Diagnosing and Treating SLC13A5-Epilepsy Patients

The Challenge: Diagnosing Rare Disease SLC13A5-Epilepsy

Epilepsy is a neurological disorder caused by various factors, including brain injury and genetic predisposition. Early Infantile Epileptic Encephalopathies (EIEE) are a heterogeneous group of rare genetic diseases characterized by severe seizures that begin in the first year of life, along with developmental delays and other neurological disorders. One of the subtypes of EIEE is caused by mutations in the SLC13A5 gene. Although genome-wide sequencing can provide a definitive diagnosis in these cases, clinical sequencing is expensive and has a relatively long turnaround time. Early diagnosis of a SLC13A5-related disorder is critical for developing better treatments and improving prognosis. Metabolomics could provide a less expensive and more expeditious method to investigate potential diagnoses analogously to genome-wide sequencing.

Metabolon Insight: Elucidating Perturbations in the Metabolome of SLC13A5-Epilepsy Patients

This study utilized the Metabolon Global Discovery Panel to profile the CSF, plasma, and urine of five confirmed SLC13A5-epilepsy patients and compared relative values of metabolites to unaffected control samples (N = 80, 78, 76 for urine, plasma, and CSF, respectively).¹ The Metabolon Global Discovery Panel’s unrivaled coverage of over 5,400 semi-quantifiable metabolites offered this group the most comprehensive solution to characterize the metabolic changes due to SLC13A5 loss of function.

The Solution: Metabolomics Reveals Perturbed Metabolites in the Urine, Plasma, and CSF of SLC13A5-Epilepsy Patients

Metabolomics identified 893, 629, and 425 metabolites in the urine, plasma, and CSF, respectively. Analysis of urine, plasma, and CSF samples revealed 32 dysregulated metabolites in SLC13A5-epilepsy patients compared to controls. Most (25) of the perturbed metabolites were detected in the CSF. Metabolomics analysis also showed increased citrate levels in the CSF and the plasma of SLC13A5-epilepsy patients compared to controls. Citrate is produced by the tricarboxylic acid cycle (TCA), which is critical for brain function, not only for energy production but also as a supply of biosynthetic precursors for amino acids and neurotransmitters. Other TCA cycle-related metabolites were found to be perturbed in the urine (fumarate) and CSF (isocitrate, 2-methylcitrate & aconitate).

Analysis of patients’ CSF samples revealed consistent alterations in multiple metabolites associated with carbohydrate metabolism, lipid synthesis, and amino acid pathways. The most upregulated metabolite was 2-methylcitrate, having an approximate 4-fold increase in the relative amount in patient CSF compared to control. In contrast, 3-hydroxybutyrate (BHBA) was the most downregulated metabolite. In urine, fumarate was reduced in the subject samples compared to controls, demonstrating that disturbances of TCA cycle metabolites were detected in all three compartments.

The Outcome: Metabolomics May Provide Better Diagnosis and Treatment for SLC13A5-Epilepsy Patients

Metabolon helped this group elucidate alterations in the plasma, CSF, and urine of SLC13A5-epilepsy patients. The most significant finding was that citrate was highly elevated in the plasma and CSF of SLC13A5-epilepsy patients compared to controls. The perturbed metabolites revealed by this study could potentially be used as biomarkers to diagnose patients with SLC13A5-epilepsy. Diagnosing a SLC13A5-related disorder early is critical for focusing treatment, prognosis, and limiting unnecessary and redundant diagnostic tests. Identifying perturbations of metabolism is also crucial for the exploration of potential therapeutic approaches in the hopes of controlling seizures.