphic features, including inverted nipples and subcutaneous fat pads; and strabismus. No treatment currently is available for the vast majority of these syndromes (CDG-Ib and CDG-IIc are exceptions), even though attempts to synthesize drugs for the most common subtype, CDG-Ia, have been made. In this review we will discuss the individual syndromes, with focus on their neuronal involvement, available and possible treatments, and future directions.
Congenital Disorder of Glycosylation Id Presenting with Hyperinsulinemic Hypoglycemia and Islet Cell Hyperplasia
CDG Family Network Foundation (2)
Attn: Cynthia Wren-Gray, President
P.O. Box 860847
Plano, Texas, 75074
CDG Related Sites:Denmark CDG Society
The Burnham Institute, San Diego, CA, USAEUROGLYCANET - European Network for the systematic study of CDG and related diseases
Codes and external Information
|Age of onset||Neonatal/infancy|
|ICD 10 code||
MIM # 602579
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