Identification of human D lactate dehydrogenase deficiency

Glen R Monroe, Albertien M van Eerde, Federico Tessadori, Karen J Duran, Sanne M C Savelberg, Johanna C van Alfen, Paulien A Terhal, Saskia N van der Crabben, Klaske D Lichtenbelt, Sabine A Fuchs, Johan Gerrits, Markus J van Roosmalen, Koen L van Gassen, Mirjam van Aalderen, Bart G Koot, Marlies Oostendorp, Marinus Duran, Gepke Visser, Tom J de Koning, Francesco CalìPaolo Bosco, Karin Geleijns, Monique G M de Sain-van der Velden, Nine V Knoers, Jeroen Bakkers, Nanda M Verhoeven-Duif, Gijs van Haaften, Judith J Jans

Research output: Contribution to journal/periodicalArticleScientificpeer-review

48 Citations (Scopus)


Phenotypic and biochemical categorization of humans with detrimental variants can provide valuable information on gene function. We illustrate this with the identification of two different homozygous variants resulting in enzymatic loss-of-function in LDHD, encoding lactate dehydrogenase D, in two unrelated patients with elevated D-lactate urinary excretion and plasma concentrations. We establish the role of LDHD by demonstrating that LDHD loss-of-function in zebrafish results in increased concentrations of D-lactate. D-lactate levels are rescued by wildtype LDHD but not by patients' variant LDHD, confirming these variants' loss-of-function effect. This work provides the first in vivo evidence that LDHD is responsible for human D-lactate metabolism. This broadens the differential diagnosis of D-lactic acidosis, an increasingly recognized complication of short bowel syndrome with unpredictable onset and severity. With the expanding incidence of intestinal resection for disease or obesity, the elucidation of this metabolic pathway may have relevance for those patients with D-lactic acidosis.

Original languageEnglish
Pages (from-to)1477
JournalNature Communications
Issue number1
Publication statusPublished - 01 Apr 2019


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