SLC35A2-related congenital disorder of glycosylation: Defining the phenotype

Abstract

We aim to further delineate the phenotype associated with pathogenic variants in the SLC35A2 gene, and review all published literature to-date. This gene is located on the X chromosome and encodes a UDP-galactose transporter. Pathogenic variants in SLC35A2 cause a congenital disorder of glycosylation. The condition is rare, and less than twenty patients have been reported to-date. The phenotype is complex and has not been fully defined. Here, we present a series of five patients with de novo pathogenic variants in SLC35A2. The patients' phenotype includes developmental and epileptic encephalopathy with hypsarrhythmia, facial dysmorphism, severe intellectual disability, skeletal abnormalities, congenital cardiac disease and cortical visual impairment. Developmental and epileptic encephalopathy with hypsarrhythmia is present in most patients with SLC35A2 variants, and is drug-resistant in the majority of cases. Adrenocorticotropic hormone therapy may achieve partial or complete remission of seizures, but the effect is usually temporary. Isoelectric focusing of transferrins may be normal after infancy, therefore a congenital disorder of glycosylation should still be considered as a diagnosis in the presence of a suggestive phenotype. We also provide evidence that cortical visual impairment is part of the phenotypic spectrum.

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

“…For comparison, there are at least eight patients described previously as detailed case reports and six patients (including patients 5 and 8 in our cohort) from larger cohort studies, where patients were studied with WES for different purposes . Recently, the clinical data of seven new female patients was published . Interestingly, the majority of the reported patients are females, and this was also seen in our cohort.…”

“…All patients were females and had epileptic seizures. Recently, a new female patient with hypsarrhythmia and CVI was reported . It is difficult to say whether CVI is an independent symptom of SLC35A2‐CDG or secondary to epilepsy.…”

“…All patients had abnormal Tf profiles, which have normalized in at least two of them, and share delayed global development, hypotonia, and absence of seizures as common manifestations. Recently, female patients with c.262G>C (p.Ala88Pro) and c.923C>T (p.Ser308Phe) were reported . Still, in the context of the entire cohort, it is not possible to make phenotype‐genotype conclusions based on these patients.…”

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

“…The majority of previously reported SLC35A2‐CDG individuals, 27 of 32 (84%; Table S1), were identified by NGS with many of those affected individuals listed in the online supplemental data of large sequencing studies (Bosch et al, ; Bruneel et al, ; Dorre et al, ; Euro, Epilepsy Phenome/Genome, & Epi, ; Kimizu et al, ; Kodera et al, ; Lelieveld et al, ; Ng et al, ; Sim et al, ; Westenfield et al, ; Winawer et al, ; Yates et al, ). This explains why the number of reported subjects cited varies among studies.…”

“…To date, molecular and clinical information on 32 individuals with de novo variants in SLC35A2 have been reported with most exhibiting neurological symptoms, especially epilepsy, developmental delay, and intellectual disability (Bosch et al, ; Bruneel et al, ; Dorre et al, ; Euro, Epilepsy Phenome/Genome, & Epi, ; Kimizu et al, ; Kodera et al, ; Lelieveld et al, ; Ng et al, ; Sim et al, ; Westenfield et al, ; Winawer et al, ; Yates et al, ). Recently, WES analysis of brain specimens from 56 individuals identified five subjects harboring somatic de novo SLC35A2 variants (Winawer et al, ).…”