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Congenital disorder of glycosylation type 1B(CDG1B)

MedGen UID:
400692
Concept ID:
C1865145
Disease or Syndrome
Synonyms: Carbohydrate-deficient glycoprotein syndrome type 1B; CDG 1B; CDG gastrointestinal type; CDG Ib; CDG1B; CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ib; Mannosephosphate isomerase deficiency; MPI deficiency; MPI-CDG (CDG-Ib); Protein-losing enteropathy-hepatic fibrosis syndrome; Saguenay Lac Saint Jean syndrome; SLSJ syndrome
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): MPI (15q24.1)
OMIM®: 602579
Orphanet: ORPHA79319

Definition

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) Freeze and Aebi (1999) reviewed CDG Ib and CDG Ic (603147). Marques-da-Silva et al. (2017) systematically reviewed the literature concerning liver involvement in CDG. [from GTR]

Additional description

From OMIM
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) Freeze and Aebi (1999) reviewed CDG Ib and CDG Ic (603147). Marques-da-Silva et al. (2017) systematically reviewed the literature concerning liver involvement in CDG.  http://www.omim.org/entry/602579

Clinical features

Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency of loose or watery bowel movements.
Hereditary factor XI deficiency disease
MedGen UID:
8770
Concept ID:
C0015523
Disease or Syndrome
Factor XI deficiency is an autosomal bleeding disorder characterized by reduced levels of factor XI in plasma (less than 15 IU/dL). Bleeding occurs mainly after trauma or surgery. On the basis of the concordance or discordance of F11 antigen and activity, the disorder is classified into the more frequent cross-reactive negative (CRM-) and the rarer CRM positive (CRM+) (summary by Duga and Salomon, 2009).
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormal enlargement of the liver.
Liver Cirrhosis
MedGen UID:
7368
Concept ID:
C0023890
Disease or Syndrome
A chronic disorder of the liver in which liver tissue becomes scarred and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Enteropathy, protein-losing
MedGen UID:
19522
Concept ID:
C0033680
Disease or Syndrome
Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy is characterized by abdominal pain and diarrhea, primary intestinal lymphangiectasia, hypoproteinemic edema, and malabsorption. Some patients also exhibit bowel inflammation, recurrent infections associated with hypogammaglobulinemia, and/or angiopathic thromboembolic disease. Patient T lymphocytes show increased complement activation, causing surface deposition of complement and generating soluble C5a (Ozen et al., 2017).
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Hepatic failure
MedGen UID:
88444
Concept ID:
C0085605
Disease or Syndrome
A disorder characterized by the inability of the liver to metabolize chemicals in the body. Causes include cirrhosis and drug-induced hepatotoxicity. Signs and symptoms include jaundice and encephalopathy. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic dehydrogenase, and alkaline phosphatase.
Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Finding
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatic fibrosis
MedGen UID:
116093
Concept ID:
C0239946
Disease or Syndrome
The presence of excessive fibrous connective tissue in the liver. Fibrosis is a reparative or reactive process.
Hypoalbuminemia
MedGen UID:
68694
Concept ID:
C0239981
Finding
A condition in which albumin level in blood (SERUM ALBUMIN) is below the normal range. Hypoalbuminemia may be due to decreased hepatic albumin synthesis, increased albumin catabolism, altered albumin distribution, or albumin loss through the urine (ALBUMINURIA).
Antithrombin III deficiency
MedGen UID:
75781
Concept ID:
C0272375
Disease or Syndrome
Deficiency of antithrombin III is a major risk factor for venous thromboembolic disease. Two categories of AT-III deficiency have been defined on the basis of AT-III antigen levels in the plasma of affected individuals. The majority of AT-III deficiency families belong in the type I (classic) deficiency group and have a quantitatively abnormal phenotype in which antigen and heparin cofactor levels are both reduced to about 50% of normal. The second category of AT-III deficiency has been termed type II (functional) deficiency. Affected individuals from these kindreds produce dysfunctional AT-III molecules; they have reduced heparin cofactor activity levels (about 50% of normal) but levels of AT-III antigen are often normal or nearly normal (summary by Bock and Prochownik, 1987). The 2 categories of antithrombmin III deficiency have been classified further. Type I (low functional and immunologic antithrombin) has been subdivided into subtype Ia (reduced levels of normal antithrombin), and type Ib (reduced levels of antithrombin and the presence of low levels of a variant). Type II (low functional but normal immunologic antithrombin) has been subdivided into subtype IIa (functional abnormalities affecting both the reactive site and the heparin-binding site of AT3); subtype IIb (functional abnormalities limited to the reactive site); and subtype IIc (functional abnormalities limited to the heparin-binding site) (summary by Lane et al., 1992).
Abnormal bleeding
MedGen UID:
264316
Concept ID:
C1458140
Disease or Syndrome
A coagulation disorder characterized by a tendency for excessive bleeding.
Type I transferrin isoform profile
MedGen UID:
324900
Concept ID:
C1837899
Finding
Abnormal transferrin isoform profile consistent with a type I congenital disorder of glycosylation. In the traditional nomenclature for congenital disorders of glycosylation, absence of entire glycans was designated type I, and loss of one or more monosaccharides as type II.
Hyperinsulinemic hypoglycemia
MedGen UID:
351247
Concept ID:
C1864903
Disease or Syndrome
An increased concentration of insulin combined with a decreased concentration of glucose in the blood.
Villous atrophy
MedGen UID:
892490
Concept ID:
C4020747
Finding
The enteric villi are atrophic or absent.
MedGen UID:
505035
Concept ID:
CN001789

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Congenital disorder of glycosylation type 1B in Orphanet.

Recent clinical studies

Etiology

Hegarty R, Hadzic N, Gissen P, Dhawan A
Eur J Pediatr 2015 Oct;174(10):1387-92. Epub 2015 Apr 24 doi: 10.1007/s00431-015-2540-6. PMID: 25902754

Diagnosis

Hegarty R, Hadzic N, Gissen P, Dhawan A
Eur J Pediatr 2015 Oct;174(10):1387-92. Epub 2015 Apr 24 doi: 10.1007/s00431-015-2540-6. PMID: 25902754
Jaeken J, Lefeber D, Matthijs G
Eur J Hum Genet 2014 Sep;22(9) Epub 2014 Feb 26 doi: 10.1038/ejhg.2014.29. PMID: 24569608Free PMC Article
Schroeder AS, Kappler M, Bonfert M, Borggraefe I, Schoen C, Reiter K
J Inherit Metab Dis 2010 Dec;33 Suppl 3:S497-502. Epub 2011 Jan 16 doi: 10.1007/s10545-010-9252-x. PMID: 21240668

Therapy

Schroeder AS, Kappler M, Bonfert M, Borggraefe I, Schoen C, Reiter K
J Inherit Metab Dis 2010 Dec;33 Suppl 3:S497-502. Epub 2011 Jan 16 doi: 10.1007/s10545-010-9252-x. PMID: 21240668

Prognosis

Hegarty R, Hadzic N, Gissen P, Dhawan A
Eur J Pediatr 2015 Oct;174(10):1387-92. Epub 2015 Apr 24 doi: 10.1007/s00431-015-2540-6. PMID: 25902754

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