What Is Diagnosis for a Baby With Cdg

Medical condition

Congenital disorders of glycosylation
Specialty	Endocrinology

A congenital disorder of glycosylation (previously called carbohydrate-deficient glycoprotein syndrome) is one of several rare inborn errors of metabolism in which glycosylation of a variety of tissue proteins and/or lipids is deficient or defective. Congenital disorders of glycosylation are sometimes known as CDG syndromes. They often cause serious, sometimes fatal, malfunction of several different organ systems (especially the nervous system, muscles, and intestines) in affected infants. The most common sub-type is PMM2-CDG (formally known as CDG-Ia) where the genetic defect leads to the loss of phosphomannomutase 2 (PMM2), the enzyme responsible for the conversion of mannose-6-phosphate into mannose-1-phosphate.

Presentation [edit]

The specific problems produced differ according to the particular abnormal synthesis involved. Common manifestations include ataxia; seizures; retinopathy; liver disease; coagulopathies; failure to thrive (FTT); dysmorphic features (e.g., inverted nipples and subcutaneous fat pads), pericardial effusion, and hypotonia. If an MRI is obtained; cerebellar hypoplasia is a common finding.^{[ citation needed ]}

Ocular abnormalities of CDG-Ia include: myopia, infantile esotropia, delayed visual maturation, peripheral neuropathy (PN), strabismus, nystagmus, optic disc pallor, and reduced rod function on electroretinography.^[1]Three subtypes PMM2-CDG, PMI-CDG, ALG6-CDG can cause congenital hyperinsulinism with hyperinsulinemic hypoglycemia in infancy.^[2]

N-Glycosylation and known defects [edit]

A biologically very important group of carbohydrates is the asparagine (Asn)-linked, or N-linked, oligosaccharides. Their biosynthetic pathway is very complex and involves a hundred or more glycosyltransferases, glycosidases, transporters and synthases. This plethora allows for the formation of a multitude of different final oligosaccharide structures, involved in protein folding, intracellular transport/localization, protein activity, and degradation/half-life. A vast amount of carbohydrate binding molecules (lectins) depend on correct glycosylation for appropriate binding; the selectins, involved in leukocyte extravasation, is a prime example. Their binding depends on a correct fucosylation of cell surface glycoproteins. Lack thereof leads to leukocytosis and increase sensitivity to infections as seen in SLC35C1-CDG(CDG-IIc); caused by a GDP-fucose (Fuc) transporter deficiency.^{[ citation needed ]}

All N-linked oligosaccharides originate from a common lipid-linked oligosaccharide (LLO) precursor, synthesized in the ER on a dolichol-phosphate (Dol-P) anchor. The mature LLO is transferred co-translationally to consensus sequence Asn residues in the nascent protein, and is further modified by trimming and re-building in the Golgi.

Deficiencies in the genes involved in N-linked glycosylation constitute the molecular background to most of the CDGs.^{[ citation needed ]}

• Type I defects involve the synthesis and transfer of the LLO
• Type II defects impair the modification process of protein-bound oligosaccharides.

Type I [edit]

Type II [edit]

The mature LLO chain is next transferred to the growing protein chain, a process catalysed by the oligosaccharyl transferase (OST) complex.^{[ citation needed ]}

• Once transferred to the protein chain, the oligosaccharide is trimmed by specific glycosidases. This process is vital since the lectin chaperones calnexin and calreticulin, involved in protein quality, bind to the Glc1Man9GlcNAc-structure and assure proper folding. Lack of the first glycosidase (GCS1) causes CDG-IIb.
• Removal of the Glc residues and the first Man residue occurs in the ER.
• The glycoprotein then travels to the Golgi, where a multitude of different structures with different biological activities are formed.
• Mannosidase I creates a Man5GlcNAc2-structure on the protein, but note that this has a different structure than the one made on LLO.
• Next, a GlcNAc residue forms GlcNAc1Man5GlcNAc2, the substrate for a-mannosidase II (aManII).
• aManII then removes two Man residues, creating the substrate for GlcNAc transferase II, which adds a GlcNAc to the second Man branch. This structure serves as substrate for additional galactosylation, fucosylation and sialylation reactions. Additionally, substitution with more GlcNAc residues can yield tri- and tetra-antennary molecules.

