D-Lactic Aciduria

A number sign (#) is used with this entry because of evidence that D-lactic aciduria (DLACD) is caused by homozygous mutation in the LDHD gene (607490) on chromosome 16q23.

Clinical Features

Duran et al. (1977) described a single child of Sicilian descent who had mental retardation, microcephaly, antimongoloid slanting of the eyes, aniridia, and bilateral inguinal hernia. Levels of lactic acid were normal in the plasma, but were high in the urine. The lactic acid was shown to be D-lactic acid. The lactic acid normally produced is L-lactic acid and only when it becomes elevated in the plasma does it 'overflow' into the urine. The authors posited that their patient had an inborn error of metabolism that leads to production of D-lactate and that lactate with this configuration is not resorbed by the renal tubule.

Monroe et al. (2019) provided a follow-up of the patient reported by Duran et al. (1977) with D-lactic aciduria, who was found to have WAGR syndrome (194072). Monroe et al. (2019) reported another patient, born of first-cousin Moluccan parents, with D-lactic aciduria. This patient was diagnosed with West syndrome. Array CGH found that both patients were homozygous for a region on chromosome 16 containing the candidate gene LDHD.

Molecular Genetics

In 2 unrelated patients with elevated D-lactate urinary excretion and plasma concentrations, Monroe et al. (2019) identified homozygous missense mutations in the LDHD gene (T463M, 607490.0001 and W374C, 607490.0002). The mutations were found by high-resolution SNP arrays, homozygosity mapping, and Sanger sequencing of the LDHD gene. Introduction of human wildtype LDHD in ldhd-knockout zebrafish with elevated D-lactate excretion could rescue the phenotype, whereas LDHD with either of the missense variants could not.