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, Stefan Kölker1. 1. Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany. 2. Division of Experimental Pediatrics and Metabolism, Department of General Pediatrics, Neonatology, and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. 3. Dr von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany. 4. Department of General Pediatrics, Metabolic Diseases, University Children's Hospital Münster, Münster, Germany. 5. Charité-Universitätsmedizin Berlin, Corporate Member of Free University Berlin, Free University of Berlin, Humboldt University of Berlin, and Berlin Institute of Health, Center for Chronically Sick Children, Berlin, Germany. 6. Department of Child Neurology, Children's Hospital Oldenburg, Oldenburg, Germany. 7. Department of Pediatrics, Pediatric Metabolic Medicine, Hannover Medical School, Hannover, Germany. 8. Children's Hospital Reutlingen, Reutlingen, Germany. 9. Department of General Pediatrics, Adolescent Medicine, and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany. 10. Department of Pediatric and Adolescent Medicine, Ulm University Medical School, Ulm, Germany. 11. Department of Pediatrics and Pediatric Neurology, University Medical Center, Göttingen, Germany. 12. Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland. 13. Department of Women and Child Health, Hospital for Children and Adolescents, Center for Pediatric Research Leipzig, University Hospitals, University of Leipzig, Leipzig, Germany. 14. Center for Inborn Metabolic Disorders, Department of Neuropediatrics, Jena University Hospital, Jena, Germany. 15. Children's Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany. 16. Division of Pediatric Neurology, University Children's Hospital Frankfurt, Frankfurt, Germany. 17. University Children's Hospital, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
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) programs 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, multicenter study includes 87 patients identified by NBS, 4 patients missed by NBS, and 3 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 during 1999-2016. Overall, cumulative sensitivity of NBS is 95.6%, but it is lower (84%) for patients with low excreter phenotype. The neurologic outcome of patients missed by NBS is as poor as in the pre-NBS era, and the clinical phenotype of diagnosed patients depends on the quality of therapeutic interventions rather than noninterventional variables. Presymptomatic start of treatment according to current guideline recommendations clearly improves the neurologic outcome (MD: 7% of patients), whereas 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 nonneurologic 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, whereas kidney dysfunction does not appear to be impacted by recommended therapy. Ann Neurol 2018;83:970-979.
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) programs 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, multicenter study includes 87 patients identified by NBS, 4 patients missed by NBS, and 3 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 during 1999-2016. Overall, cumulative sensitivity of NBS is 95.6%, but it is lower (84%) for patients with low excreter phenotype. The neurologic outcome of patients missed by NBS is as poor as in the pre-NBS era, and the clinical phenotype of diagnosed patients depends on the quality of therapeutic interventions rather than noninterventional variables. Presymptomatic start of treatment according to current guideline recommendations clearly improves the neurologic outcome (MD: 7% of patients), whereas 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 nonneurologic 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, whereas kidney dysfunction does not appear to be impacted by recommended therapy. Ann Neurol 2018;83:970-979.
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