A new case of UDP‐galactose transporter deficiency (SLC35A2‐CDG): molecular basis, clinical phenotype, and therapeutic approach

Abstract

Congenital disorders of glycosylation (CDG) are a group of hereditary metabolic diseases characterized by abnormal glycosylation of proteins and lipids. Often, multisystem disorders with central nervous system involvement and a large variety of clinical symptoms occur. The main characteristics are developmental delay, seizures, and ataxia. In this paper we report the clinical and biochemical characteristics of a 5-year-old girl with a defective galactosylation of N-glycans, resulting in developmental delay, muscular hypotonia, epileptic seizures, inverted nipples, and visual impairment. Next generation sequencing revealed a de novo mutation (c.797G > T, p.G266V) in the X-chromosomal gene SLC35A2 (solute carrier family 35, UDP-galactose transporter, member A2; MIM 300896). While this mutation was found heterozygous, random X-inactivation of the normal allele will lead to loss of normal SLC35A2 activity in respective cells. The functional relevance of the mutation was demonstrated by complementation of UGT-deficient MDCK-RCA(r) and CHO-Lec8 cells by normal UGT-expression construct but not by the mutant version. The effect of dietary galactose supplementation on glycosylation was investigated, showing a nearly complete normalization of transferrin glycosylation.

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy

“…Based on these findings, SLC35A2 was included as a cause of type IIm congenital disorders of glycosylation, multisystem disorders associated with seizures. Subsequently, germline heterozygous putative loss‐of‐function de novo variants, including missense, nonsense, and frameshift indels, in SLC35A2 have been identified in multiple girls with epileptic encephalopathy (see Fig ) . The lack of males with germline variants in this gene likewise supports the assertion that an intact allele, in at least some tissues of the body, is required for survival.…”

UDP-galactose and acetyl-CoA transporters as Plasmodium multidrug resistance genes

“…In humans, mutations in SLC35A2 cause a congenital disorder of glycosylation 35 . Although further work is required to understand the native function of PfUGT in Plasmodium , the ER localization is consistent with a function in transporting UDP-galactose from the cytosol into the ER where it may play a role in post-translational modification of proteins 14,36,37 .…”

Novel genetic causes for cerebral visual impairment

“…28,32,33 Variants in SLC35A2 lead to CDG type 2m, featured by ID, epilepsy, facial dysmorphisms, and transient abnormalities in transferin testing. [34][35][36] In the seven reported patients with CDG type 2m, CVI has not been mentioned, but other features, including the facial dysmorphism, epilepsy and severe ID were present in patient 6. The third glycosylation gene in which a variant was identified, PGAP1 (patient 12, reported elsewhere), is important in the GPI-anchor synthesis pathway.…”