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

• Published in: Rheumatology 2023-12, Vol.62 (12), p.3978-3983
• Main Authors: Bardin, Thomas, Ducrot, Yves-Marie, Nguyen, Quang, Letavernier, Emmanuel, Zaworski, Jeremy, Ea, Hang-Korng, Touzain, Fréderic, Do, Minh Duc, Colot, Julien, Barguil, Yann, Biron, Antoine, Resche-Rigon, Matthieu, Richette, Pascal, Collet, Corinne
• Format: Article
• Language: English
• Subjects: Endocrinology and metabolism; Gout - genetics; Homozygote; Human health and pathology; Humans; Hyperuricemia - genetics; Lactate Dehydrogenases - genetics; Lactic Acid; Life Sciences; Male
• ISSN: 1462-0324; 1462-0332; 1460-2172
• DOI: 10.1093/rheumatology/kead118

To investigate whether the lactate dehydrogenase D (LDHD) gene deficiency causes juvenile-onset gout. 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. 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)]. 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.