Congenital Disorder Of Glycosylation, Type Iie

A number sign (#) is used with this entry because congenital disorder of glycosylation type IIe (CDG2E) is caused by homozygous mutation in the gene encoding component of oligomeric Golgi complex-7 (COG7; 606978) on chromosome 16p12.

Description

CDG IIe is caused by a mutation that impairs the integrity of the conserved oligomeric Golgi (COG) complex and alters Golgi trafficking, resulting in the disruption of multiple glycosylation pathways.

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

Clinical Features

In 2 sibs with manifestations consistent with a congenital disorder of glycosylation, Wu et al. (2004) confirmed abnormal glycosylation on IEF analysis of their serum transferrin. The patients had perinatal asphyxia and dysmorphia, including low-set dysplastic ears, micrognathia, short neck, and loose, wrinkled skin. Generalized hypotonia, hepatosplenomegaly, and progressive jaundice developed shortly after birth. X-ray examination revealed that the male sib lacked humeral and tibial epiphyses, whereas the female had short extremities. The male also had a large space at the cisterna cerebelli superior on CT scan. Both sibs developed severe epilepsy and died from recurrent infections and cardiac insufficiency, the male at age 5 weeks and the female at age 10 weeks. Their parents were consanguineous, and an earlier-born sib had died shortly after birth with similar congenital defects. Spaapen et al. (2005) provided a clinical report of the patients reported by Wu et al. (2004), who were born of consanguineous Tunisian parents. Laboratory studies showed increased liver enzymes and bilirubin, and a CDG type 2 pattern on isoelectric focusing of sialotransferrins, with reduced penta- and tetrasialotransferrin and increased tri-, di-, mono-, and asialotransferrin. The findings indicated a defect in both O- and N-glycosylation, consistent with a generalized glycosylation disturbance.

Morava et al. (2007) described 2 sibs and another child from 2 unrelated consanguineous Moroccan families who presented with growth retardation, progressive severe microcephaly, hypotonia, adducted thumbs, feeding problems due to gastrointestinal pseudoobstruction, failure to thrive, cardiac anomalies, wrinkled skin, and episodes of extreme hyperthermia. A combined disorder in the biosynthesis of N- and O-linked glycosylation with hyposialylation was detected. The patients died at 7, 8, and 9 months of age, respectively. The authors stated that the phenotype was similar to that of the 2 sibs previously described by Wu et al. (2004), except for lack of skeletal anomalies and only mild liver involvement in these patients.

Ng et al. (2007) reported a female infant, born of consanguineous Moroccan parents, with CDG IIe due to homozygosity for a splice site mutation in the COG7 gene (606978.0001). She had a flat face, full lips, protruding tongue, and inverted nipples. Other features included hepatomegaly with abnormal liver enzymes, severe hypotonia, and distal arthrogryposis. She later developed seizures, had poor ocular fixation, little development, and polyneuropathy. Brain MRI showed delayed myelination. She died at age 3.5 months of respiratory insufficiency associated with laryngeal spasm.

Zeevaert et al. (2009) reported 2 brothers, born of consanguineous Moroccan parents, with CDG IIe. Although the proband appeared normal at birth, he developed diarrhea with severe dehydration, hepatomegaly, cholestasis, anemia, thrombocytopenia, and mild proteinuria at age 1 month. Brain MRI showed cerebral atrophy and a hypodensity in the periventricular white matter. Psychomotor development was delayed and there was hypotonia, areflexia of the lower limbs, and failure to thrive. He died of high fever of unknown origin at age 17 months. His younger brother showed psychomotor retardation, feeling problems, behavioral problems, and elevated serum transaminases at age 10 months. He had poor growth, but was alive at age 4.5 years. Genetic analysis of the proband showed a homozygous mutation in the COG7 gene (606978.0002); DNA from the younger sib was not available. Biochemical studies of patient fibroblasts showed a defect in retrograde vesicular transport of the Golgi.

Molecular Genetics

In 2 sibs with a fatal form of CDG, Wu et al. (2004) found disruption of multiple glycosylation pathways similar to that seen in Chinese hamster ovary cell lines with mutations in genes encoding COG1 (606973) and COG2 (606974). COG7 was undetectable in the fibroblasts of both patients, and sequencing revealed that both had a homozygous A-to-C transversion at position +4 in intron 1 of the COG7 gene (IVS1+4A-C; 606978.0001). Wu et al. (2004) concluded that these cases represented a new type of CDG, which they termed CDG IIe, in which the molecular defect lies in a protein that affects the trafficking and function of the glycosylation machinery.

In 3 patients from 2 unrelated consanguineous Moroccan families with a fatal CDG, Morava et al. (2007) identified homozygosity for the IVS1+4A-C mutation in COG7 previously found in 2 sibs by Wu et al. (2004). Morava et al. (2007) analyzed the other subunits of the COG complex in 1 patient from each family but did not detect any other pathogenic mutations.