Clinical, neuroradiological, and biochemical features of SLC35A2‐CDG patients

Abstract

SLC35A2-CDG is caused by mutations in the X-linked SLC35A2 gene encoding the UDP-galactose transporter. SLC35A2 mutations lead to hypogalactosylation of Nglycans. SLC35A2-CDG is characterized by severe neurological symptoms and, in many patients, early-onset epileptic encephalopathy. In view of the diagnostic challenges, we studied the clinical, neuroradiological, and biochemical features of 15 patients (11 females and 4 males) with SLC35A2-CDG from various centers. We describe nine novel pathogenic variations in SLC35A2. All affected individuals presented with a global developmental delay, and hypotonia, while 70% were nonambulatory. Epilepsy was present in 80% of the patients, and in EEG hypsarrhythmia and findings consistent with epileptic encephalopathy were frequently seen. The most common brain MRI abnormality was cerebral atrophy with delayed myelination and multifocal inhomogeneous abnormal patchy white matter hyperintensities, which seemed to be nonprogressive. Thin corpus callosum was also common, and all the patients had a corpus callosum shorter than normal for their age. Variable dysmorphic features and growth deficiency were noted. Biochemically, normal mucin type O-glycosylation and lipid glycosylation were found, while transferrin mass spectrometry was found to be more specific in the identification of SLC35A2-CDG, as compared to routine screening tests. Although normal glycosylation studies together with clinical variability and genetic results complicate the diagnosis of SLC35A2-CDG, our data indicate that the combination of these three elements can support the pathogenicity of mutations in SLC35A2. K E Y W O R D SCDG, congenital glycosylation disorders, epileptic encephalopathy, infantile spasms, SLC35A2

SLC35A2‐CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals

“…CDG‐0248 carried a novel missense variant c.818 G > A (p.Gly273Asp) that was absent from the mother, but the father was unavailable for testing. However, in a recent separate study on SLC35A2‐CDG, an unrelated affected individual was identified carrying the same c.818 G > A (p.Gly273Asp) as a de novo variant showing a slightly abnormal CDT (Vals et al, ; doi: https://doi.org/10.1002/jimd.12055) Two individuals from this paper (CDG‐0389, CDG‐0469) and the paper from Vals et al () are shared.…”

What does a defect in N-glycosylation mean for neuronal migration and function?

“…In a recent case series, Vals et al failed to see a correlation between the phenotype severity and the estimated quantity of pathogenic SLC35A2 variants. 5 Of interest in the current study, variant proportions did not correlate with the messenger RNA expression of the alternative allele, suggesting the possibility of a nonsense-mediated decay. Because the UGT protein was not assessed, relationship among the varied proportions of the alternative allele to UGT quantities or function remain unclear.…”

“…N-glycosylation defects linked to pathogenic variants in the Solute Carrier Family 35 Member A2 gene (SLC35A2) have emerged as causal to an X-linked early onset epileptic encephalopathy typically manifested with infantile spasms or West syndrome in women or in mosaic men and most recently, they were also identified in approximately 30% of NAFE because of FCD type 1. 5,6 SLC35A2 encodes a uridine diphosphate galactose transporter (UGT). A defect in the UGT results in a reduced galactosylation of N-glycosylated proteins, glycosphingolipids, and proteoglycans, which affects neuronal migration, axon guidance, and synaptic physiology.…”

Dissecting Total Plasma and Protein-Specific Glycosylation Profiles in Congenital Disorders of Glycosylation

“…Hypogalactosylation of transferrin is a reported marker of the genetic galactosylation deficiencies SLC35A2-CDG and B4GALT1-CDG [ 26 , 48 ], although SLC35A2-CDG has been reported to result in hypogalactosylation of transferrin N -glycans in only about half of the patients [ 49 , 50 ]. Here, we likewise observed reduced galactosylation for total plasma proteins and IgG connected to these diseases.…”