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Newborn Screening, a Disease‐Changing Intervention for Glutaric Newborn screening, a disease-changing intervention for glutaric aciduria type 1 Nikolas Boy1, Katharina Mengler1, Eva Thimm2, Katharina A. Schiergens3, Thorsten Marquardt4, Natalie Weinhold5, Iris Marquardt6, Anibh M. Das7, Peter Freisinger8, Sarah C. Grünert9, Judith Vossbeck10, Robert Steinfeld11, Matthias R. Baumgartner12, Skadi Beblo13, Andrea Dieckmann14, Andrea Näke15, Martin Lindner16, Jana Heringer1, Georg F. Hoffmann1, Chris Mühlhausen17, Esther M. Maier3, Regina Ensenauer2, Sven F. Garbade1, and Stefan Kölker1 Running Head: Newborn screening for glutaric aciduria type 1 1Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg 2Division of Experimental Paediatrics and Metabolism, Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany 3Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, Germany 4Department of General Paediatrics, Metabolic Diseases, University Children's Hospital Muenster, Muenster, Germany 5Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Center for Chronically Sick Children, Berlin, Germany 6Department of Child Neurology, Children's Hospital Oldenburg, Oldenburg, Germany 7Department of Paediatrics, Paediatric Metabolic Medicine, Hannover Medical School, Hannover, Germany 8Children's Hospital Reutlingen, Reutlingen, Germany 9Department of General Paediatrics, Adolescent Medicine and Neonatology, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany 10Department of Paediatric and Adolescent Medicine, Ulm University Medical School, Ulm, Germany 11Department of Paediatrics and Paediatric Neurology, University Medical Center, Göttingen, Germany 12Division of Metabolism and Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland 13Department of Women and Child Health, Hospital for Children and Adolescents, Centre for Paediatric Research Leipzig (CPL), University Hospitals, University of Leipzig, Leipzig, Germany 14Centre for Inborn Metabolic Disorders, Department of Neuropediatrics, Jena University Hospital, Jena, Germany 15Children's Hospital Carl Gustav Carus, Technical University Dresden, Germany 16Division of Paediatric Neurology, University Children’s Hospital Frankfurt, Frankfurt, Germany 17University Children´s Hospital, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany Corresponding author: Prof. Dr. Stefan Kölker, MD University Hospital Heidelberg, Centre for Pediatrics and Adolescent Medicine, Department of General Paediatrics, Division of Paediatric Neurology and Metabolic Medicine, D-69120 Heidelberg, Germany. E-mail: [email protected] Phone: +49 6221 5638277 Number of characters of the title: 79 Number of characters of the running head: 46 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/ana.25233 This article is protected by copyright. All rights reserved. Page 3 of 28 Annals of Neurology Number of words in the body of the manuscript: 4,103 Word count (abstract): 249 Word count (Introduction): 443 Word Count (Discussion): 1,359 Number of figures: 4 Number of colour figures: 2 Number of tables: 0 Number of Suppl. Tables: 2 John Wiley & Sons 2 This article is protected by copyright. All rights reserved. Annals of Neurology Page 4 of 28 Abstract Objective: Untreated individuals with glutaric aciduria type 1 (GA1) commonly present with a complex, predominantly dystonic movement disorder (MD) following acute or insidious onset striatal damage. Implementation of GA1 into newborn screening (NBS) programmes has improved the short-term outcome. It remains unclear, however, whether NBS changes the long-term outcome and which variables are predictive. Methods: This prospective, observational, multi-centre study includes 87 patients identified by NBS, four patients missed by NBS and three women with GA1 identified by positive NBS results of their unaffected children. Results: The study population comprises 98.3% of individuals with GA1 identified by NBS in Germany between 1999-2016. Overall, cumulative sensitivity of NBS is 95.6%, but is lower (84%) for patients with low excretor phenotype. Neurologic outcome of patients missed by NBS is as poor as in the pre-NBS era, while the clinical phenotype of diagnosed patients depends on the quality of therapeutic interventions rather than non- interventional variables: Presymptomatic start of treatment according to current guideline recommendations clearly improves the neurologic outcome (MD: 7% of patients), while delayed emergency treatment results in acute onset MD (100%), and deviations