Not all structures are fully modified, some remain as high-mannose structures, others as hybrids (one unmodified Man branch and one modified), but the majority become fully modified complex type oligosaccharides.^{[ citation needed ]}

In addition to glycosidase I, mutations have been found:^{[ citation needed ]}

• in MGAT2, in GlcNAc transferase II (CDG-IIa)
• in SLC35C1, the GDP-Fuc transporter (CDG-IIc)
• in B4GALT1, a galactosyltransferase (CDG-IId)
• in COG7, the conserved oligomeric Golgi complex-7 (CDG-IIe)
• in SLC35A1, the CMP-sialic acid (NeuAc) transporter (CDG-IIf)

However, the use of >100 genes in this process, presumably means that many more defects are to be found.

Diagnosis [edit]

Classification [edit]

Historically, CDGs are classified as Types I and II (CDG-I and CDG-II), depending on the nature and location of the biochemical defect in the metabolic pathway relative to the action of oligosaccharyltransferase. The most commonly used screening method for CDG, analysis of transferrin glycosylation status by isoelectric focusing, ESI-MS, or other techniques, distinguish between these subtypes in so called Type I and Type II patterns.^{[ citation needed ]}

Currently, twenty-two CDG Type-I and fourteen Type-II subtypes of CDG have been described.^[20]

Since 2009, most researchers use a different nomenclature based on the gene defect (e.g. CDG-Ia = PMM2-CDG, CDG-Ib = PMI-CDG, CDG-Ic = ALG6-CDG etc.).^[21] The reason for the new nomenclature was the fact that proteins not directly involved in glycan synthesis (such as members of the COG-family^[22] and vesicular H+-ATPase)^[23] were found to be causing the glycosylation defect in some CDG patients.

Also, defects disturbing other glycosylation pathways than the N-linked one are included in this classification. Examples are the α-dystroglycanopathies (e.g. POMT1/POMT2-CDG (Walker-Warburg syndrome and Muscle-Eye-Brain syndrome)) with deficiencies in O-mannosylation of proteins; O-xylosylglycan synthesis defects (EXT1/EXT2-CDG (hereditary multiple exostoses) and B4GALT7-CDG (Ehlers-Danlos syndrome, progeroid variant)); O-fucosylglycan synthesis (B3GALTL-CDG (Peter's plus syndrome) and LFNG-CDG (spondylocostal dysostosis III)).^{[ citation needed ]}

Type I [edit]

• Type I disorders involve disrupted synthesis of the lipid-linked oligosaccharide precursor (LLO) or its transfer to the protein.

Types include:

Type II [edit]

• Type II disorders involve malfunctioning trimming/processing of the protein-bound oligosaccharide chain.

Types include:

Disorders of O-mannosylation [edit]

• Disorders with deficient α-dystroglycan O-mannosylation.

Mutations in several genes have been associated with the traditional clinical syndromes, termed muscular dystrophy-dystroglycanopathies (MDDG). A new nomenclature based on clinical severity and genetic cause was recently proposed by OMIM.^[24] The severity classifications are A (severe), B (intermediate), and C (mild). The subtypes are numbered one to six according to the genetic cause, in the following order: (1) POMT1, (2) POMT2, (3) POMGNT1, (4) FKTN, (5) FKRP, and (6) LARGE.^{[ citation needed ]}

Most common severe types include:

Treatment [edit]

No treatment is available for most of these disorders. Mannose supplementation relieves the symptoms in MPI-CDG for the most part,^[25] even though the hepatic fibrosis may persist.^[26] Fucose supplementation has had a partial effect on some SLC35C1-CDG patients.^[27]

History [edit]

The first CDG patients (twin sisters) were described in 1980 by Jaeken et al.^[28] Their main features were psychomotor retardation, cerebral and cerebellar atrophy and fluctuating hormone levels (e.g.prolactin, FSH and GH). During the next 15 years the underlying defect remained unknown but since the plasmaprotein transferrin was underglycosylated (as shown by e.g. isoelectric focusing), the new syndrome was named carbohydrate-deficient glycoprotein syndrome (CDGS)^[29] Its "classical" phenotype included psychomotor retardation, ataxia, strabismus, anomalies (fat pads and inverted nipples) and coagulopathy.

