2. Academic Validation
  3. SLC13A3 variants cause acute reversible leukoencephalopathy and α-ketoglutarate accumulation

SLC13A3 variants cause acute reversible leukoencephalopathy and α-ketoglutarate accumulation

  • Ann Neurol. 2019 Mar;85(3):385-395. doi: 10.1002/ana.25412.
Joseph P Dewulf 1 2 3,  Elsa Wiame 1 2,  Imen Dorboz 4,  Monique Elmaleh-Bergès 5,  Apolline Imbard 6 7,  Dana Dumitriu 8,  Malgorzata Rak 4,  Agnès Bourillon 6 7,  Raphaël Helaers 9,  Alisha Malla 10,  Florence Renaldo 4 11 12,  Odile Boespflug-Tanguy 4 11 12,  Marie-Françoise Vincent 3,  Jean-François Benoist 6 7,  Ron A Wevers 13,  Avner Schlessinger 10,  Emile Van Schaftingen 1 2,  Marie-Cécile Nassogne 14,  Manuel Schiff 4 11 15
Affiliations

Affiliations

  • 1 Laboratory of Physiological Chemistry, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
  • 2 Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Brussels, Belgium.
  • 3 Department of Laboratory Medicine, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
  • 4 UMR1141, PROTECT, INSERM, Paris Diderot University, Sorbonne Paris Cité, Paris, France.
  • 5 Department of Pediatric Imaging, Robert Debré University Hospital, Public APHP, Paris, France.
  • 6 Laboratory of Biochemistry, Robert Debré University Hospital, APHP, France.
  • 7 Paris-Sud University, Châtenay-Malabry, France.
  • 8 Department of Pediatric Imaging, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
  • 9 Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
  • 10 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
  • 11 Department of Pediatric Neurology and Metabolic Diseases, Robert Debré University Hospital, APHP, Paris, France.
  • 12 Reference Center for Leukodystrophies and Rare Leukoencephalopathies, LEUKOFRANCE, Robert Debré University Hospital, APHP, Paris, France.
  • 13 Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 14 Pediatric Neurology Unit, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
  • 15 Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, APHP, Paris, France.
PMID: 30635937 DOI: 10.1002/ana.25412
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.

Figures