The biochemical subtype is a predictor for cognitive function in glutaric aciduria type 1 : a national prospective follow-up study

Affiliation
Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
Märtner, E. M. Charlotte;
Affiliation
Division of Experimental Paediatrics and Metabolism, Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children’s Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Thimm, Eva;
Affiliation
Children’s Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Guder, Philipp;
Affiliation
Dr. Von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, Germany
Schiergens, Katharina A.;
Affiliation
Department of General Paediatrics, Metabolic Diseases, University Children’s Hospital Muenster, Muenster, Germany
Rutsch, Frank;
Affiliation
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
Roloff, Sylvia;
Affiliation
Department of Child Neurology, Children’s Hospital Oldenburg, Oldenburg, Germany
Marquardt, Iris;
Affiliation
Department of Paediatrics, Paediatric Metabolic Medicine, Hannover Medical School, Hannover, Germany
Das, Anibh M.;
Affiliation
Children’s Hospital Reutlingen, Reutlingen, Germany
Freisinger, Peter;
Affiliation
Department of General Paediatrics, Adolescent Medicine and Neonatology, Medical Centre, University of Freiburg, Faculty of Medicine, Freiburg, Germany
Grünert, Sarah C.;
Affiliation
Department of Pediatric Neurology and Inborn Errors of Metabolism, Children’s Hospital, University of Ulm, Ulm, Germany
Krämer, Johannes;
Affiliation
Division of Metabolism and Children’s Research Centre, University Children’s Hospital Zurich, Zurich, Switzerland
Baumgartner, Matthias R.;
Affiliation
Department of Women and Child Health, Hospital for Children and Adolescents, Centre for Paediatric Research Leipzig (CPL), University Hospitals, University of Leipzig, Leipzig, Germany
Beblo, Skadi;
Affiliation
Department of Pediatrics, Helios Klinikum, Erfurt, Germany
Haase, Claudia;
GND
121149358
Affiliation
Centre for Inborn Metabolic Disorders, Department of Neuropediatrics, Jena University Hospital, Jena, Germany
Dieckmann, Andrea;
Affiliation
Division of Paediatric Neurology, University Children’s Hospital Frankfurt, Frankfurt, Germany
Lindner, Martin;
Affiliation
Children’s Hospital Carl Gustav Carus, Technical University, Dresden, Germany
Näke, Andrea;
Affiliation
Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
Hoffmann, Georg F.;
Affiliation
Department of Pediatrics and Adolescent Medicine, University Medical Center, Göttingen, Germany
Mühlhausen, Chris;
Affiliation
Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
Walter, Magdalena;
Affiliation
Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
Garbade, Sven F.;
Affiliation
Dr. Von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, Germany
Maier, Esther M.;
Affiliation
Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
Kölker, Stefan;
Affiliation
Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
Boy, Nikolas

The aim of the study was a systematic evaluation of cognitive development in individuals with glutaric aciduria type 1 (GA1), a rare neurometabolic disorder, identified by newborn screening in Germany. This national, prospective, observational, multi-centre study includes 107 individuals with confirmed GA1 identified by newborn screening between 1999 and 2020 in Germany. Clinical status, development, and IQ were assessed using standardized tests. Impact of interventional and non-interventional parameters on cognitive outcome was evaluated. The majority of tested individuals (n = 72) showed stable IQ values with age (n = 56 with IQ test; median test age 11 years) but a significantly lower performance (median [IQR] IQ 87 [78–98]) than in general population, particularly in individuals with a biochemical high excreter phenotype (84 [75–96]) compared to the low excreter group (98 [92–105]; p = 0.0164). For all patients, IQ results were homogenous on subscale levels. Sex, clinical motor phenotype and quality of metabolic treatment had no impact on cognitive functions. Long-term neurologic outcome in GA1 involves both motor and cognitive functions. The biochemical high excreter phenotype is the major risk factor for cognitive impairment while cognitive functions do not appear to be impacted by current therapy and striatal damage. These findings implicate the necessity of new treatment concepts.

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