Tyrosine hydroxylase (TH) catalyses the rate-limiting step in dopamine biosynthesis. Autosomal recessive tyrosine hydroxylase deficiency (THD) leads to clinical phenotypes reflecting the deficiency of dopamine, norepinephrine, or epinephrine in the central nervous system (CNS), presenting along a continuous spectrum from mild to severe forms of the disease. The diagnosis is suggested by the detection of low CSF homovanillic acid (HVA) and confirmed by identifying biallelic pathogenic variants in the TH gene. L-dopa/decarboxylase inhibitor (DCI) supplementation is often the first-line treatment, and most patients have a good therapeutic response. However, initiation of therapy can be challenging in patients with severe disease forms who develop L-dopa/DCI-induced dyskinesia. Therefore, alternative treatment options, such as monoamine oxidase (MAO) inhibitors, must be evaluated to optimize motor symptom control. Clinical experience suggests that early diagnosis and treatment initiation may improve the outcome. Additionally, a multidisciplinary treatment approach should be utilized to monitor neurocognitive development and other comorbidities that may occur in THD. In this consensus guideline, representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) and patient advocates evaluated all the evidence available in the literature on the diagnosis and management of THD and developed recommendations using the SIGN and GRADE methodologies. Based on the limited evidence, practical recommendations have been developed to support clinical diagnosis, laboratory testing, neuroimaging, medical treatment, and non-medical interventions. Research topics for further development were identified. This guideline aims to improve the care of patients with THD worldwide and raise general awareness of this rare disease.

1st Department of Paediatrics Agia Sofia Hospital National and Kapodistrian University of Athens Athens Greece

Child Neurology and Psychiatry Unit Department of Neuroscience Mental Health Policlinico Umberto 1 Rome Italy

Clinic for Neurology and Psychiatry for Children and Youth Belgrade Serbia

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

Department of Neuroscience Biomedicine and Movement Sciences Verona University Verona Italy

Department of Pediatrics and Inherited Metabolic Disorders Charles University and General University Hospital Prague Prague Czech Republic

Department of Pediatrics Pediatric Neurology and Metabolic Unit Research Group Vitality Universitair Ziekenhuis Brussel Brussels Belgium

Developmental Neurosciences Zayed Centre for Research UCL GOS ICH; Department of Neurology Great Ormond Street Hospital London UK

Division of Biochemical Genetics Vancouver General Hospital and BC Children's Hospital Vancouver British Columbia Canada

Division of Neurology Nationwide Children's Hospital The Ohio State University College of Medicine Columbus Ohio USA

Heidelberg University Medical Faculty Heidelberg Center for Paediatric and Adolescent Medicine Department 1 Division of Pediatric Neurology and Metabolic Medicine Heidelberg Germany

Lil' Brave One Patient Organization for Rare Neurotransmitter Diseases Novi Sad Serbia

Neurometabolic Unit and Synaptic Metabolism Lab Neurology Department Institut Pediàtric de Recerca Hospital Sant Joan de Déu Barcelona Spain

Neuropediatric Service CHU Montpellier Montpellier France

Neuropediatric Unit Pediatric Department Hospital Universitari Germans Trias 1 Pujol Badalona Spain

Pediatric Department Son Llàtzer University Hospital Palma Spain

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