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

Autor: Kwong AK; Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China., Wong SS; Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China.; Department of Paediatrics and Adolescent Medicine Hong Kong Children's Hospital Hong Kong SAR China., Rodenburg RJT; Radboud Centre for Mitochondrial Medicine, Department of Paediatrics Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Centre Nijmegen The Netherlands., Smeitink J; Radboud Centre for Mitochondrial Medicine, Department of Paediatrics Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Centre Nijmegen The Netherlands., Chan GCF; Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China.; Department of Paediatrics and Adolescent Medicine Hong Kong Children's Hospital Hong Kong SAR China., Fung CW; Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China.; Department of Paediatrics and Adolescent Medicine Hong Kong Children's Hospital Hong Kong SAR China.
Jazyk: angličtina
Zdroj: JIMD reports [JIMD Rep] 2021 May 21; Vol. 60 (1), pp. 15-22. Date of Electronic Publication: 2021 May 21 (Print Publication: 2021).
DOI: 10.1002/jmd2.12220
Abstrakt: 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.
Competing Interests: 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.
(© 2021 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)
Databáze: MEDLINE
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