Congenital Disorder Of Glycosylation, Type Ig

A number sign (#) is used with this entry because congenital disorder of glycosylation type Ig (CDG1G) is caused by homozygous or compound heterozygous mutation in the gene encoding dolichyl-P-mannose:Man-7-GlcNAc-2-PP-dolichyl-alpha-6-mannosyltransferase (ALG12; 607144) on chromosome 22q13.

Description

Congenital disorders of glycosylation (CDG), previously called carbohydrate-deficient glycoprotein syndromes (CDGSs), are a group of hereditary multisystem disorders first recognized by Jaeken et al. (1980). 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. For a general discussion of CDGs, see CDG1A (212065) and CDG1B (602579).

Clinical Features

Chantret et al. (2002) reported a girl born of nonconsanguineous parents who presented with weak suckling, failure to thrive, hypotonia, psychomotor involvement, microcephaly, facial dysmorphism, and recurrent ear, nose, throat, and respiratory infections. Blood chemistries were normal, except for decreased IgG levels, and isoelectric focusing of serum transferrin revealed hypoglycosylation profiles characteristic of CDG type I. Zdebska et al. (2003) described subsequent severe psychomotor retardation in this patient at age 3 years.

Thiel et al. (2002) reported an Indian girl with CDG Ig. She had delayed motor and mental development as an infant and presented with seizures at age 14 months. At 3.5 years, she had microcephaly, muscular hypotonia, prolonged partial thromboplastin time, supragluteal fat pads, and facial dysmorphism. Brain MRI showed widening of the side ventricles without hydrocephalus. Biochemical studies showed transferrin patterns consistent with CDG type I.

Kranz et al. (2007) described a brother and sister with clinical findings including a unique short limb skeletal dysplasia, IgG deficiency, psychomotor retardation, blindness and deafness, male genital hypoplasia, immunodeficiency, generalized edema, and cardiac abnormalities. Both sibs died before 2 years of age, one of overwhelming sepsis and the other of cardiorespiratory failure related to cardiomyopathy. Fibroblast studies were suggestive of CDG Ig, and mutation analysis revealed compound heterozygosity for ALG12 mutations (607144.0003 and 607144.0004) in both sibs. Unique skeletal findings in these 2 patients were delayed ossification of cervical vertebrae and signs of a generalized epiphyseal dysplasia including lack of ossification at the pubic bones, knee epiphyses, and tali. Kranz et al. (2007) noted similarities between this phenotype and Roifman syndrome (300258), and suggested that some cases of Roifman syndrome may be congenital disorders of glycosylation.

Biochemical Features

By biochemical analysis, Chantret et al. (2002) showed that the fibroblasts of a patient with CDG I were deficient in their capacity to add the eighth mannose residue onto the lipid-linked oligosaccharide precursor (LLO). Further studies of this patient by Zdebska et al. (2003) showed red cell membrane band-3 (109270) abnormalities in the absence of anemia: moderate hypoglycosylation (27%) with normal mannose content, and severe hypoglycosylation (64%) with excess mannose and reduced N-acetylglucosamine residues, in fractions with low and high electrophoretic mobility, respectively. Zdebska et al. (2003) proposed that the incomplete biosynthesis of the N-linked glycan was caused primarily by persistence of the 3-linked mannose residue on the 6-mannose arm of the trimannosyl moiety.

Molecular Genetics

Chantret et al. (2002) screened the human ALG12 cDNA from a patient with CDG I and identified a homozygous point mutation that caused an amino acid substitution in a conserved region of the peptide sequence (F142V; 607144.0001). Both parents were found to be heterozygous for the mutation. The pathologic phenotype of the fibroblasts of the patient was largely normalized upon transduction of the wildtype gene, demonstrating that the F142V mutation was the underlying cause of CDG in this patient, which was designated CDG Ig.

In the fibroblasts of a 2.5-year-old boy with CDG Ig, born of nonconsanguineous Danish parents, who presented with clinical and biochemical features similar to the patient described by Chantret et al. (2002), Grubenmann et al. (2002) demonstrated the biosynthetic intermediate GlcNAc-2-Man-7 oligosaccharide both on the lipid carrier dolichyl pyrophosphate and on newly synthesized glycoproteins, thus pointing to a defect in the ALG12 gene. Grubenmann et al. (2002) identified compound heterozygosity for mutations in ALG12 (T67M, 607144.0002; R146Q, 607144.0003).

In a patient with CDG Ig, Thiel et al. (2002) identified compound heterozygosity for 2 mutations in the ALG12 gene (607144.0005 and 607144.0006).