A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type IIn (CDG2N) is caused by homozygous or compound heterozygous mutation in the SLC39A8 gene (608732) on chromosome 4q24.

Congenital disorder of glycosylation type IIn (CDG2N) is an autosomal recessive severe multisystem developmental disorder characterized by delayed psychomotor development apparent from infancy, hypotonia, and variable additional features, such as short stature, seizures, visual impairment, and cerebellar atrophy. Serum transferrin analysis shows a CDG type II pattern (summary by Boycott et al., 2015 and Park et al., 2015).

For a discussion of genetic heterogeneity of CDG type II, see CDG2A (212066).

Boycott et al. (2015) reported 6 patients of Hutterite descent, including 2 patients from a large kindred from the Dariusleut group and 4 patients from 3 consanguineous families from the Schmiedeleut group, with a severe multisystem developmental disorder. The patients ranged in age from 6 to 23 years. They all had profound psychomotor retardation with delayed head control, severe hypotonia, inability to walk, variable ability to sit independently, and profound intellectual disability. Other features included strabismus, short stature, and recurrent infections; 2 patients had osteopenia, and 2 had seizures. Two sibs from a consanguineous Egyptian family had a similar phenotype, with severely delayed psychomotor development, hypotonia and hyperreflexia. Brain imaging in all patients showed cerebellar atrophy; 1 patient also had cortical atrophy. Laboratory studies showed decreased levels of manganese (Mn) and zinc (Zn) in blood, whereas urine levels tended to be high, indicating renal wasting. In addition, Park et al. (2015) found that 3 of the patients reported by Boycott et al. (2015) had abnormal transferrin glycosylation patterns, with decreased tetrasialo-transferrin and increased trisialo-, monosialo- and disialo-transferrin in a type II pattern.

Park et al. (2015) reported 2 unrelated females with CDG2N. The first patient, born of unrelated German parents, was noted to have short stature, short limbs, and cutaneous syndactyly of the feet at birth. She presented at age 4 months with disproportionate dwarfism, craniosynostosis, absence of visual fixation, strabismus, and hearing impairment. She had a flat face and low-set ears, and brain imaging showed cerebral atrophy and enlarged ventricles with a normal cerebellum. Severe refractory seizures, associated with hypsarrhythmia on EEG, occurred up to 5 times a day. A few months later, she had episodic apnea/hypopnea and liver disease, both of which resolved. Serum and urinary manganese concentrations were undetectable, and serum transferrin analysis showed a pattern consistent with a type II congenital disorder of glycosylation, with increased amounts of asialo-, monosialo-, disialo-, and trisialo-transferrin compared to controls. The patient was treated with dietary galactose, which resulted in a dramatic improvement in the transferrin glycosylation defect, although the clinical benefits were unclear. The second patient was a 19-year-old who had short stature and severely delayed global development apparent in the first year of life. She was hypotonic, confined to a wheelchair without the ability to sit or walk without support, and had very poor speech. She had seizures as a child that remitted. Other features included hyperopia, astigmatism, strabismus, nystagmus, mild elbow and knee contractures, and cerebellar atrophy. Laboratory studies showed undetectable manganese and a type II CDG pattern of serum transferrin.

The transmission pattern of CDG2N in the families reported by Boycott et al. (2015) and Park et al. (2015) was consistent with autosomal recessive inheritance.

In 6 patients of Hutterite descent and in 2 sibs, born of consanguineous Egyptian parents, with CDG2N, Boycott et al. (2015) identified the same homozygous missense mutation in the SLC39A8 gene (G38R; 608732.0001). The mutations, which were found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the families. Haplotype analysis did not suggest a founder effect between the Hutterite and Egyptian patients. Patient cells showed normal localization of the mutant protein, but blood levels of Zn and Mn were low and urine levels of these cations were high, suggesting renal wasting and consistent with the mutation causing a loss of transporter function. Functional studies of the variant were not performed.

In 2 unrelated patients with CDG2N, Park et al. (2015) identified compound heterozygous mutations in the SLC39A8 gene (608732.0001-608732.0004). The mutations in the first patient were found by whole-exome sequencing; mutations in the second patient were found by direct sequencing of the SLC39A8 gene in patients with unknown glycosylation defects. Functional studies of the variants were not performed, but the patients had no detectable serum or urinary manganese, consistent with a loss of transporter function. The findings linked a trace element deficiency to an inherited glycosylation disorder.

Galvez-Peralta et al. (2012) found that mice homozygous for a hypomorphic Slc39a8 allele had stunted growth, severe anemia, dysregulation of hematopoiesis, and failure of multiple organs, such as spleen, liver, kidney, and lung, to develop normally in utero, all of which ultimately resulted in neonatal lethality. Other features included malformed cranium, hypoplastic hind limbs, and underdeveloped eyes. The mutant mice had decreased zinc, iron, and manganese levels in multiple tissues. The findings indicated that Slc39a8 is indispensable for proper embryonic development, and highlighted the importance of zinc homeostasis during this period.