Early-onset gout and rare deficient variants of the lactate dehydrogenase D gene

Abstract

Objectives To investigate whether lactate dehydrogenase D (LDHD) gene deficiency causes juvenile-onset gout. Methods We used whole exome sequencing (WES) for two families and a targeted gene-sequencing panel for an isolated patient. D-lactate dosages were analyzed by using ELISA. Results We demonstrated linkage of juvenile-onset gout to homozygous carriage of 3 rare distinct LDHD variants in 3 different ethnicities. In a Melanesian family, the variant was [NM_153486.3: c(206 C > T); rs1035398551] and, as compared with non-homozygotes, homozygotes had higher hyperuricemia (p= 0.02), lower fractional clearance of urate (FCU) (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.

Gout: one year in review 2023

“…• The prevalence of gout and its incidence is steadily increasing all around the world with an important rise on annual incidence rates in the Middle East and North Africa region (6). High D-lactate levels in the blood and/ or urine due to these mutations may lead to gouty arthropathy (12). Another study has found associations between gene expression of inflammatory regulators including free fatty acid receptor 2 (FFAR2) and suppressor of cytokine signalling 3 (SOCS3), and gout flares, suggesting a role in the initiation and resolution of flare, respectively (13).…”