Efeito da Leucovorina na Respiração Mitocondrial e Metabolismo de Um Carbono na Distúrbio do Espectro de Autismo: Subestudo Controlado com Placebo Duplo

Resumo original em inglês

O que aconteceu

Mitochondrial dysfunction and impaired methylation are implicated in autism spectrum disorder (ASD). Leucovorin, a reduced folate that bypasses both dihydrofolate reductase and folate receptor alpha, has shown clinical benefit in small trials in children with ASD, but the underlying biology is incompletely understood. In this pre-specified biomarker substudy of a completed double-blind placebo-controlled trial (NCT02000284; NCT01602016), children with ASD received leucovorin (2 mg/kg/day, maximum 50 mg/day) or a matched placebo for 12 weeks. Peripheral blood mononuclear cell respiration was measured by extracellular flux with a graded 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) challenge (38 participants; 17 leucovorin, 21 placebo) and plasma thiol-methylation metabolites were measured pre- and post-treatment (42 participants; 18 leucovorin, 24 placebo). Leucovorin increased basal, ATP-linked, proton-leak, maximal, and reserve respiration relative to the placebo (Group × Visit p ≤ 0.012, all q ≤ 0.012; Cohen's d 0.48-0.92); there was no evidence that the treatment effect varied across the tested DMNQ concentrations. In exploratory moderator analyses, folate receptor alpha autoantibody (FRAA) status modified the effect on maximal respiratory capacity and reserve capacity (both p p = 0.020 and 0.050) but neither survived false-discovery-rate correction within the thiol family. The findings support the folate-mitochondrial-redox axis as a candidate therapeutic target in ASD and warrant replication in larger independent cohorts.

Resumo publicado sob licença CC BY. A tradução para o português ainda não chegou a este estudo.