Neuropediatrics 2018; 49(S 02): S1-S69
DOI: 10.1055/s-0038-1675896
Oral Presentation
Movement Disorders II
Georg Thieme Verlag KG Stuttgart · New York

FV 754. Newborn Screening, a Disease-Modifying Intervention for Glutaric Aciduria Type 1

Nikolas Boy
1   Division of Child Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
,
Katharina Mengler
1   Division of Child Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
,
Eva Thimm
2   Division of Experimental Paediatrics and Metabolism, Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children’s Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
,
Katharina A. Schiergens
3   Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, Munich, Germany
,
Thorsten Marquardt
4   Department of General Paediatrics, Metabolic Diseases, University Children’s Hospital Muenster, Muenster, Germany
,
Natalie Weinhold
5   Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Center for Chronically Sick Children, Berlin, Germany
,
Iris Marquardt
6   Department of Child Neurology, Children’s Hospital Oldenburg, Oldenburg, Germany
,
Anibh M. Das
7   Department of Paediatrics, Paediatric Metabolic Medicine, Hannover Medical School, Hannover, Germany
,
Peter Freisinger
8   Children’s Hospital Reutlingen, Reutlingen, Germany
,
Sarah C. Grünert
9   Department of General Paediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Judith Vossbeck
10   Department of Paediatric and Adolescent Medicine, Ulm University Medical School, Ulm, Germany
,
Robert Steinfeld
11   Department of Paediatrics and Paediatric Neurology, University Medical Center, Göttingen, Germany
,
Matthias R. Baumgartner
12   Division of Metabolism and Children’s Research Centre, University Children’s Hospital Zurich, Zurich, Switzerland
,
Skadi Beblo
13   Department of Women and Child Health, Centre for Paediatric Research Leipzig (CPL), Hospital for Children and Adolescents, University Hospitals, University of Leipzig, Lepzig, Germany
,
Andrea Dieckmann
14   Department of Neuropediatrics, Centre for Inborn Metabolic Disorders, Jena University Hospital, Jena, Germany
,
Andrea Näke
15   Children’s Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
,
Martin Lindner
16   Division of Paediatric Neurology, University Children’s Hospital Frankfurt, Frankfurt, Germany
,
Jana Heringer
1   Division of Child Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
,
Georg F. Hoffmann
1   Division of Child Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
,
Chris Mühlhausen
17   University Medical Centre Hamburg-Eppendorf, University Children’s Hospital, Hamburg, Germany
,
Esther M. Maier
3   Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, Munich, Germany
,
Regina Ensenauer
2   Division of Experimental Paediatrics and Metabolism, Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children’s Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
,
Sven F. Garbade
1   Division of Child Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
,
Stefan Kölker
1   Division of Child Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
30 October 2018 (online)

 

Background: Glutaric aciduria type 1 (GA1, OMIM #231670) is a rare inherited neurometabolic disorder of L-lysine, L-hydroxylysine, and L-tryptophan metabolism due to deficiency of glutaryl-CoA dehydrogenase resulting in accumulation of glutaryl-CoA, glutaric acid (GA), and 3-hydroxyglutaric acid (3-OH-GA), especially within the brain. Two arbitrarily defined biochemical subgroups, low (LE) and high excretors (HE), have been described according to the amount of urinary GA. Untreated individuals commonly present with a complex, predominantly dystonic movement disorder (MD) following acute or insidious onset of striatal damage. Implementation of GA1 into national newborn screening (NBS) programs has improved the neurologic short-term outcome. However, it is unclear whether NBS changes the long-term outcome and which outcome variables are predictive.

Aims: To investigate the long-term neurologic and nonneurologic outcomes in patients treated and prospectively followed after positive NBS, to identify major disease-modifying effects of interventional and noninterventional parameters, and to evaluate the overall benefit of the NBS program for GA1 patients.

Methods: This prospective, observational, multicenter study with a cumulative follow-up time of 710.6 years includes 87 patients identified by NBS, four patients missed by NBS and three mothers with GA1 identified by positive NBS results of their unaffected children. Clinical and biochemical follow-up parameters were assessed prospectively. Neurologic manifestations were separated into major motor symptoms, that is, manifestation of a MD, and minor motor symptoms, that is, fine motor deficits and/or delayed achievement of motor milestones in the absence of MD.

Results: The study population comprises 98.3% of individuals with GA1 identified by NBS in Germany between 1999 and 2016. Overall, cumulative sensitivity of NBS is 95.6% but is lower (84%) for patients with LE 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 noninterventional variables (gender, biochemical subtype, and migration). Presymptomatic start of treatment according to recent guideline recommendations (AWMF no. 027-018), that is, low lysine diet and carnitine supplementation for maintenance treatment and intermittent emergency treatment during episodes likely to induce catabolism, 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%) and, less pronounced, minor motor symptoms. Patients with severe MD have a much lower life expectancy (n = 5; median age at death, 3.3 years) than those being asymptomatic or having mild or moderate MD (p < 0.001). Nonadherence to recommended emergency treatment has a major negative impact on survival (p = 0.0036). Independent of the neurologic phenotype, kidney function tends to decline with age, a nonneurologic manifestation not predicted by any variable included in this study.

Conclusion: NBS is a beneficial, disease-modifying intervention for GA1. However, improved neurologic outcome critically depends on adherence to recommended therapy regimen while kidney dysfunction does not appear to be impacted by recommended therapy.