Opladen et al. Orphanet Journal of Rare Diseases (2020) 15:202 https://doi.org/10.1186/s13023-020-01464-y CORRECTION Open Access Correction to: Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies Thomas Opladen1*†, Eduardo López-Laso2†, Elisenda Cortès-Saladelafont3,4†, Toni S. Pearson5, H. Serap Sivri6, Yilmaz Yildiz6, Birgit Assmann1, Manju A. Kurian7,8, Vincenzo Leuzzi9, Simon Heales10, Simon Pope10, Francesco Porta11, Angeles García-Cazorla3, Tomáš Honzík12, Roser Pons13, Luc Regal14, Helly Goez15, Rafael Artuch16, Georg F. Hoffmann1, Gabriella Horvath17, Beat Thöny18, Sabine Scholl-Bürgi19, Alberto Burlina20, Marcel M. Verbeek21, Mario Mastrangelo9, Jennifer Friedman22, Tessa Wassenberg14, Kathrin Jeltsch1†, Jan Kulhánek12*†, Oya Kuseyri Hübschmann1† and on behalf of the International Working Group on Neurotransmitter related Disorders (iNTD) Correction to: Orphanet Journal of Rare Diseases 15, 126 (2020) https://doi.org/10.1186/s13023-020-01379-8 Following the original article's publication [1] the authors asked for the correction of Fig. 2, since the names of the disease genes [GCH1 and PCBD1] in the figure published did not match the listed diseases [AR-GTPCHD and PCDD]. The correct Fig. 2 is shown below: In the context of the manuscript correction and in order to match the text content, the words "apart from DHPRD" should be removed from the second row and second column of Table 4, as shown below: The original article can be found online at https://doi.org/10.1186/s13023- 020-01379-8. * Correspondence: Thomas.Opladen@med.uni-heidelberg.de; Jan.Kulhanek@vfn.cz † Thomas Opladen, Eduardo López-Laso, Elisenda Cortès-Saladelafont, Kathrin Jeltsch, Jan Kulhánek and Oya Kuseyri Hübschmann contributed equally to this work. 1 Division of Child Neurology and Metabolic Disorders, University Children’s Hospital, Heidelberg, Germany 12 Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Opladen et al. Orphanet Journal of Rare Diseases (2020) 15:202 Page 2 of 5 Fig. 2 (See legend on next page.) Opladen et al. Orphanet Journal of Rare Diseases (2020) 15:202 Page 3 of 5 (See figure on previous page.) Fig. 2 Diagnostic flowchart for differential diagnosis of BH4Ds with and without HPA. 1Consider genetic HPA workup depending on availability and financial resources. The gene panel should include the QDPR, GCH1, PTS PCBD1, SPR genes as well as DNAJC12. For GCH1, consider MLPA if Sanger sequencing is negative. 2The analysis in urine is more sensitive than in DBS and pathological patterns suggestive for PCDD and SRD can only be detected in urine but not in DBS. 3Primapterin measurement in urine is only elevated in PCDD. 4Aminoacids in CSF are not required for diagnosis of BH4Ds. 5CSF analysis should always include standard measurements (cell count, proteins, glucose and lactate). 6Recommendation against measurements of HVA, 5-HIAA, 5-MTHF, and pterins in CSF in the case of PCDD. (*) A diagnostic L-Dopa trial should be limited to children with symptoms suggestive of dopa-responsive dystonia or to situations where biochemical and genetic diagnostic tools are not available. If the diagnostic L-Dopa trial is positive but the results of CSF biochemical and/or molecular genetic testing are not compatible with AD-GTPCHD or SRD, further aetiologies for dopa responsive dystonia should be considered (e.g. juvenile parkinsonism (PARK2gene)). (**) Can be considered if available. See text for more detailed information. Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; 5-MTHF, 5-methyltetrahydrofolate; AA: amino acids; AD−/AR- GTPCHD: guanosine triphosphate cyclohydrolase I deficiency; BH4, tetrahydrobiopterin; Bio: biopterin; CSF: cerebrospinal fluid; DBS: dry blood spot; DHPR: q-dihydropteridine reductase; DHPRD, dihydropteridine reductase deficiency; HVA, homovanillic acid; MRI, magnetic resonance imaging; N: normal; NBS: newborn screening; Neo: neopterin; NR: not reported; PAH: phenylalanine hydroxylase; Phe: phenylalanine; PKU: phenylketonuria; Prim: primapterin; PTPSD, 6-pyruvoyltetrahydropterin synthase deficiency; SRD: sepiapterin reductase deficiency; Tyr: tyrosine; u: urine; (+) = positive effect; (−) = no or no clear effect Opladen et al. Orphanet Journal of