Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle

Abstract

Objective: To interrogate the metabolic profile of five subjects from three families with rare, nonsense and missense mutations in SLC13A5 and Early Infantile Epileptic Encephalopathies (EIEE) characterized by severe, neonatal onset seizures, psychomotor retardation and global developmental delay.

Methods: Mass spectrometry of plasma, CSF and urine was used to identify consistently dysregulated analytes in our subjects.

Results: Distinctive elevations of citrate and dysregulation of citric acid cycle intermediates, supporting the hypothesis that loss of SLC13A5 function alters tricarboxylic acid cycle (TCA) metabolism and may disrupt metabolic compartmentation in the brain.

Significance: Our results indicate that analysis of plasma citrate and other TCA analytes in SLC13A5 deficient patients define a diagnostic metabolic signature that can aid in diagnosing children with this disease.

Keywords: Metabolomics; SLC13A5; Seizure; Tricarboxylic acid cycle.

Conflict of interest statement

Conflicts of Interest

MNB is a founder of Codified Genomics LLC a variant interpretation company. The other authors declare no conflicts of interest.

Copyright © 2017 Elsevier Inc. All rights reserved.

Figures

Figure 1

Pedigree, disease and mutation status for three families, A, B and C. Hashing indicates disease/carrier status (full/half, respectively).

Figure 2. Citrate is elevated in plasma and CSF in SLC13A5 patients

Box and whisker plots of (A) CSF (n=3) (B) plasma (n=5) and (C) urine (n=4) citrate levels between controls and subjects.