Early-onset gout and rare deficient variants of the lactate dehydrogenase D gene
Thomas Bardin, Yves‐Marie Ducrot, Quang Vinh Nguyễn, Emmanuel Letavernier, Jérémy Zaworski, Hang‐Korng Ea, F. Touzain, Duc M, Julien Colot, Yann Barguil, Antoine Biron, Matthieu Resche‐Rigon, Pascal Richette, Corinne Collet
Abstract
OBJECTIVES: To investigate whether the lactate dehydrogenase D (LDHD) gene deficiency causes juvenile-onset gout. METHODS: We used whole-exome sequencing for two families and a targeted gene-sequencing panel for an isolated patient. d-lactate dosages were analysed using ELISA. RESULTS: We demonstrated linkage of juvenile-onset gout to homozygous carriage of three rare distinct LDHD variants in three different ethnicities. In a Melanesian family, the variant was (NM_153486.3: c.206C>T; rs1035398551) and, as compared with non-homozygotes, homozygotes had higher hyperuricaemia (P = 0.02), lower fractional clearance of urate (P = 0.002), and higher levels of d-lactate in blood (P = 0.04) and urine (P = 0.06). In a second, Vietnamese, family, very severe juvenile-onset gout was linked to homozygote carriage of an undescribed LDHD variant (NM_153486.3: c.1363dupG) leading to a frameshift followed by a stop codon, p.(AlaGly432fsTer58). Finally, a Moroccan man, with early-onset and high d-lactaturia, whose family was unavailable for testing, was homozygous for another rare LDHD variant [NM_153486.3: c.752C>T, p.(Thr251Met)]. CONCLUSION: Rare, damaging LDHD variants can cause autosomal recessive early-onset gout, the diagnosis of which can be suspected by measuring high d-lactate levels in the blood and/or urine.