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

Presented By:

Willemijn J. van Rijta*, Bsc, Sacha Ferdinandusseb*, PhD, Panagiotis Giannopoulosa, Bsc, Jos P. N.
Ruiterb, Ing, Lonneke de Boerc, MD PhD, Annet M. Boschd, MD PhD, Hidde H. Huidekoper, MD PhDe,
M. Estela Rubio-Gozalbof, MD PhD, Gepke Visserg, MD PhD, Monique Williamse, MD PhD, Ronald J.A.
Wandersb, PhD and Terry G.J. Derksa, MD PhD *Willemijn J. van Rijt and Sacha Ferdinandusse should
be considered joint first author

a Division of Metabolic Diseases, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; b Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; c Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; d Department of Pediatrics, Division of Metabolic Disorders, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; e Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center, Rotterdam, The Netherlands; f Department of Pediatrics and Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands; gDepartment of Metabolic Diseases, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.

Address correspondence to: Terry G. J. Derks, Section of Metabolic Diseases, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, PO box 30 001, 9700 RB, Groningen, the Netherlands, +31 (0)50 3614944, t.g.j.derks@umcg.nl.

Background: 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 symptoms and signs and 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. Inclusion criteria comprised an MADD (biochemical) phenotype, supported by DNA analysis. Index patients identified after clinical presentation were included in inferential and correlation analyses.

Results: Eighteen patients, diagnosed between 1989 and 2014, were identified. The MADD-DS3 entails enumeration of eight domain scores, which are each calculated by averaging the available symptom scores. Lifetime MADD-DS3 scores of patients in our cohort ranged from 0-29. FAO flux and [U-13C]C2-,
C5- and [U-13C]C16-acylcarnitines were identified as key variables that discriminated neonatal (n=3) from later onset patients (n=5) (all p<0.05) and strongly correlated to MADD-DS3 scores (oleate: r=-0.86; myristate: r=-0.91; [U-13C]C2- acylcarnitine: r=-0.96; C5-acylcarnitine: r=0.97; [U-13C]C16-acylcarnitine: r=0.98, all p<0.01).

Discussion: 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) treatment and follow-up appropriately. This is especially relevant in view of the inclusion of MADD in population newborn screening programs.