Laboratory of Physiological Chemistry, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Brussels, Belgium.
Ann Neurol. 2019 Mar;85(3):385-395. doi: 10.1002/ana.25412. Epub 2019 Jan 29.
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.
Whole exome sequencing (WES) was performed. Our teams were connected through GeneMatcher.
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.
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.
SLC13A3 编码的是质膜 Na+/二羧酸共转运蛋白 3，它将细胞内 4 到 6 个碳二羧酸和 N-乙酰天冬氨酸（NAA）摄入细胞内。SLC13A3 主要在肾脏、星形胶质细胞和脉络丛中表达。我们描述了两名无关联的患者，他们在发热性疾病期间出现急性、可逆（且在其中一名患者中复发）的神经功能恶化。两名患者均表现出可逆性脑白质病和尿液中 α-酮戊二酸（αKG）排泄显著增加并持续时间较长。在一名患者中，观察到脑脊液 NAA 和二羧酸（包括 αKG）浓度增加。广泛的检查均未成功，怀疑存在遗传原因。
进行全外显子组测序（WES）。我们的团队通过 GeneMatcher 建立了联系。
WES 分析显示 SLC13A3 存在变异。在第一名患者中发现了一个纯合错义突变（p.Ala254Asp）。第二名患者为另一个错义突变（p.Gly548Ser）和影响剪接的内含子突变的杂合子，这通过在肌肉组织中进行逆转录酶聚合酶链反应（c.1016 + 3A > G）证实。突变和分离通过 Sanger 测序得到确认。在瞬时转染野生型和突变 SLC13A3 的 HEK293T 细胞中进行的功能研究表明，这些错义突变导致 αKG、琥珀酸和 NAA 的转运能力显著降低。
SLC13A3 缺乏导致急性和可逆性脑白质病，伴有明显的 αKG 积累。对于不明原因的可逆性脑白质病，应筛选尿液有机酸（尤其是 αKG 和 NAA）和 SLC13A3 突变，SLC13A3 缺乏是一种新的鉴别诊断。ANN NEUROL 2019;85:385-395.
