Congenital Disorder Of Glycosylation, Type In

A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type In (CDG In, CDG1N) is caused by homozygous or compound heterozygous mutation in the RFT1 gene (611908) on chromosome 3p21.

Description

Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. Type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein. These disorders can be identified by a characteristic abnormal isoelectric focusing profile of plasma transferrin (Leroy, 2006).

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

Clinical Features

Stibler et al. (1998) identified a patient with an untyped disorder of N-linked glycosylation on the basis of detection of abnormal isoelectric focusing of serum transferrin. The patient, designated KS by Imtiaz et al. (2000), showed symptoms often encountered in CDG, namely, marked developmental delay, hypotonia, seizures, hepatomegaly, and coagulopathy.

Vleugels et al. (2009) reported 3 unrelated children with CDG1N. One was of Scottish descent, the second was born of consanguineous Italian parents, and the third was born of consanguineous Algerian parents. All were severely affected and presented in infancy with feeding difficulties and failure to thrive. Dysmorphic features were somewhat variable, but included microcephaly, micrognathia, short neck, adducted thumbs, valgus foot deformities, and inverted nipples. All had severe mental retardation with limited development, hypotonia, seizures, myoclonic jerks, decreased visual acuity, and sensorineural deafness. One patient died at age 8 months. All had normal liver function, but 1 patient had a coagulopathy. Biochemical analysis showed a type 1 pattern of serum sialotransferrins and accumulation of the incomplete oligosaccharide Man(5)GlcNAc(2)-PP-dolichol.

Jaeken et al. (2009) reported 2 unrelated children with CDG1N. Common features included feeding problems, failure to thrive, severe developmental delay, epilepsy, hypotonia, and sensorineural deafness. Both children also had deficiencies in coagulation factors.

Ondruskova et al. (2012) reported 2 sibs, born of unrelated Czech parents, with CDG1N. The patients were 19 and 21 years old at the time of the report. Both had delayed psychomotor development apparent in infancy, as well as early-onset seizures. As young adults, both had significant cognitive impairment, short stature, mild dysmorphic features, ataxia, axial hypotonia, mild spasticity with hyperreflexia, and a mild coagulopathy without clinical consequences. Only 1 sib had hearing impairment, which was diagnosed at age 13 years. Laboratory studies were consistent with CDG1N. Ondruskova et al. (2012) noted that the phenotype in these sibs was milder than that previously reported in patients with CDG1N.

Biochemical Features

To determine whether the glycosylation disorder in patient KS (Imtiaz et al., 2000) was related to a defect of lipid-linked oligosaccharide (LLO) assembly, Haeuptle et al. (2008) analyzed the LLO composition of the patient. The profile was marked by an accumulation of the intermediate LLO DolPP-GlcNAc(2)Man(5) and a strong reduction of complete LLO DolPP-GlcNAc(2)Man(9)Glc(3). The biochemical phenotype of DolPP-GlcNAc(2)Man(5) accumulation and severe protein underglycosylation was reminiscent of that seen in yeast depleted for the Rft1 protein.

Inheritance

The transmission pattern of CDG1N in the families reported by Vleugels et al. (2009) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a patient with an untyped congenital disorder of glycosylation, Haeuptle et al. (2008) found a homozygous point mutation in the RFT1 gene (R67C; 611908.0001). Despite the low sequence identity (22%) between yeast and human RFT1 protein, Haeuptle et al. (2008) demonstrated both their functional orthology and the pathologic effect of the human R67C mutation by complementation assay in Rft1-deficient yeast cells. The causality of the RFT1 R67C mutation was further established by restoration of normal glycosylation profiles in patient-derived fibroblasts after lentiviral expression of the normal RFT1 cDNA.

In 3 unrelated children with CDG1N, Vleugels et al. (2009) identified 3 different homozygous missense mutations in the RFT1 gene (611908.0001-611908.0003). All mutations were located in 1 of the hydrophilic loops predicted to be within the ER lumen. Patient fibroblasts showed accumulation of Man(5)GlcNAc(2)-PP-dolichol and decreased DNase I secretion compared to controls, and these defects were restored by expression of wildtype RFT1.

In 2 unrelated children with CDG1N, Jaeken et al. (2009) identified biallelic mutations in the RFT1 gene (611908.0002; 611908.0004-611908.0005).

In 2 sibs, born of unrelated Czech parents, with CDG1N, Ondruskova et al. (2012) identified compound heterozygous missense mutations in the RFT1 gene (M408V; 611908.0006 and R442Q; 611908.0007). Functional studies were not performed, but both mutations occurred in the transmembrane domain, unlike previous RFT1 mutations that occurred in the luminal loops. The phenotype in the Czech sibs was somewhat milder compared to other patients, which Ondruskova et al. (2012) postulated may be due to the location of the mutation.