from maintenance treatment increase the risk of insidious onset MD (50%). Independent of the neurologic phenotype, kidney function tends to decline with age, a non-neurologic manifestation not predicted by any variable included in this study. Interpretation: NBS is a beneficial, disease-changing intervention for GA1. However, improved neurologic outcome critically depends on adherence to recommended therapy while kidney dysfunction does not appear to be impacted by recommended therapy. John Wiley & Sons 3 This article is protected by copyright. All rights reserved. Page 5 of 28 Annals of Neurology References to electronic databases Glutaric aciduria type 1: OMIM # 231670 Glutaryl-CoA dehydrogenase: EC 1.3.8.6 Abbreviations 3OHGA, 3-hydroxyglutaric acid C5DC, glutarylcarnitine CI, confidence interval CKD, chronic kidney disease EC, encephalopathic crisis (A)ET, (adequate) emergency treatment (according to guideline recommendations) GA, glutaric acid GA1, glutaric aciduria type 1 GFR, glomerular filtration rate HE, high excretor HUS, hemolytic uremic syndrome IQR, interquartile range LE, low excretor MD, movement disorder MS/MS, tandem mass spectrometry (A)MT, (adequate) maintenance treatment (according to guideline recommendations) NBS, newborn screening SDH, subdural hemorrhage Key words Glutaric aciduria type 1; glutaric acidemia type 1; newborn screening John Wiley & Sons 4 This article is protected by copyright. All rights reserved. Annals of Neurology Page 6 of 28 Introduction Glutaric aciduria type 1 (GA1, OMIM #231670) is a rare inherited disorder of L-lysine, L-hydroxylysine and L- tryptophan metabolism due to deficiency of glutaryl-CoA dehydrogenase (EC 1.3.8.6) resulting in accumulation of glutaryl-CoA and its dicarboxylic derivatives, glutaric acid (GA), 3-hydroxyglutaric acid (3OHGA), glutaconic acid and glutarylcarnitine (C5DC) in body tissues, especially within the brain. The estimated incidence in Germany is 1 in 112,700 newborns [95% confidence interval (CI), 1 in 129,455-95,953].1 Between ages 3-36 months, most untreated patients develop a complex movement disorder (MD) with predominant dystonia due to bilateral striatal damage associated with high morbidity and mortality.2, 3 This prognostically relevant event may occur acutely following an acute encephalopathic crisis (EC)3 or insidiously without preceding crisis.1, 4, 5 Due to the primarily neurologic phenotype, GA1 is considered a cerebral organic aciduria. However, peripheral nervous system6 and kidneys7 might also be involved in the long-term disease course. Two arbitrarily defined biochemical subgroups, low (LE) and high excretors (HE)8, have been described according to the amount of urinary GA, both sharing the same risk of developing MD if untreated.3, 9 However, studies revealed a higher frequency of progressive extrastriatal CNS abnormalities in HE patients, though their clinical relevance is unclear.10, 11 Metabolic treatment consisting of a low lysine diet and carnitine supplementation for maintenance treatment (MT) and intermittent emergency treatment (ET) during episodes likely to induce catabolism such as infections, has improved neurologic short-term outcome in early diagnosed individuals in most studies.1, 3, 12-16 Evidence- based recommendations have been developed and recently revised.17, 18 Noteworthy, treatment reduces cerebral accumulation of putatively neurotoxic dicarboxylic metabolites and improves outcome in Gcdh- deficient mice thereby linking neurotoxicity to the clinical phenotype.19, 20 Since C5DC can be detected by electrospray-ionisation tandem mass spectrometry (MS/MS) and early treatment is thought to be effective, GA1 has been increasingly included in national newborn screening (NBS) programmes.21, 22 In Germany, pilot NBS projects for GA1 were initiated in single metabolic centres in 1999, followed by nationwide start of a MS/MS-based NBS in 2005. The prospective observational study on GA1 patients identified by NBS started in 1999 and, to our knowledge, follows the largest cohort of early diagnosed and treated patients worldwide. Previous interim analyses of this longitudinal study have improved our knowledge about this rare disease demonstrating that NBS and adherence to guideline recommendations improves the short-term outcome of affected individuals.1, 16 However, impact on long-term outcome is unknown. The major aims of this study are to investigate long-term neurologic and non-neurologic outcome in patients treated and prospectively
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