Deficiência na desidrogenase dos acil-CoA de cadeia média e disfunção cardíaca: mecanismos de patogénese e novas intervenções terapêuticas

After four decades of research on MCADD, there are still many unanswered questions to be addressed: 1. Upon implementation of a new evaluation protocol, cardiac involvement was observed during metabolic crisis in several MCADD patients followed at the LRC-IM, a finding that has never been reported. Is this cardiac involvement a result of accumulation of specific metabolites? Are these events predictive of HD later in life? 2. Elevated MCFA and derivatives were suggested as potential biomarkers of CMD as increased acyl-carnitines were observed in these patients, C8 FA was associated with cardiovascular mortality and reduced heart function, MC-dicarboxylic carnitines were found to be predictive of cardiovascular events in individuals with coronary artery disease, MCFA were positively associated with diabetic cardiomyopathy risk in type 2 diabetes [8-10, 20]. Is there a correlation between metabolic profiles of CMD patients and MCADD patients? Does a metabolic signature exist in these patients? 4. MCADD treatment with L-carnitine supplementation is still controversial. Is this supplementation effective in normalizing accumulated biomarkers in large MCADD patient cohorts? Would CMD patients also benefit from this supplementation? 5. Although for riboflavin-associated IMD supplementation with this vitamin is an established therapy, for MCADD this approach has only been partially evaluated in a restrict group of patients (n=5) [21]. As FAD-misincorporation was found for the majority of MCAD disease-variants, is it possible to rescue the activity of MCAD variants via riboflavin (FAD) supplementation? And if so, what is the mechanism behind this effect? 6. A pharmacological therapy is highly needed for MCADD to avoid metabolic decompensations and risk of fatal outcomes. From the 23 hit molecules identified with a potential to stabilize and rescue the p.K329E function, are there molecules that can evolve to lead molecules? In order to address these questions a multidisciplinary team (paediatricians, internists, cardiologists, paediatric cardiologists, geneticists, nutritionists, biochemists, and biophysicists) is joining for the first time. Using innovative approaches, the aim is to: • Identify the metabolic signature of MCADD and CMD patients and find the correlation for those presenting cardiac involvement (mechanisms of disease). • Characterize the metabolic risk factors with predictive value for HD episodes. • Validate the effectiveness and further implement preventive therapeutic strategies (L-carnitine and/or riboflavin supplementation) in MCADD patients. • Assess the riboflavin status of MCADD patients and identify its potential correlation with cellular MCAD activity, patients’ metabolic signature, number of metabolic crises and cardiac involvement (mechanisms of disease). • Investigate the impact of FAD misincorporation on the stability and activity of wild-type and p.K329E variant at the biochemical/biophysical and cellular level (mechanisms of disease). • Characterize 23 hit molecules at the biochemical/biophysical and cellular level to identify lead molecules (1 to 3) with the potential to evolve to a pharmacological therapy. Due to its translational nature, the project outcomes will impact clinical practice contributing to improve MCADD patients’ quality of life and to shed more light on the pathogenesis of the vast group of CMD thereby broadening, far beyond IMD, the cluster of patients benefiting from the project’s findings.