Rare Diseases (2020) 15:202 Page 4 of 5 Table 4 Recommended drugs and doses for BH4 disorders Disorder Starting dose Doses Target dose Maximum dose Management Comment suggestion First line treatments Phe-reduced diet All BH4D Titrate Phe Follow PKU national treatment with HPA restriction recommendations according to Use either Phe reduced diet or Phe levels in Sapropterin dihydrochloride to DBS or plasma control Phe levels Sapropterin All BH4D 2-5 mg/kg BW/ Divided 5–10 mg/kg BW/ 20 mg/kg BW/day Titrate dose Follow PKU national treatment dihydrochloride with HPA day in 1–3 day according to recommendations doses/ Phe levels in Use either Phe reduced diet or day DBS or plasma Sapropterin dihydrochloride to control Phe levels L-Dopa/DC inhibitor All BH4D 0.5 mg–1 mg/kg Divided AD-GTPCHD: Depending on Increase 0.5–1 In young infants at least as many (carbidopa/ apart from BW/day in 2–6 3–7 mg/kg BW/ clinical symptoms. mg/kg BW/day dosages as meals would be ideal benserazide) 4:1 PCDD Dose doses/ day Some patients need per week (usually 5–6 /day) recommendation day All other BH4D: more than 10 mg/kg Follow BW relates to L-Dopa 10 mg/kg BW/day BW/day for resolving adaption until component! or maximally clinical symptoms the BW of 40 kg. tolerated dosage After 40 kg Dose adjust recommendation depending on relates to L-Dopa clinical component! symptoms Consider analysis of CSF HVA for dose adjustment 5- All BH4D 1–2 mg/kg BW/ Divided Published target Titrate slowly 5-HTP should follow L-Dopa/DCI Hydroxytryptophan apart from day in 3–6 dose (1–2 mg/kg BW/ treatment initiation (5-HTP) AD-GTPCHD doses/ recommendations day per week) Always in combination with a and PCDD day are highly variable depending on peripheral decarboxylase inhibitor 5-HTP doses are clinical picture (for example by simultaneous usually lower than and side effects application with L-Dopa/DC L-Dopa doses Consider inhibitor) analysis of CSF 5HIAA for dose finding Folinic acid In DHPRD Divided 10–20 mg/day No titration and all in 1–2 needed BH4D with doses/ Consider low 5-MTHF day analysis of CSF in CSF 5MTHF for dose finding Second line treatments Pramipexolea All BH4D 3.5–7 μg/kg/BW/ Divided Titrate to clinical 75 μg/kg BW/day Increase (Dopamine agonist) apart from day (base) in 3 Symptoms (3.3 mg/d base / 4 every 7 days by PCDD 5–10 μg/kgBW/ equal mg/d salt) 5 μg/kg BW/d day (salt) doses/ Note: Distinction day in salt and base content! (see product insert) Bromocriptinea All BH4D 0.1 mg/kg BW/ Divided Titrate to clinical 0.5 mg/kg/d Increase (Dopamine agonist) apart from day in 2–3 Symptoms (or 30 mg/d) every 7 days by PCDD doses/ 0.1 mg/kg BW/d day Rotigotinea All BH4D 2 mg/day Titrate to clinical 8 mg/day Increase weekly Children > 12 years (transdermal dopamine apart from Symptoms by Exchange patch every 24 h agonist) PCDD 1 mg Selegilinea All BH4D 0.1 mg/kg BW/ Divided Titrate to clinical 0.3 mg/kg/d Increase every 2 Can cause sleep disturbances – (MAO B inhibitor) apart from day in 2 Symptoms (or 10 mg/d) weeks by morning and afternoon or PCDD (−3) 0.1 mg/kg BW/d lunchtime dosage is possible doses/ ATTENTION: orally disintegrating day preparation needs much less dosage because the first-pass ef- fect of the liver is avoided Opladen et al. Orphanet Journal of Rare Diseases (2020) 15:202 Page 5 of 5 Table 4 Recommended drugs and doses for BH4 disorders (Continued) Disorder Starting dose Doses Target dose Maximum dose Management Comment suggestion Third line treatments Trihexyphenidyla All BH4D < 15 kg: start 0.5– < 15 kg: Effective dose Maximum dose: Increase every 7 Consider side effects: like dry (Anticholinergic drugs) apart from 1 mg/day in 1 highly variable < 15 kg BW days mouth, dry PCDD > 15 kg: start 2 dose (6–60 mg) 30 mg/day by 1–2 mg/d in eyes, blurred vision (mydriasis), mg/day > 15 kg: Titrate to clinical > 15 kg BW 2–4 doses/d urine retention, constipation. in 2 Symptoms 60 mg/d doses Entacaponea All BH4D 200 mg Up to 2.000 mg In many countries licensed only (COMT inhibitor) apart from (adult) for adults. PCDD Comedication with L-Dopa/DC inhibitor Consider reduction of concomitant L-Dopa supplementa- tion (10–30%) Sertalinea All BH4D 6–12 years: 25 6–12 Children 50 mg/ 50 