Prevalence of Congenital Disorders of Glycosylation in Childhood Epilepsy and Effects of Anti-Epileptic Drugs on the Transferrin Isoelectric Focusing Test

Silver, Grace; Bahl, Shalini; Cordeiro, Dawn; Thakral, Abhinav; Athey, Taryn; Mercimek‐Andrews, Saadet

doi:10.3390/genes12081227

Cited by 5 publications

(3 citation statements)

References 25 publications

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“…Abnormal N -linked glycosylation causes the majority of CDGs and the disease is divided into two main subtypes: CDG-I where the assembly of lipid-linked oligosaccharides or their transfer to newly synthesised proteins is altered; and CDG-II which is characterised by defects in the processing of the protein-attached oligosaccharides 9 . CDG patients are diagnosed as having a significant neurological component, often presented as developmental delay, and abnormal glycosylation of serum transferrin 10 , 11 . Next-generation sequencing is an important tool for identifying potential CDG variants at the genomic level 12 , 13 , but discriminating pathogenic from non-pathogenic variants is challenging and requires systematic testing in relevant models.…”

Section: Introductionmentioning

confidence: 99%

Functional classification of DDOST variants of uncertain clinical significance in congenital disorders of glycosylation

Kas,

Mundra,

Smith

et al. 2023

Sci Rep

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Congenital disorders of glycosylation (CDG) are rare genetic disorders with a spectrum of clinical manifestations caused by abnormal N-glycosylation of secreted and cell surface proteins. Over 130 genes are implicated and next generation sequencing further identifies potential disease drivers in affected individuals. However, functional testing of these variants is challenging, making it difficult to distinguish pathogenic from non-pathogenic events. Using proximity labelling, we identified OST48 as a protein that transiently interacts with lysyl oxidase (LOX), a secreted enzyme that cross-links the fibrous extracellular matrix. OST48 is a non-catalytic component of the oligosaccharyltransferase (OST) complex, which transfers glycans to substrate proteins. OST48 is encoded by DDOST, and 43 variants of DDOST are described in CDG patients, of which 34 are classified as variants of uncertain clinical significance (VUS). We developed an assay based on LOX N-glycosylation that confirmed two previously characterised DDOST variants as pathogenic. Notably, 39 of the 41 remaining variants did not have impaired activity, but we demonstrated that p.S243F and p.E286del were functionally impaired, consistent with a role in driving CDG in those patients. Thus, we describe a rapid assay for functional testing of clinically relevant CDG variants to complement genome sequencing and support clinical diagnosis of affected individuals.

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Section: Introductionmentioning

confidence: 99%

Functional classification of DDOST variants of uncertain clinical significance in congenital disorders of glycosylation

Kas,

Mundra,

Smith

et al. 2023

Sci Rep

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“…A 29-month-old female presented with global developmental delay, hypotonia, and a history of poor weight gain, and a 14-year-old Hispanic male patient with a history of myoclonic epilepsy, global developmental delay, hypertonia, and microcephaly [Haanpaa et al, 2019]. Multidrug resistance, generalized tonic-clonic epilepsy, dystonia, global developmental delay, and microcephaly were the clinical findings of 2 patients [Silver et al, 2021]. In the carbohydrate-deficient transferrin analysis, increased di-and asialo-transferrin and decreased tetrasialotransferrin can be detected.…”

Section: Discussionmentioning

confidence: 99%

Autism Spectrum Disorder in Two Unrelated Patients with Homozygous Variants in Either ALG8 or ALG11

et al. 2023

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Background: Autism spectrum disorder (ASD) is used to describe individuals with a specific combination of disorders in social communication and repetitive behaviors, highly restricted interests, and/or sensory behavior that begin early in life. The prevalence of ASD has been increasing rapidly in recent years. Pathophysiology of ASDs remains still unclear; however, genetic defects and multifactorial causes have been reported to play an important role in genetic disorders. The prevalence of inborn errors of metabolism (IEM) reported among patients with ASD is 2–5%. The clinical presentation of congenital disorders of glycosylation (CDG) may be in the form of psychiatric disorder only. Case Study: Case 1: a 5-year-old female patient was admitted for investigation of ASD. She had a dysmorphic facial appearance, inverted nipples, abnormal fat distribution, ataxic gait, and autistic features. Her transferrin isoelectric focusing test was compatible with a type 1 CDG pattern. A homozygous variant in ALG8 gene revealed the diagnosis of ALG8-CDG (CDG Type 1H). Case 2: a 2-year-old male patient was admitted with complaints of ASD for investigation of an underlying IEM due to speech delay. Physical examination revealed hypertelorism, small hands, and autistic behavior. Transferrin isoelectric focusing test was also found normal. As a result of the WES, a homozygous variant was detected in ALG11 confirming the diagnosis of CDG type 1p. Conclusion: CDG should also be considered in the differential diagnosis of autistic patients with dysmorphic findings. The aim of our study was to emphasize that autism should be listed among the neurological findings of CDG.

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“…Congenital disorders of glycosylation (CDGs) are a large and heterogenous group of rare genetic metabolic diseases caused by defects in glycan synthesis and/or modification pathways [ 20 ]. To date, more than 130 CDG subtypes have been characterized.…”

Section: Introductionmentioning

confidence: 99%

SLC35A2 Deficiency Promotes an Epithelial-to-Mesenchymal Transition-like Phenotype in Madin–Darby Canine Kidney Cells

Kot

Mazurkiewicz

Wiktor

et al. 2022

Cells

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In mammalian cells, SLC35A2 delivers UDP–galactose for galactosylation reactions that take place predominantly in the Golgi lumen. Mutations in the corresponding gene cause a subtype of a congenital disorder of glycosylation (SLC35A2-CDG). Although more and more patients are diagnosed with SLC35A2-CDG, the link between defective galactosylation and disease symptoms is not fully understood. According to a number of reports, impaired glycosylation may trigger the process of epithelial-to-mesenchymal transition (EMT). We therefore examined whether the loss of SLC35A2 activity would promote EMT in a non-malignant epithelial cell line. For this purpose, we knocked out the SLC35A2 gene in Madin–Darby canine kidney (MDCK) cells. The resulting clones adopted an elongated, spindle-shaped morphology and showed impaired cell–cell adhesion. Using qPCR and western blotting, we revealed down-regulation of E-cadherin in the knockouts, while the fibronectin and vimentin levels were elevated. Moreover, the knockout cells displayed reorganization of vimentin intermediate filaments and altered subcellular distribution of a vimentin-binding protein, formiminotransferase cyclodeaminase (FTCD). Furthermore, depletion of SLC35A2 triggered Golgi compaction. Finally, the SLC35A2 knockouts displayed increased motility and invasiveness. In conclusion, SLC35A2-deficient MDCK cells showed several hallmarks of EMT. Our findings point to a novel role for SLC35A2 as a gatekeeper of the epithelial phenotype.

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Prevalence of Congenital Disorders of Glycosylation in Childhood Epilepsy and Effects of Anti-Epileptic Drugs on the Transferrin Isoelectric Focusing Test

Cited by 5 publications

References 25 publications

Functional classification of DDOST variants of uncertain clinical significance in congenital disorders of glycosylation

Functional classification of DDOST variants of uncertain clinical significance in congenital disorders of glycosylation

Autism Spectrum Disorder in Two Unrelated Patients with Homozygous Variants in Either ALG8 or ALG11

SLC35A2 Deficiency Promotes an Epithelial-to-Mesenchymal Transition-like Phenotype in Madin–Darby Canine Kidney Cells

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