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Prediction of Disease Severity in Multiple Acyl‐Coa

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Prediction of Disease Severity in Multiple Acyl‐Coa Received: 17 May 2019 Revised: 24 June 2019 Accepted: 1 July 2019 DOI: 10.1002/jimd.12147 ORIGINAL ARTICLE Prediction of disease severity in multiple acyl-CoA dehydrogenase deficiency: A retrospective and laboratory cohort study Willemijn J. van Rijt1 | Sacha Ferdinandusse2 | Panagiotis Giannopoulos1 | Jos P. N. Ruiter2 | Lonneke de Boer3 | Annet M. Bosch4 | Hidde H. Huidekoper5 | M. Estela Rubio-Gozalbo6 | Gepke Visser7 | Monique Williams5 | Ronald J. A. Wanders2 | Terry G. J. Derks1 1Division of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands 2Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands 3Department of Pediatrics, Radboud University Medical Center, Nijmegen, the Netherlands 4Department of Pediatrics, Division of Metabolic Disorders, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands 5Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center, Rotterdam, the Netherlands 6Department of Pediatrics and Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands 7Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands Correspondence Terry G. J. Derks, Section of Metabolic Summary Diseases, Beatrix Children's Hospital, Multiple acyl-CoA dehydrogenase deficiency (MADD) is an ultra-rare inborn error University Medical Center Groningen, of mitochondrial fatty acid oxidation (FAO) and amino acid metabolism. Individual University of Groningen, PO box 30 001, Groningen 9700 RB, the Netherlands. phenotypes and treatment response can vary markedly. We aimed to identify Email: [email protected] markers that predict MADD phenotypes. We performed a retrospective nationwide cohort study; then developed an MADD-disease severity scoring system (MADD- Communicating Editor: Sander M. Houten DS3) based on signs and symptoms with weighed expert opinions; and finally cor- related phenotypes and MADD-DS3 scores to FAO flux (oleate and myristate oxi- dation 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 Abbreviations: DS3, disease severity scoring system; ETF, electron transfer flavoprotein; FAO, fatty acid oxidation; IEM, inborn error of metabolism; MADD, multiple acyl-CoA dehydrogenase deficiency.; NBS, newborn bloodspot screening. Willemijn J. van Rijt and Sacha Ferdinandusse should be considered joint first author. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM J Inherit Metab Dis. 2019;1–12. wileyonlinelibrary.com/journal/jimd 1 2 VAN RIJT ET AL. (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). Func- tional 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 inclu- sion 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 1 | INTRODUCTION acyl-CoA dehydrogenase deficiency, long-chain FAO flux analysis in fibroblasts12,13 has been shown to correlate with Multiple acyl-CoA dehydrogenase deficiency (MADD, or the phenotype in patients using a clinical severity score.14 glutaric aciduria type II; MIM #231680) is an ultra-rare Comparable studies in fibroblasts of neonatal onset MADD- (ie, <1:50 000)1 mitochondrial fatty acid oxidation patients demonstrated a markedly reduced FAO activity, in (FAO) disorder caused by pathogenic variants in the contrast to a less diminished or even normal flux in fibro- genes encoding the electron transfer flavoproteins (ETFs; blasts of later-onset patients.8,15,16 To date, outcomes of ETFA or ETFB) or ETF dehydrogenase (ETFDH). The functional studies in fibroblasts have not been correlated disrupted transfer of reduced flavin adenine dinucleotides with standardized MADD disease severity. toward the mitochondrial respiratory chain results in an To identify markers that predict disease phenotypes, we impaired mitochondrial FAO and accumulation of toxic retrospectively studied a nationwide cohort of MADD- metabolites.2 MADD-patients are historically classified patients, developed an MADD-disease severity scoring sys- into three groups: neonatal-onset with/without congenital tem (DS3) as described previously for other IEMs,14,17-19 anomalies (type I/II) or with a later onset, relatively mild and correlated phenotypes and MADD-DS3 scores to the phenotype (type III).2 Patients with a neonatal onset suf- results of functional studies in fibroblasts. fer from life-threatening symptoms such as metabolic derangements, cardiomyopathy, leukodystrophy, and 2 | METHODS hypotonia. The clinical course of later onset patients ranges from recurrent hypoglycemia to cyclic vomiting, 2.1 | Retrospective cohort study lipid storage myopathy, exercise intolerance, and chronic fatigue.2 Symptoms in later onset patients can also be The medical care of Dutch pediatric patients with inborn fatal, but only in rare cases and usually associated with errors of metabolism (IEM) is centralized in the metabolic metabolic stress.3-5 Patients are identified through clini- divisions of six university hospitals. The pediatric metabolic cal presentation and in some countries also via population divisions of all university hospitals and their affiliated meta- newborn bloodspot screening (NBS).6,7 Treatment bolic laboratories were asked to participate. The Medical options include dietary fat- and protein- restrictions, Ethical Committee of the University Medical Center Gro- fasting avoidance, and supplementation with carnitine, ningen stated that the Medical Research Involving Human glycine, and riboflavin. Despite early identification and Subjects Act was not applicable and that official study treatment, neonatal mortality remains high.2,7,8 approval by the Medical Ethical Committee was not required Several laboratory studies can be used to characterize (METc code 2014/249). MADD-patients, including urine organic acid analysis, Patients with an MADD phenotype or biochemical pro- plasma acylcarnitine profiling, and ultimately molecular file (plasma acylcarnitines or urinary organic acids), studies to pinpoint the genetic defect.2,9,10 Unfortunately, supported by at least one identified variant in ETFA, ETFB, prognostic biomarkers that may predict disease severity are or ETFDH, were included. Outcome parameters included not available. In fibroblasts, FAO flux activities provide an data on clinical history, follow-up, and outcomes of labora- estimate of the rate of mitochondrial FAO, whereas tory studies performed according to certified, standardized acylcarnitine profiling improves insight on both the site and protocols. All data were obtained by examining the medical the severity of the enzymatic block.11 In very long-chain files and documented in case record forms which were VAN RIJT ET AL. 3 discussed by WR and TD. Data collection was completed in incubations were performed in quadruplicate (FAO flux) or December 2014. duplicate (acylcarnitine profiling) in least two independent experiments for each functional test. The presented results 2.2 | Multiple acyl-CoA dehydrogenase are the mean of independent experiments. deficiency-disease severity scoring system 2.4 | Statistical analysis A systematic literature review and a meta-analysis were per- formed to establish MADD associated disease symptoms and Data analysis was performed using GraphPad Prism v7.02 -domains and to identify their occurrence rates. The “PRI- (GraphPad Software, La Jolla, California) and SIMCA Soft- SMA-IPD”-guidelines were followed as accurately as possi- ware, v14.0 (Umetrics, Umea, Sweden). Categorical variables ble.20 Data extraction included reported clinical symptoms are presented as numbers and percentages. Remaining contin- and general patient characteristics. Disease domains were uous variables are presented as median (range). Fisher's exact defined based on organ systems involved in MADD. Occur- test or Mann-Whitney U test were used to test for significant rence rates were expressed as numbers and percentages. differences between neonatal and later onset patients. P- The relative importance of disease domains and symp- values of <.05 were considered statistically significant. A toms to be included in the MADD-DS3 was determined principal component analysis and discriminant
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