Prediction of disease severity in multiple acyl-CoA dehydrogenase deficiency:a retrospective and laboratory cohort study

INTRODUCTION: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an ultra-rare inborn error of mitochondrial fatty acid oxidation (FAO) and amino acid metabolism. Individual phenotypes and treatment response can vary markedly. We aimed to identify markers that predict MADD phenotypes.METHODS: We performed a retrospective nationwide cohort study; then developed an MADD -disease severity scoring system (MADD-DS3) based on signs and symptoms with weighed expert opinions; and finally correlated phenotypes and MADD-DS3 scores to FAO flux (oleate and myristate oxidation rates) and acylcarnitine profiles after palmitate loading in fibroblasts.RESULTS: Eighteen patients, diagnosed between 1989 and 2014, were identified. The MADD-DS3 entails enumeration of eight domain scores, which are calculated by averaging the relevant symptom scores. Lifetime MADD-DS3 scores of patients in our cohort ranged from 0-29. FAO flux and [U-13 C]C2-, C5- and [U-13 C]C16-acylcarnitines were identified as key variables that discriminated neonatal from later onset patients (all p<0.05) and strongly correlated to MADD-DS3 scores (oleate: r=-0.86; myristate: r=-0.91; [U-13 C]C2-acylcarnitine: r=-0.96; C5-acylcarnitine: r=0.97; [U-13 C]C16-acylcarnitine: r=0.98, all p<0.01).CONCLUSION: Functional studies in fibroblasts were found to differentiate between neonatal and later onset MADD-patients and were correlated to MADD-DS3 scores. Our data may improve early prediction of disease severity in order to start (preventive) and follow-up treatment appropriately. This is especially relevant in view of the inclusion of MADD in population newborn screening programs. This article is protected by copyright. All rights reserved.