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Case Reports
. 2021 May 21;60(1):15-22.
doi: 10.1002/jmd2.12220. eCollection 2021 Jul.

Human d-lactate dehydrogenase deficiency by LDHD mutation in a patient with neurological manifestations and mitochondrial complex IV deficiency

Anna Ka-Yee Kwong  1 , Sheila Suet-Na Wong  1   2 , Richard J T Rodenburg  3 , Jan Smeitink  3 , Godfrey Chi Fung Chan  1   2 , Cheuk-Wing Fung  1   2
Affiliations
Case Reports

Human d-lactate dehydrogenase deficiency by LDHD mutation in a patient with neurological manifestations and mitochondrial complex IV deficiency

Anna Ka-Yee Kwong et al. JIMD Rep. .

Abstract

Background: d-lactate, one of the isomers of lactate, exists in a low concentration in healthy individuals and it can be oxidized to pyruvate catalyzed by d-lactate dehydrogenase. Excessive amount of d-lactate causes d-lactate acidosis associated with neurological manifestations.

Methods and results: We report here a patient with developmental delay, cerebellar ataxia, and transient hepatomegaly. Enzyme analysis in the patient's skin fibroblast showed decreased mitochondrial complex IV activity. Using whole exome sequencing, we identified compound heterozygous variants in the LDHD gene, which encodes the d-lactate dehydrogenase, consisting of a splice site variant c.469+1dupG and a missense variant c.752C>T, p.(Thr251Met) which are pathogenic and likely pathogenic respectively according to the American College of Medical Genetics and Genomics (ACMG) classification. The serum d-lactate level was subsequently detected to be elevated (0.61 mmol/L, reference value: 0-0.25 mmol/L).

Conclusion: This is the third report on LDHD mutations associated with d-lactate elevation and was first reported to have decreased mitochondrial complex IV activity. The study provides more information on this rare metabolic condition but the association of LDHD deficiency with the clinical presentations requires further investigations.

Keywords: LDHD; ataxia; complex IV deficiency; developmental delay; d‐lactate dehydrogenase; neurological.

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Conflict of interest statement

J. S. is the CEO of Khondrion, a pharmaceutical company developing compounds to potentially treat mitochondrial disease. All the other authors declare that they have no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Identification of human LDHD variants. A, Sanger sequencing of index patient, father and mother. Two LDHD heterozygous variants, NM_153486.3: c.469+1dupG and c.752C>T, p.(Thr251Met) were confirmed by genomic DNA sequencing. Sanger sequencing of the cDNA revealed that only one allele with the missense variant was expressed. Father is heterozygous carrier of the splice site variant c.469+1dupG and the mother is heterozygous carrier of the missense variant p.(Thr251Met). Arrows point to the specific nucleotide changes. B, Multiple alignments of LDHD amino acid sequences across yeast and different vertebrates showed that the variant p.(Thr251Met) encodes for the amino acid methionine (Met) instead of the normally present amino acid threonine (Thr) in a region that is highly conserved. cDNA, complementary DNA
See this image and copyright information in PMC

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