Prediction of disease severity in multiple acyl-CoA dehydrogenase deficiency: A retrospective and laboratory cohort study
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. 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. 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 to 29. FAO flux and [U-13C]C2-, C5-, and [U-13C]C16-acylcarnitines were identified as key variables that discriminated neonatal from later onset patients (all P <.05) and strongly correlated to MADD-DS3 scores (oleate: r = −.86; myristate: r = −.91; [U-13C]C2-acylcarnitine: r = −.96; C5-acylcarnitine: r =.97; [U-13C]C16-acylcarnitine: r =.98, all P <.01). 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.
|Keywords||disease severity scoring system, fatty acid oxidation, functional fibroblast studies, multiple acyl-CoA dehydrogenase deficiency, prognostic marker|
|Persistent URL||dx.doi.org/10.1002/jimd.12147, hdl.handle.net/1765/118477|
|Journal||Journal of Inherited Metabolic Disease|
van Rijt, W.J. (Willemijn J.), Ferdinandusse, S, Giannopoulos, P. (Panagiotis), Ruiter, J.P.N, de Boer, L. (Lonneke), Bosch, A.M, … Derks, T.G.J. (2019). Prediction of disease severity in multiple acyl-CoA dehydrogenase deficiency: A retrospective and laboratory cohort study. Journal of Inherited Metabolic Disease. doi:10.1002/jimd.12147