In 1994, a new phenotype was described and named CDGS-II.^[30] In 1995, Van Schaftingen and Jaeken showed that CDGS-I (now PMM2-CDG) was caused by the deficiency of the enzyme phosphomannomutase. This enzyme is responsible for the interconversion of mannose-6-phosphate and mannose-1-phosphate, and its deficiency leads to a shortage in GDP-mannose and dolichol (Dol)-mannose (Man), two donors required for the synthesis of the lipid-linked oligosaccharide precursor of N-linked glycosylation.^{[ citation needed ]}

In 1998, Niehues described a new CDG syndrome, MPI-CDG, which is caused by mutations in the enzyme metabolically upstream of PMM2, phosphomannose isomerase (PMI).^[17] A functional therapy for MPI-CDG, alimentary mannose was also described.

The characterization of new defects took increased and several new Type I and Type II defects were delineated.^[31]

In 2012, Need described the first case of a congenital disorder of deglycosylation, NGLY1 deficiency.^[32] A 2014 study of NGLY1 deficient patients found similarities with traditional congenital disorders of glycosylation.^[33]

See also [edit]

• Inborn error of metabolism
• Leukocyte adhesion deficiency
• PMM2 deficiency

References [edit]

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2. ^ Sun L, Eklund EA, Chung WK, Wang C, Cohen J, Freeze HH (July 2005). "Congenital disorder of glycosylation id presenting with hyperinsulinemic hypoglycemia and islet cell hyperplasia". The Journal of Clinical Endocrinology and Metabolism. 90 (7): 4371–5. doi:10.1210/jc.2005-0250. PMID 15840742.
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13. ^ 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 SE (July 2002). "Congenital disorders of glycosylation type Ig is defined by a deficiency in dolichyl-P-mannose:Man7GlcNAc2-PP-dolichyl mannosyltransferase". The Journal of Biological Chemistry. 277 (28): 25815–22. doi:10.1074/jbc.m203285200. PMID 11983712.
14. ^ Körner C, Knauer R, Holzbach U, Hanefeld F, Lehle L, von Figura K (1998). "Carbohydrate-deficient glycoprotein syndrome type V: deficiency of dolichyl-P-Glc:Man9GlcNAc2-PP-dolichyl glucosyltransferase". Proceedings of the National Academy of Sciences of the United States of America. 95 (22): 13200–5. Bibcode:1998PNAS...9513200K. doi:10.1073/pnas.95.22.13200. PMC23759. PMID 9789065.
15. ^ 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 SE (March 2003). "A deficiency in dolichyl-P-glucose:Glc1Man9GlcNAc2-PP-dolichyl alpha3-glucosyltransferase defines a new subtype of congenital disorders of glycosylation". The Journal of Biological Chemistry. 278 (11): 9962–71. doi:10.1074/jbc.m211950200. PMID 12480927.
16. ^ Kranz C, Denecke J, Lehrman MA, Ray S, Kienz P, Kreissel G, Sagi D, Peter-Katalinic J, Freeze HH, Schmid T, Jackowski-Dohrmann S, Harms E, Marquardt T (2001). "A mutation in the human MPDU1 gene causes congenital disorder of glycosylation type If (CDG-If)". The Journal of Clinical Investigation. 108 (11): 1613–9. doi:10.1172/JCI13635. PMC200991. PMID 11733556.
17. ^ ^{a b} Niehues R, Hasilik M, Alton G, Körner C, Schiebe-Sukumar M, Koch HG, Zimmer KP, Wu R, Harms E, Reiter K, von Figura K, Freeze HH, Harms HK, Marquardt T (1998). "Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy". The Journal of Clinical Investigation. 101 (7): 1414–20. doi:10.1172/JCI2350. PMC508719. PMID 9525984.
18. ^ Matthijs G, Schollen E, Pardon E, Veiga-Da-Cunha M, Jaeken J, Cassiman JJ, Van Schaftingen E (May 1997). "Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome)". Nature Genetics. 16 (1): 88–92. doi:10.1038/ng0597-88. PMID 9140401. S2CID 22959423.
