Congenital Disorder Of Glycosylation, Type Ib

A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type Ib (CDG Ib, CDG1B) is caused by compound heterozygous mutation in the gene encoding mannosephosphate isomerase (MPI; 154550) on chromosome 15q24.

Description

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.

Clinical Features

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 (613118), 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.

From a review of the literature on liver-related symptoms in CDG, Marques-da-Silva et al. (2017) suggested that the finding of 'congenital hepatic fibrosis' or 'ductal plate malformation' on liver biopsy should prompt immediate testing for CDG Ib.

Clinical Management

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).

Molecular Genetics

Niehues et al. (1998) identified a heterozygous mutation in the MPI gene (R219Q; 154550.0001) in a patient with CDG Ib. Subsequently, Schollen et al. (2000) identified a second MPI mutation (116insC; 154550.0004) in this patient, confirming compound heterozygosity and autosomal recessive inheritance.

In a patient with CDG Ib, Jaeken et al. (1998) identified compound heterozygosity for 2 mutations in the MPI gene (154550.0002, 154550.0003).

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.