BACKGROUND: Tetrahydrobiopterin (BH4) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4 biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4 deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH4 deficiencies. CONCLUSION: Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH4 deficient patients.

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

Clinic for Pediatrics 1 Medical University of Innsbruck Anichstr 35 Innsbruck Austria

Clinical biochemistry department Institut de Recerca Sant Joan de Déu CIBERER and MetabERN Hospital Sant Joan de Déu Barcelona Spain

Department of Neurology Great Ormond Street Hospital London UK

Department of Neurology Washington University School of Medicine St Louis USA

Department of Paediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Pediatric Pediatric Neurology and Metabolism Unit UZ Brussel Brussels Belgium

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

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

Department of Pediatrics Section of Metabolism Hacettepe University Faculty of Medicine 06100 Ankara Turkey

Department of Pediatrics University of Alberta Glenrose Rehabilitation Hospital Edmonton Canada

Departments of Neurology and Laboratory Medicine Alzheimer Centre Radboud University Medical Center Donders Institute for Brain Cognition and Behaviour Nijmegen The Netherlands

Developmental Neurosciences UCL Great Ormond Street Institute of Child Health London UK

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

Division of Metabolism University Children's Hospital Zurich Zürich Switzerland

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

Neurometabolic Unit National Hospital Queen Square London UK

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 USA

Unit of Child Neurology and Psychiatry Department of Human Neuroscience Sapienza University of Rome Rome Italy

Unit of Pediatric Neurology and Metabolic Disorders Department of Pediatrics Hospital Germans Trias i Pujol and Faculty of Medicine Universitat Autònoma de Barcelona Badalona Spain

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Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines

U-IMD: the first Unified European registry for inherited metabolic diseases

Correction to: Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies