SLC13A3 variants cause acute reversible leukoencephalopathy and αKG accumulation

Abstract

Objective

SLC13A3 encodes the plasma membrane Na⁺/Dicarboxylate Cotransporter 3 (NaDC3), which imports inside the cell four to six carbon dicarboxylates as well as N‐acetylaspartate (NAA). SLC13A3 is mainly expressed in kidney, in astrocytes and in the choroid plexus. We describe two unrelated patients presenting with acute, reversible (and recurrent in one) neurological deterioration during a febrile illness. Both patients exhibited a reversible leukoencephalopathy and a markedly increased and persisting over time urinary excretion of α‐ketoglutarate (αKG). In one patient, increased cerebrospinal fluid NAA and dicarboxylates (including αKG) concentrations were observed. Extensive workup was unsuccessful and a genetic cause was suspected.

Methods

Whole exome sequencing (WES) was performed. Our teams were connected through GeneMatcher.

Results

WES analysis revealed variants in SLC13A3. A homozygous missense mutation (p.Ala254Asp) was found in the first patient. The second patient was heterozygous for another missense mutation (p.Gly548Ser) and an intronic mutation affecting splicing as demonstrated by RT‐PCR performed in muscle tissue (c.1016+3A>G). Mutations and segregation were confirmed by Sanger sequencing. Functional studies performed on HEK293T cells transiently transfected with wild type and mutant SLC13A3 indicated that the missense mutations caused a marked reduction in the capacity to transport αKG, succinate and NAA.

Interpretation

SLC13A3 deficiency causes acute and reversible leukoencephalopathy with marked accumulation of αKG. Urine organic acids (especially αKG and NAA) and SLC13A3 mutations should be screened in patients presenting with unexplained reversible leukoencephalopathy for which SLC13A3 deficiency is a novel differential diagnosis.

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