Congenital Disorder Of Glycosylation, Type Iid

A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type IId (CDG IId, CDG2D) is caused by homozygous mutation in the beta-1,4-galactosyltransferase gene (B4GALT1; 137060) on chromosome 9p21.

Description

Congenital disorders of glycosylation (CDG) are a group of hereditary multisystem disorders that are commonly associated with severe psychomotor and mental retardation. The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing (IEF) of serum transferrin. Type I CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type II CDG comprises defects of trimming, elongation, and processing of protein-bound glycans (summary by Hansske et al., 2002).

For a general discussion of CDGs, see CDG1A (212065).

Clinical Features

The clinical phenotype of all CDGs is dominated by severe psychomotor and mental retardation, as well as blood coagulation abnormalities presenting as thrombosis, bleeding, or stroke-like episodes (Jaeken et al., 1980).

Peters et al. (2002) reported a boy born of nonconsanguineous parents who presented with macrocephaly due to Dandy-Walker malformation, hypotonia, coagulopathy, myopathy with elevated creatine kinase, mild developmental delay, statomotor retardation, and abnormal serum transferrin pattern by isoelectric focusing. Peters et al. (2002) noted that myopathy was an unusual feature of CDG and that the Dandy-Walker malformation may be coincidental.

Biochemical Features

By isoelectric focusing, Peters et al. (2002) detected marked elevation of serum tri-, di-, mono-, and asialotransferrin fractions, together with deficiency of normal tetrasialotransferrin in their patient. This pattern was different from that in earlier recognized forms of CDG. Transferrin was found to be abnormal, with loss of sialic acid and galactose residues from both oligosaccharide side chains. Analysis of alpha-1-antitrypsin and alpha-1-antichymotrypsin also showed severely reduced sialic acid content, thus indicating a disorder of glycosylation type II, which was determined to be caused by deficiency of beta-1,4-galactosyltransferase.

Molecular Genetics

In the patient reported by Peters et al. (2002), Hansske et al. (2002) identified a single nucleotide insertion (137060.0001), predicted to result in a premature translation stop with loss of 50 amino acids at the C terminus. The patient was homozygous and his parents heterozygous for the mutation. Expression of the mutant cDNA in COS-7 cells led to the synthesis of a truncated, inactive polypeptide which was retained in the endoplasmic reticulum.