SLC13A3 variants cause acute reversible leukoencephalopathy and α-ketoglutarate accumulation.

Abstract

OBJECTIVE:

SLC13A3 encodes the plasma membrane Na+ /dicarboxylate cotransporter 3, which imports inside the cell 4 to 6 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 urinary excretion of α-ketoglutarate (αKG) that was markedly increased and persisted over time. In one patient, increased concentrations of cerebrospinal fluid NAA and dicarboxylates (including αKG) 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 reverse transcriptase polymerase chain reaction 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. ANN NEUROL 2019;85:385-395.

• Authors: Joseph P Dewulf, Elsa Wiame, Imen Dorboz, Monique Elmaleh-Bergès, Apolline Imbard, Dana Dumitriu, Malgorzata Rak, Agnès Bourillon, Raphaël Helaers, Alisha Malla, Florence Renaldo, Odile Boespflug-Tanguy, Marie-Françoise Vincent, Jean-François Benoist, Ron A Wevers, Avner Schlessinger, Emile Van Schaftingen, Marie-Cécile Nassogne, Manuel Schiff
• Journal: Annals of neurology (Ann Neurol) Vol. 85 Issue 3 Pg. 385-395 (03 2019) ISSN: 1531-8249 [Electronic] United States
• PMID: 30635937 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 American Neurological Association.

Chemical References

• Ketoglutaric Acids
• SLC13A3 protein, human
• Symporters
• Aspartic Acid
• N-acetylaspartate
• Succinic Acid

Topics

• Adolescent
• Aspartic Acid (analogs & derivatives, cerebrospinal fluid, metabolism)
• Child, Preschool
• Female
• HEK293 Cells
• Humans
• Ketoglutaric Acids (cerebrospinal fluid, metabolism, urine)
• Leukoencephalopathies (genetics, metabolism)
• Magnetic Resonance Imaging
• Magnetic Resonance Spectroscopy
• Male
• Mutation, Missense
• Pedigree
• Respiratory Tract Infections
• Succinic Acid (metabolism)
• Symporters (genetics, metabolism)
• Tonsillitis
• Exome Sequencing