Inherited disorders of neurotransmitter metabolism are rare neurodevelopmental diseases presenting with movement disorders and global developmental delay. This study presents the results of the first standardized deep phenotyping approach and describes the clinical and biochemical presentation at disease onset as well as diagnostic approaches of 275 patients from the registry of the International Working Group on Neurotransmitter related Disorders. The results reveal an increased rate of prematurity, a high risk for being small for gestational age and for congenital microcephaly in some disorders. Age at diagnosis and the diagnostic delay are influenced by the diagnostic methods applied and by disease-specific symptoms. The timepoint of investigation was also a significant factor: delay to diagnosis has decreased in recent years, possibly due to novel diagnostic approaches or raised awareness. Although each disorder has a specific biochemical pattern, we observed confounding exceptions to the rule. The data provide comprehensive insights into the phenotypic spectrum of neurotransmitter disorders.

1st Department of Pediatrics Aristotle University of Thessaloniki Egnatia St 106 Thessaloniki Greece

1st Department of Pediatrics of the University of Athens Aghia Sofia Hospital Athens Greece

Children's Hospital University Medical Center Hamburg Eppendorf Hamburg Germany

Childrenś Department Division of Child Neurology Oslo University Hospital Rikshospitalet Pb 4956 Nydalen Oslo Norway

Clinic for Pediatrics 1 Medical University of Innsbruck Innsbruck Austria

Computational Oncology Molecular Diagnostics Program National Center for Tumor Diseases DKFZ Heidelberg Germany

Çukurova University Faculty of Medicine Department of Pediatrics Division of Pediatric Metabolism and Nutrition Adana Turkey

Department of Human Neuroscience Unit of Child Neurology and Psychiatry Università degli Studi di Roma La Sapienza Rome Italy

Department of Neurology Donders Institute for Brain Cognition and Behaviour Radboud University Medical Center Nijmegen The Netherlands

Department of Neurology Washington University School of Medicine St Louis MO USA

Department of Pediatric Immunology Hematology and Oncology Heidelberg University Hospital Heidelberg Germany

Department of Pediatrics and Adolescent Medicine The Hong Kong Childrenś Hospital Hong Kong Hong Kong

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Pediatrics AOU Città della Salute e della Scienza Torino Italy

Department of Pediatrics Pediatric Neurology Unit UZ Brussel VUB Brussels Belgium

Department of Pediatrics University of Alberta Glenrose Rehabilitation Hospital Edmonton AB Canada

Developmental Neurosciences UCL Great Ormond Street Institute of Child Health and Department of Neurology Great Ormond Street Hospital London UK

Division of Clinical and Metabolic Genetics Department of Pediatrics University of Toronto The Hospital for Sick Children 555 University Avenue Toronto Toronto ON Canada

German Cancer Consortium Heidelberg Germany

Hacettepe University Faculty of Medicine Department of Pediatrics Section of Metabolism Ankara Turkey

Heidelberg Institute for Stem cell Technology and Experimental Medicine Heidelberg Germany

Inborn Errors of Metabolism and Child Neurology Unit Department of Pediatrics Hospital Germans Trias i Pujol Badalona and Faculty of Medicine Universitat Autònoma de Barcelona Barcelona Spain

Inborn errors of metabolism Unit Department of Neurology Institut de Recerca Sant Joan de Déu and CIBERER ISCIII Barcelona Spain

Pediatric Neurology Unit Department of Pediatrics University Hospital Reina Sofía IMIBIC and CIBERER Córdoba Spain

U O C Malattie Metaboliche Ereditarie Dipartimento della Salute della Donna e del Bambino Azienda Ospedaliera Universitaria di Padova Campus Biomedico Pietro d'Abano Padova Italy

UCSD Departments of Neuroscience and Pediatrics; Rady Children's Hospital Division of Neurology Rady Children's Institute for Genomic Medicine San Diego CA USA

University Children's Hospital Heidelberg Dietmar Hopp Metabolic Center Heidelberg Germany

University Children's Hospital Heidelberg Division of Child Neurology and Metabolic Disorders Heidelberg Germany

University of British Columbia Department of Pediatrics Division of Biochemical Genetics BC Children's Hospital Vancouver BC Canada

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