The First Metabolome Analysis in Children with Epilepsy and ALG13-CDG Resulting from c.320A>G Variant.

Justyna Paprocka,Łukasz Boguszewicz,Aleksandra Jezela-Stanek,Maria Sokół,Ewa Jamroz,Anna Tylki-Szymańska,Patryk Lipiński,Ewa Emich-Widera

doi:10.3390/children8030251

Abstract

Background: ALG13-CDG belongs to the congenital disorders of glycosylation (CDG), which is an expanding group of multisystemic metabolic disorders caused by the N-linked, O-linked oligosaccharides, shared substrates, glycophosphatidylinositol (GPI) anchors, and dolichols pathways with high genetic heterogeneity. Thus, as far as clinical presentation, laboratory findings, and treatment are concerned, many questions are to be answered. Three individuals presented here may serve as a good example of clinical heterogeneity. This manuscript describes the first metabolomic analysis using NMR in three patients with epileptic encephalopathy due to the recurrent c.320A>G variant in ALG13, characterized to date only in about 60 individuals (mostly female). This is an important preliminary step in the understanding of the pathogenesis of the disease associated with this variant in the rare genetic condition. The disease is assumed to be a disorder of N-glycosylation given that this is the only known function of the ALG13 protein. Despite this, protein electrophoresis, which is abnormal in most conditions due to abnormalities in N-glycosylation, has been normal or only mildly abnormal in the ALG13 patients. Methods: Nuclear magnetic resonance (NMR) spectroscopy in conjunction with multivariate and univariate modelling were used to analyze the metabolic profile of the blood serum samples acquired from the studied patients. Results: Three metabolites were identified as potential biomarkers: betaine, N-acetyl-glycoprotein, and carnitine. Conclusions: Since presented data are the first to be collected so far, they need be verified in further studies. Our intention was to turn attention toward possible CDG-ALG13 laboratory markers that would have clinical significance.

Highlights

Glycosylation is the most common post-translational modification of proteins and lipids, and its biological role is crucial in the processes of development, growth, and functioning of the body
This paper describes the first metabolomic analysis using proton high resolution nuclear magnetic resonance (1H HR Nuclear magnetic resonance (NMR)) spectroscopy in three patients with epileptic encephalopathy due to the recurrent c.320A>G variant in ALG13
The results present the orthogonal partial least-squares discriminant analysis (OPLS-DA) model calculated on the quantified metabolites, which drastically reduced the number of the variables and, at least to a small extent, reduced the risk of overfitting

Summary

Introduction

Glycosylation is the most common post-translational modification of proteins and lipids, and its biological role is crucial in the processes of development, growth, and functioning of the body. The highest diagnostic yield for CDG is broadened genetic testing using next-generation-based methodology, especially whole-exome sequencing (WES) or clinical exome sequencing (CES) They allow for diagnosis and definition of the CDG type, including ALG13 type. Three individuals presented here may serve as a good example of clinical heterogeneity This manuscript describes the first metabolomic analysis using NMR in three patients with epileptic encephalopathy due to the recurrent c.320A>G variant in ALG13, characterized to date only in about 60 individuals (mostly female). This is an important preliminary step in the understanding of the pathogenesis of the disease associated with this variant in the rare genetic condition. Our intention was to turn attention toward possible CDG-ALG13 laboratory markers that would have clinical significance

Methods

Results

Discussion

Conclusion