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

Willemijn J Van Rijt,M Estela Rubio‐Gozalbo,Gepke Visser,Annet M Bosch,Hidde H Huidekoper,Terry G J Derks,Monique Williams,Ronald J A Wanders,Jos P N Ruiter,Lonneke De Boer,Sacha Ferdinandusse,Panagiotis Giannopoulos

doi:10.1002/jimd.12147

Abstract

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-13 C]C2-, C5-, and [U-13 C]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-13 C]C2-acylcarnitine: r = -.96; C5-acylcarnitine: r = .97; [U-13 C]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.

Highlights

Multiple acyl-CoA dehydrogenase deficiency (MADD, or glutaric aciduria type II; MIM #231680) is an ultra-rare[1] mitochondrial fatty acid oxidation (FAO) disorder caused by pathogenic variants in the genes encoding the electron transfer flavoproteins (ETFs; ETFA or ETFB) or ETF dehydrogenase (ETFDH)
To identify markers that predict disease phenotypes, we retrospectively studied a nationwide cohort of MADDpatients, developed an MADD-disease severity scoring system (DS3) as described previously for other inborn errors of metabolism (IEM),[14,17,18,19] and correlated phenotypes and MADD-DS3 scores to the results of functional studies in fibroblasts
Oleate and myristate flux rates were significantly lower in fibroblasts from neonatal onset patients compared to patients with a later onset (median 13% vs 94% (48-103%), P = .0357; 1% (0-7%) vs 70% (57-108%), P = .0357, respectively)