19. ^ Lefeber DJ, Schönberger J, Morava E, Guillard M, Huyben KM, Verrijp K, Grafakou O, Evangeliou A, Preijers FW, Manta P, Yildiz J, Grünewald S, Spilioti M, van den Elzen C, Klein D, Hess D, Ashida H, Hofsteenge J, Maeda Y, van den Heuvel L, Lammens M, Lehle L, Wevers RA (July 2009). "Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies". American Journal of Human Genetics. 85 (1): 76–86. doi:10.1016/j.ajhg.2009.06.006. PMC2706967. PMID 19576565.
20. ^ Freeze HH, Eklund EA, Ng BG, Patterson MC (May 2012). "Neurology of inherited glycosylation disorders". The Lancet. Neurology. 11 (5): 453–66. doi:10.1016/S1474-4422(12)70040-6. PMC3625645. PMID 22516080.
21. ^ Jaeken, J., Hennet, T., Matthijs, G., and Freeze, H.H. (2009) CDG nomenclature: time for a change! Biochim Biophys Acta. 1792, 825-6.
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25. ^ Mention K, Lacaille F, Valayannopoulos V, Romano S, Kuster A, Cretz M, Zaidan H, Galmiche L, Jaubert F, de Keyzer Y, Seta N, de Lonlay P (2008). "Development of liver disease despite mannose treatment in two patients with CDG-Ib". Molecular Genetics and Metabolism. 93 (1): 40–3. doi:10.1016/j.ymgme.2007.08.126. PMID 17945525.
26. ^ Westphal V, Kjaergaard S, Davis JA, Peterson SM, Skovby F, Freeze HH (2001). "Genetic and metabolic analysis of the first adult with congenital disorder of glycosylation type Ib: long-term outcome and effects of mannose supplementation". Molecular Genetics and Metabolism. 73 (1): 77–85. doi:10.1006/mgme.2001.3161. PMID 11350186.
27. ^ Eklund EA, Freeze HH (2006). "The congenital disorders of glycosylation: a multifaceted group of syndromes". NeuroRx. 3 (2): 254–63. doi:10.1016/j.nurx.2006.01.012. PMC3593443. PMID 16554263.
28. ^ Jaeken, J., Vanderschueren-Lodeweyckx, M., Casaer, P., Snoeck, L., Corbeel, L., Eggermont, E., and Eeckels, R. (1980) Pediatr Res 14, 179
29. ^ Jaeken J, Carchon H (1993). "The carbohydrate-deficient glycoprotein syndromes: an overview". Journal of Inherited Metabolic Disease. 16 (5): 813–20. doi:10.1007/bf00714272. PMID 8295395. S2CID 10219089.
30. ^ Jaeken J, Schachter H, Carchon H, De Cock P, Coddeville B, Spik G (1994). "Carbohydrate deficient glycoprotein syndrome type II: a deficiency in Golgi localised N-acetyl-glucosaminyltransferase II". Archives of Disease in Childhood. 71 (2): 123–7. doi:10.1136/adc.71.2.123. PMC1029941. PMID 7944531.
31. ^ Haeuptle MA, Hennet T (2009). "Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides" (PDF). Human Mutation. 30 (12): 1628–41. doi:10.1002/humu.21126. PMID 19862844. S2CID 46281092.
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33. ^ Enns GM, Shashi V, Bainbridge M, Gambello MJ, Zahir FR, Bast T, et al. (October 2014). "Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway". Genetics in Medicine. 16 (10): 751–8. doi:10.1038/gim.2014.22. PMC4243708. PMID 24651605.

External links [edit]

Classification	D ICD-10: E77.8 ICD-9-CM: 271.8 OMIM: 212065 212066 MeSH: D018981 DiseasesDB: 2012
External resources	Orphanet: 137

• GeneReviews/NIH/NCBI/UW entry on PMM2-CDG (CDG-Ia)Carbohydrate-Deficient Glycoprotein Syndrome, Type 1a; Congenital Disorder of Glycosylation Type 1a; Jaeken Syndrome
• OMIM entries on Carbohydrate-Deficient Glycoprotein Syndrome, Type 1a; Congenital Disorder of Glycosylation Type 1a; Jaeken Syndrome
• GeneReviews/NIH/NCBI/UW entry on Congenital Disorders of Glycosylation Overview

What Is Diagnosis for a Baby With Cdg

Source: https://en.wikipedia.org/wiki/Congenital_disorder_of_glycosylation

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