Congenital Disorder Of Glycosylation, Type Ic

A number sign (#) is used with this entry because congenital disorder of glycosylation type Ic (CDG Ic, CDG1C) is caused by homozygous or compound heterozygous mutation in the ALG6 gene (604566) on chromosome 1p31.

Description

Congenital disorders of glycosylation, previously called carbohydrate-deficient glycoprotein syndromes (CDGSs), are caused by defects in mannose addition during N-linked oligosaccharide assembly. CDGs can be divided into 2 types, depending on whether they impair lipid-linked oligosaccharide (LLO) assembly and transfer (CDG I), or affect trimming of the protein-bound oligosaccharide or the addition of sugars to it (CDG II) (Orlean, 2000).

CDG Ic is characterized by psychomotor retardation with delayed walking and speech, hypotonia, seizures, and sometimes protein-losing enteropathy. It is the second largest subtype of CDG (summary by Sun et al., 2005).

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

Freeze and Aebi (1999) reviewed CDG Ib (602579) and CDG Ic.

Clinical Features

Burda et al. (1998) reported 4 related patients from a consanguineous Dutch family with type I CDG. There were 3 girls and 1 boy, aged 3 to 7 years. The most striking feature of the patients was a neurologic involvement. Biochemical data showed a CDG type 1 serum sialotransferrin pattern but normal levels of PMM2 (601785) activity. The clinical symptomatology was mild compared to patients with CDG1A.

Korner et al. (1998) reported a 7-year-old girl who had been noted in her first year to have a convergent squint, recurrent edema of the upper eyelids, and recurrent infections. Muscular hypotonia, ataxia, and mental and motor developmental retardation were present at the age of 6 months. Beginning at the age of 11 months, seizures occurred during infections. Nerve conduction velocity was always normal. MRI at the age of 4 years showed a slight general atrophy of the cerebrum and cerebellum. She had atrophic retinal pigmentation, reduction of retinal vascularization, and hyperopia. Pathologic coagulation parameters and levels of coagulation factors were found. The parents were described as healthy and unrelated; the family history was said to be 'inconspicuous.'

Sun et al. (2005) reported a woman with CDG Ic. She had severe mental retardation, seizures, broad-based gait, dysmetria, and intention tremor. She also had unusual characteristics, including distal limb defects and endocrine disturbances with hyperandrogenism. She had menarche at age 15, but menses were irregular. She developed pronounced virilization with facial hair, male pattern baldness, and low voice. Abdominal CT scan suggested polycystic ovaries. Hormonal workup showed low FSH and LH and increased testosterone. Insulin and glucose levels, as well as brain MRI, were normal. Sun et al. (2005) noted that the hormonal imbalances in females with CDG may be due to reduced bioactivity and bioavailability of FSH.

Miller et al. (2011) reported an 18-year-old woman with CDG Ic. She was hypotonic in infancy and showed developmental delay. Neurologic features included cortical blindness, partial agenesis of the corpus callosum, myoclonic episodes, and cerebellar dysfunction, with dysarthria, wide-based gait, and ataxia. She also had hyperinsulinemic hypoglycemia and gastrointestinal issues. Puberty was slightly delayed, with thelarche at age 13 years and menarche at age 15. At 18 years, she had severe premenstrual syndrome, but menses were regular. She had normal secondary sex characteristics. Hormonal laboratory workup showed no abnormalities and no evidence of increased androgen, in contrast to the report of Sun et al. (2005). Miller et al. (2011) suggested that the variable degrees of virilization reported in CDG females may be due to impaired glycosylation and function of the aromatase enzyme (CYP19A1; 107910).

Biochemical Features

Burda et al. (1998) found that fibroblasts from 4 patients with CDG1C showed a specific deficiency in the assembly of the dolichol-linked oligosaccharide. There was an impaired glycosylation of the oligosaccharide leading to accumulation of dolichylpyrophosphate-linked Man(9)GlcNAc(2). The hypoglycosylation of serum proteins in these patients was thought to be explained by the fact that nonglycosylated oligosaccharides are suboptimal substrates in the protein glycosylation process that is catalyzed by the oligosaccharyltransferase complex. This explains the reduced efficiency of N-linked protein glycosylation that was found in fibroblasts from these patients.

Korner et al. (1998) described a form of CDG, originally designated type V, which clinically resembled the classic type Ia. Biochemical studies showed a deficiency of the glycosyltransferase that transfers glucose from dolichyl phosphate glucose (Dol-P-Glc) onto the lipid-linked oligosaccharide Man(9)GlcNAc(2)-PP-Dol. The defect was leaky and allowed for a residual synthesis of glucosylated forms of LLOs, which are known to be the preferred substrate of oligosaccharyltransferase. The biochemical phenotype was characterized by an accumulation of nonglucosylated LLOs, a marked reduction of glucosylated LLOs, and incomplete utilization of N-glucosylation sites in nascent glycoproteins. The enzyme deficient in this case was referred to as dolichyl-P-Glc:Man(9)GlcNAc(2)-PP-dolichyl glucosyltransferase.

Molecular Genetics

Imbach et al. (1999) showed that all 4 of the patients with CDG1C described by Burda et al. (1998) had the same homozygous ala333-to-val point mutation in the ALG6 gene (A333V; 604566.0001).

Imbach et al. (2000) identified 7 additional patients with CDG1C. Four patients were homozygous for the previously described A333V mutation, and haplotype analysis indicated a founder effect. The other 3 patients had a different mutation in the ALG6 gene (604566.0002; 604566.0003).

Westphal et al. (2000) identified compound heterozygosity for 2 pathogenic mutations in the ALG6 gene (604566.0003 and 604566.0004) in a patient with CDG1C.

Sun et al. (2005) identified compound heterozygous mutations in the ALG6 gene (604566.0005 and 604566.0006) in a woman with CDG1C.

Miller et al. (2011) identified a homozygous mutation in the ALG6 gene (604566.0007) in a woman with CDG1C.