mg/day 6–12 years: Don’t stop treatment suddenly (SSRI) apart from mg/day years: day < 12 years increase after 7 Note: Elevated risk of serotonin PCDD in 1 dose in 1 200 mg/day days to 50 mg/ syndrome > 12 years: 50 dose > 12 years day (SS) or malignant neuroleptic mg/day in 1 dose > 12 in 1 dose syndrome (MNS) when used with years: > 12 years 50 drugs impacting serotonergic in 1 mg/day in 1 pathway (e.g. 5-HTP, MAO dose dose inhibitors) Melatonina All BH4D 0.01–0.03 mg/kg/ 5–8 mg/day Slow release preparation for sleep- apart from day maintenance insomnia available in PCDD some countries Please note: The doses given are in a range typically used and have been published. In individual patients, some adjustment may be necessary depending on symptom response and side effects a The evaluated literature did not provide BH4D specific treatment dose recommendations for this drug. The listed doses, therefore, indicate treatment recommendations from Summary of Product Characteristics (SmPC) or neurotransmitter related publications (e.g. [119]) Abbreviations: 5-HIAA 5-hydroxyindoleacetic acid, 5-HTP 5-hydroxytryptophan, 5-MTHF 5- methyltetrahydrofolate, HVA Homovanillic acid, AD-GTPCHD Autosomal- dominant guanosine triphosphate cyclohydrolase I deficiency, BH4D Tetrahydrobiopterin deficiency, BW Body weight, COMT Catechol-O-methyl transferase, CSF Cerebrospinal fluid, DBS Dry blood spot, DC Decarboxylase, DCI Decarboxylase inhibitor, DHPRD Dihydropteridine reductase deficiency, L-Dopa L-3,4- dihydroxyphenylalanine, MAO B Monoamine oxidase B, PCDD Pterin-4-alpha-carbinolamine dehydratase deficiency, Phe Phenylalanine, PKU Phenylketonuria, SSRI Selective serotonin reuptake inhibitor Author details Medical Center, Donders Institute for Brain, Cognition and Behaviour, 1 Division of Child Neurology and Metabolic Disorders, University Children’s Nijmegen, The Netherlands. 22UCSD Departments of Neuroscience and Hospital, Heidelberg, Germany. 2Pediatric Neurology Unit, Department of Pediatrics, Rady Children’s Hospital Division of Neurology, Rady Children’s Pediatrics, University Hospital Reina Sofía, IMIBIC and CIBERER, Córdoba, Institute for Genomic Medicine, San Diego, USA. Spain. 3Inborn errors of metabolism Unit, Institut de Recerca Sant Joan de Déu and CIBERER-ISCIII, Barcelona, Spain. 4Unit of Pediatric Neurology and Metabolic Disorders, Department of Pediatrics, Hospital Germans Trias i Pujol, and Faculty of Medicine, Universitat Autònoma de Barcelona, Badalona, Reference Spain. 5Department of Neurology, Washington University School of Medicine, 1. Opladen, et al. Consensus guideline for the diagnosis and treatment of St. Louis, USA. 6Department of Pediatrics, Section of Metabolism, Hacettepe tetrahydrobiopterin (BH4) deficiencies. Orphanet Journal of Rare Diseases. University, Faculty of Medicine, 06100 Ankara, Turkey. 7Developmental 2020;15:126. https://doi.org/10.1186/s13023-020-01379-8. Neurosciences, UCL Great Ormond Street-Institute of Child Health, London, UK. 8Department of Neurology, Great Ormond Street Hospital, London, UK. 9 Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy. 10Neurometabolic Unit, National Hospital, Queen Square, London, UK. 11Department of Pediatrics, AOU Città della Salute e della Scienza, Torino, Italy. 12Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. 13 First Department of Pediatrics of the University of Athens, Aghia Sofia Hospital, Athens, Greece. 14Department of Pediatric, Pediatric Neurology and Metabolism Unit, UZ Brussel, Brussels, Belgium. 15Department of Pediatrics, University of Alberta Glenrose Rehabilitation Hospital, Edmonton, Canada. 16 Clinical biochemistry department, Institut de Recerca Sant Joan de Déu, CIBERER and MetabERN Hospital Sant Joan de Déu, Barcelona, Spain. 17 Department of Pediatrics, Division of Biochemical Genetics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada. 18Division of Metabolism, University Children’s Hospital Zurich, Zürich, Switzerland. 19Clinic for Pediatrics I, Medical University of Innsbruck, Anichstr 35, Innsbruck, Austria. 20U.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. 21Departments of Neurology and Laboratory Medicine, Alzheimer Centre, Radboud University