Congenital Disorder Of Glycosylation, Type Iih

A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type IIh (CDG IIh, CDG2H) is caused by homozygous or compound heterozygous mutation in the COG8 gene (606979) on chromosome 16q22.

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

Clinical Features

Foulquier et al. (2007) described an 8 year-old Spanish female with a congenital disorder of glycosylation who was the product of a consanguineous relationship. Although the neonatal period and early infancy were normal, at age 6 months she presented with an acute encephalopathy and loss of psychomotor abilities, hypotonia, alternating esotropia, pseudoptosis, and mental retardation. At 17 months during gastroenteritis she had a unilateral status epilepticus and lethargy lasting for 5 days. This was the only episode of seizure activity. At various times she developed spontaneous hematomas, coincident with alteration of the coagulation factors and a decrease in prothrombin time, together with increased levels of transaminases and creatine kinase. At 6 years brain magnetic resonance imaging (MRI) showed cerebellar atrophy and slight brainstem atrophy. Minor dysmorphic features were seen. Cerebellar ataxia worsened from the age of 7 years. At the age of 8 years she had some simple language and understanding.

Kranz et al. (2007) described an 8 year-old male with a congenital disorder of glycosylation. By age 7 months the patient was recognized to be hypotonic with poor head control. At this age he did not reach for objects, sit, or roll over; reflexes were decreased. Nerve biopsy showed chronic axonal neuropathy, and a muscle biopsy showed a neurogenic process. Further evaluation by MRI showed ventriculomegaly ex vacuo with atrophy, and sonar spectroscopy revealed high levels of lactate in the gray matter. At age 18 to 24 months he developed myoclonic jerks with electroencephalographic slow waves consistent with seizures. At age 8.5 years the patient was severely mentally retarded with no speech or bowel/bladder control. He presented striking lack of muscle in all areas, resembling severe malnutrition.

Biochemical Features

The patient described by Foulquier et al. (2007) demonstrated elevations of asialo-, mono-, di-, and trisialotransferrins as well as abnormal isoelectric focusing of APOC-III, (indicative of an O-glycosylation defect). She also exhibited decreased levels of beta-1,4-galactosyltransferase (see 137060).

The patient described by Kranz et al. (2007) demonstrated an increase in monosialylated glycans and relative deficiency of more highly sialylated species.

Molecular Genetics

The patient described by Foulquier et al. (2007) was homozygous for a nonsense mutation in the COG8 gene (606979.0001).

The patient described by Kranz et al. (2007) was compound heterozygous for 2 mutations in COG8: a splice donor mutation in intron 3 (606979.0002) and a dinucleotide deletion in exon 5 (606979.0003).