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 Calì, Paolo Bosco, Karin Geleijns, Monique G. M. de Sain-van der Velden, Nine V. Knoers, Jeroen Bakkers, Nanda M. Verhoeven-Duif, Gijs van Haaften () and Judith J. Jans
Additional contact information
Glen R. Monroe: University Medical Center Utrecht
Albertien M. van Eerde: University Medical Center Utrecht
Federico Tessadori: University Medical Center Utrecht
Karen J. Duran: University Medical Center Utrecht
Sanne M. C. Savelberg: University Medical Center Utrecht
Johanna C. van Alfen: Bartiméus, Institute for the Visually Impaired
Paulien A. Terhal: University Medical Center Utrecht
Saskia N. van der Crabben: University Medical Center Utrecht
Klaske D. Lichtenbelt: University Medical Center Utrecht
Sabine A. Fuchs: University Medical Center Utrecht
Johan Gerrits: University Medical Center Utrecht
Markus J. van Roosmalen: University Medical Center Utrecht
Koen L. van Gassen: University Medical Center Utrecht
Mirjam van Aalderen: University Medical Center Utrecht
Bart G. Koot: Academic Medical Center
Marlies Oostendorp: University Medical Center Utrecht
Marinus Duran: Academic Medical Center
Gepke Visser: University Medical Center Utrecht
Tom J. de Koning: University Medical Center Groningen
Francesco Calì: Oasi Research Institute—IRCCS
Paolo Bosco: Oasi Research Institute—IRCCS
Karin Geleijns: University Medical Center Utrecht
Monique G. M. de Sain-van der Velden: University Medical Center Utrecht
Nine V. Knoers: University Medical Center Utrecht
Jeroen Bakkers: Hubrecht Institute-KNAW and University Medical Center Utrecht
Nanda M. Verhoeven-Duif: University Medical Center Utrecht
Gijs van Haaften: University Medical Center Utrecht
Judith J. Jans: University Medical Center Utrecht

Nature Communications, 2019, vol. 10, issue 1, 1-8

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-09458-6

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