Congenital Disorder Of Glycosylation, Type Iim

A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type IIm (CDG2M) is caused by hemizygous or heterozygous mutation in the SLC35A2 gene (314375) on chromosome Xp11.

Description

Congenital disorder of glycosylation type IIm, or early infantile epileptic encephalopathy-22, is an X-linked dominant severe neurologic disorder characterized by infantile-onset seizures, hypsarrhythmia, hypotonia, and severe intellectual disability with lack of speech. Brain malformations include cerebral and cerebellar atrophy. Additionally, some patients had dysmorphic features or coarse facies (Ng et al., 2013; Kodera et al., 2013).

For a general discussion of CDGs, see CDG1A (212065) and CDG2A (212066). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).

Clinical Features

Ng et al. (2013) reported 2 unrelated boys and an unrelated girl with developmental delay, hypotonia, variable ocular anomalies, and variable brain malformations associated with an unusual serum transferrin profile consistent with a congenital disorder of glycosylation. Other more variable clinical features included seizures, hypsarrhythmia, poor feeding, microcephaly, recurrent infections, dysmorphic features, shortened limbs, and coagulation defects. One patient had acute nephrotic syndrome and gastroesophageal reflux. Brain malformations included small cerebellum in 1 patient, thinning of the corpus callosum with delayed myelination in another, and cerebral atrophy in the third. Laboratory studies of the patients showed an abnormal serum transferrin pattern with loss of galactose and sialic acid from multiple branches of complex type N-glycans. However, all patients showed normalization of the abnormal transferrin pattern with age without clinical improvement, suggesting that there is a limited diagnostic window for the relevant test.

Kodera et al. (2013) reported 3 unrelated Japanese girls with early-infantile epileptic encephalopathy. The girls developed severe, intractable seizures between 6 days and 3 months of age. EEG showed diffuse spike or sharp and slow-wave complexes as well as hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Each had severely delayed psychomotor development, with no head control in 2 and lack of speech in all. Brain imaging showed several anomalies, including cerebral and cerebellar atrophy, delayed myelination, and thin corpus callosum. The girls also had dysmorphic facial features, including coarse facies, thick eyebrows, broad nasal bridge, thick lips, semi-open mouth, and maxillary prognathism. There were no skin abnormalities or coagulation defects. Laboratory studies showed normal glycosylation patterns of serum proteins.

Molecular Genetics

In 3 unrelated patients with congenital disorder of glycosylation type II, Ng et al. (2013) identified 3 different de novo mutations in the SLC35A2 gene. Two boys carried a hemizygous mutation in the somatic mosaic state (314375.0001 and 314375.0002, respectively), whereas the girl carried a heterozygous mutation (314375.0003). Ng et al. (2013) hypothesized that retention of a functional SLC35A2 allele may be required for survival. Flow cytometry analysis of patient fibroblasts showed incomplete galactosylation, which leads to incomplete sialylation. Patient cells also showed reduced Golgi transport of UDP-galactose compared to controls. However, the presence of partially galactosylated glycans on serum glycoproteins suggested the possible existence of a previously unrecognized UDP-gal transporter.

In 3 unrelated Japanese girls with early infantile epileptic encephalopathy, Kodera et al. (2013) identified 3 different de novo heterozygous mutations in the SLC35A2 gene (314375.0004-314375.0006). The first 2 mutations were found by whole-exome sequencing; the third patient was 1 of a cohort of 328 patients with a similar disorder who underwent targeted SLC35A2 sequencing. Two of the mutations resulted in truncated proteins, suggesting a loss of function, and 1 was a missense mutation with no functional studies. X-chromosome inactivation studies in the patients with the truncating mutations showed a markedly skewed pattern, with expression only of the wildtype allele. Although none of the patients had evidence of abnormal glycosylation of serum proteins, Kodera et al. (2013) hypothesized that neurons may express the mutant allele and thus have defective galactosylation.