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

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.