The emerging role of citrate as a diagnostic biomarker in SLC13A5-developmental and epileptic encephalopathy

SLC13A5-developmental and epileptic encephalopathy (SLC13A5-DEE) is a rare autosomal recessive disorder characterized by neonatal-onset seizures, global developmental delay, and amelogenesis imperfecta. Diagnosis can be particularly challenging when genetic testing identifies variants of uncertain significance (VUS). To highlight the diagnostic value of citrate quantification in confirming SLC13A5-DEE. We report a female infant, born to consanguineous parents, who presented with refractory seizures at 14 hours of life. Partial seizure control was initially achieved with oxcarbazepine and lacosamide; however, complete seizure control occurred after the introduction of valproic acid. Brain MRI demonstrated punctate white matter abnormalities. Genetic testing identified a homozygous missense variant in SLC13A5 (c.1268G>A, p.Gly423Glu), classified as a VUS. Subsequently, biochemical analysis showed markedly elevated plasma citrate levels (820 μmol/L; control values: 19-83), and increased urinary citrate excretion (5615 mmol/mol creatinine; control values: 162-2200), consistent with plasmatic membrane Na⁺-coupled citrate transporter dysfunction. The abnormally increased citrate levels supported the reclassification of the variant as likely pathogenic according to ACMG criteria (PP4). At 8 months of age, the patient remained seizure-free but exhibited mild developmental delay. This case underscores the diagnostic value of plasma and urinary citrate quantification as reliable and accessible biomarkers in the diagnostic workup of SLC13A5-DEE. Furthermore, early treatment with valproic acid may improve seizure control and potentially improve developmental outcomes.