SLC13A5 and Developmental and Epileptic Encephalopathy 25

Biallelic variants in SLC13A5 cause an autosomal recessive syndrome known as Developmental and Epileptic Encephalopathy 25, characterized by neonatal-onset refractory seizures, spastic quadriplegia, global developmental delay, intellectual disability, microcephaly, and amelogenesis imperfecta. The disorder typically presents with intractable seizures in the first days of life, evolving into severe motor and cognitive impairment and characteristic tooth enamel defects. Early recognition of this phenotype is critical for genetic testing and management of epilepsy.

Multiple case series have established the genetic basis. In one cohort of nine patients from six consanguineous families, biallelic SLC13A5 variants resulted in early neonatal seizures, developmental delay, and dental anomalies (PMID:27261973). A recent analysis of four additional families encompassing four patients from diverse ancestries reported novel homozygous missense and large-scale deletions with similar phenotypes (PMID:38113697). Altogether, these studies encompass 13 probands (PMID:27261973; PMID:38113697).

The inheritance is strictly autosomal recessive. Segregation analyses confirmed co-segregation of biallelic variants with disease in all pedigrees. The allele spectrum comprises splice-site mutations (e.g., c.1437+5G>A), missense substitutions (e.g., c.680C>T (p.Thr227Met)), frameshifts, and structural alterations, reflecting diverse molecular mechanisms. The recurrent splice-site variant c.1437+5G>A has been observed in multiple families, suggesting a potential population-specific allele.

Functional assays in heterologous systems consistently demonstrate loss of transporter activity. Transient expression of mutant NaCT proteins in COS-7 and HEK293 cells revealed absent citrate uptake for missense variants and splice mutants, despite variable effects on membrane localization and protein expression (PMID:27261973; PMID:30054523). Structural homology models based on bacterial transporters have rationalized the impact of mutations on helix packing and substrate binding, reinforcing a loss-of-function mechanism.

Animal studies corroborate the pathogenic mechanism. Slc13a5-knockout mice exhibit heightened hippocampal neuronal excitability, increased seizure propensity, and altered brain citrate concentrations, mirroring the human electrographic and metabolic phenotype (PMID:32682952). Comparative homology modeling delineated species-specific functional differences of human versus mouse NaCT (PMID:33040525). A deep mutational scanning covering ~90% of missense variants provided an unbiased landscape of structure–function relationships and mechanistic insights to guide precision therapeutics (PMID:40577459).

Beyond neurological manifestations, a cohort of 15 patients underwent evaluation for non-neurologic health. These individuals exhibited moderate gastrointestinal complications (feeding difficulties, reflux, vomiting) and varied respiratory complaints, with growth parameters mostly within normal limits in early childhood but a trend toward slower adolescent growth (PMID:34822404). Dental enamel defects consistent with amelogenesis imperfecta were universally reported.

Together, the robust genetic and experimental data substantiate a strong gene–disease relationship for SLC13A5 in autosomal recessive developmental and epileptic encephalopathy 25. The combination of multiple pedigrees, full segregation, diverse pathogenic variants, concordant in vitro and in vivo functional studies, and detailed phenotypic profiling across organ systems provides a solid foundation for clinical diagnostic application, variant interpretation, and future therapeutic development. Key Take-home: Biallelic loss-of-function mutations in SLC13A5 cause a clinically recognizable syndrome of neonatal epilepsy, severe neurodevelopmental impairment, and amelogenesis imperfecta, with extensive functional validation supporting pathogenicity.

References

• Molecular medicine (Cambridge, Mass.) • 2016 • Mutations in the Na(+)/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. PMID:27261973
• Scientific reports • 2018 • Analysis of naturally occurring mutations in the human uptake transporter NaCT important for bone and brain development and energy metabolism. PMID:30054523
• Neurobiology of disease • 2020 • Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus. PMID:32682952
• Chemical reviews • 2021 • Functional Distinction between Human and Mouse Sodium-Coupled Citrate Transporters and Its Biologic Significance: An Attempt for Structural Basis Using a Homology Modeling Approach. PMID:33040525
• Metabolites • 2021 • Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder. PMID:34822404
• Pediatric neurology • 2024 • Novel Homozygous Variants of SLC13A5 Expand the Functional Heterogeneity of a Homogeneous Syndrome of Early Infantile Epileptic Encephalopathy. PMID:38113697
• Science advances • 2025 • Large-scale experimental assessment of variant effects on the structure and function of the citrate transporter SLC13A5. PMID:40577459

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