SLC13A3 and Acute Reversible Leukoencephalopathy with α-Ketoglutarate Accumulation

SLC13A3 encodes the Na⁺/dicarboxylate cotransporter 3 (NaDC3), a plasma membrane transporter highly expressed in kidney, astrocytes, and the choroid plexus. NaDC3 mediates uptake of four- to six-carbon dicarboxylates and N-acetylaspartate into the cytosol. Biallelic pathogenic variants in SLC13A3 cause an autosomal recessive acute reversible leukoencephalopathy with increased urinary excretion of α-ketoglutarate (leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate). Clinically, patients present with febrile-triggered episodes of neurological deterioration, reversible white matter changes on MRI, and persistent α-ketoglutarateuria.

Initial genetic evidence came from two unrelated patients with ARLIAK: one homozygous missense variant p.Ala254Asp and a second compound heterozygote for p.Gly548Ser and the splice variant c.1016+3A>G demonstrated by reverse transcriptase PCR (2 probands) (PMID:30635937). A subsequent Chinese case reported compound heterozygous c.331C>T (p.Arg111Ter) and c.185C>T (p.Thr62Met) in a 13-year-old girl with reversible leukoencephalopathy and α-ketoglutarateuria (1 proband) (PMID:34966709). A 2023 series added four more patients, expanding the allelic and phenotypic spectrum (4 probands) (PMID:38235040).

The variant spectrum includes missense changes (p.Thr62Met, p.Ala254Asp, p.Gly548Ser), a nonsense mutation (p.Arg111Ter), and a splice-site alteration (c.1016+3A>G). All variants are absent or extremely rare in population databases. No recurrent or founder alleles have been identified to date.

Segregation analysis in multiple families confirmed phasing of compound heterozygous and homozygous variants; parents are heterozygous carriers and clinically unaffected. No additional affected relatives beyond the described probands were reported.

Functional assays in HEK293T cells transiently expressing mutant NaDC3 demonstrated a marked reduction in uptake of α-ketoglutarate, succinate, and N-acetylaspartate, consistent with a loss-of-function mechanism (PMID:30635937). These results align with the clinical phenotype of reversible leukoencephalopathy and α-ketoglutarate accumulation.

Together, seven probands from five unrelated families, confirmed segregation, and concordant functional data support a Strong clinical validity for the SLC13A3–ARLIAK association. Genetic testing for SLC13A3 should be included in diagnostic panels for unexplained reversible leukoencephalopathy with α-ketoglutarateuria. Key Take-home: Biallelic SLC13A3 variants underlie an autosomal recessive, reversible leukoencephalopathy with α-ketoglutarate accumulation and have clear diagnostic utility.

References

• Annals of Neurology • 2019 • SLC13A3 variants cause acute reversible leukoencephalopathy and α-ketoglutarate accumulation PMID:30635937
• Frontiers in Pediatrics • 2021 • Case Report: Compound Heterozygous Variants of SLC13A3 Identified in a Chinese Patient With Acute Reversible Leukoencephalopathy and α-Ketoglutarate Accumulation PMID:34966709
• Neurology: Genetics • 2023 • Novel SLC13A3 Variants and Cases of Acute Reversible Leukoencephalopathy and α-Ketoglutarate Accumulation and Literature Review PMID:38235040

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