Hepatorenal tyrosinaemia (HT1) is an autosomal recessive disorder of tyrosine degradation resulting in hepatic and renal dysfunction, neurological sequelae may occur in some patients. The use of nitisinone (NTBC) has revolutionised treatment and outcome of this disorder. NTBC has to be combined with a low protein diet. While NTBC modulates the disease course in HT1 patients, several issues are open. Optimal dosage, doses per day, therapeutic range of NTBC concentration, mode of protein restriction and biomarkers are not well defined. HCC and neurocognitive deficits are long-term sequelae. Early diagnosis and treatment are essential to minimise the risk for these complications. Clinical guidance for management of HT1-patients is required. Randomised clinical studies are difficult in the presence of therapeutic options. We discussed these issues in a consensus group of 10 paediatricians, 1 adult hepatologist, 1 geneticist, 2 dieticians, 2 newborn screening specialists with experience in HT1, 1 psychologist and 2 representatives of a patient group from the German-speaking countries (DACH). Recommendations were based on scientific literature and expert opinion, also taking into account recent experience with newborn screening. There was strong consensus that newborn screening using succinylacetone (SA) and early treatment are essential for a good outcome. The dose of NTBC should be as low as possible without losing metabolic control. This has to be accompanied by a low protein diet, in some patients a simplified diet without calculation of protein intake. Specific education and psychosocial support are recommended. Indications for liver transplantation were defined. Monitoring shall include clinical findings, levels of SA, tyrosine, phenylalanine and NTBC in (dried) blood.

Charité University hospital Berlin Germany

Clinic for Gastroenterology Hepatology and Infectiology University Clinic Düsseldorf Düsseldorf Germany

Clinic for Paediatrics Division of Inherited Metabolic Disorders Medical University of Innsbruck Innsbruck Austria

Department of General Paediatrics Adolescent Medicine and Neonatology Faculty of Medicine Medical Centre University of Freiburg Freiburg Germany

Department of Human Genetics Hannover Medical School Hannover Germany

Department of Medical Psychology Hannover Medical School Hannover Germany

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

Department of Paediatrics Charité University hospital Berlin Germany

Department of Paediatrics Klinik für Kinder und Jugendmedizin Kreiskliniken Reutlingen Reutlingen Germany

Division of Metabolism and Children's Research Center University Children's Hospital Zurich University of Zurich Zurich Switzerland

German Patients Association for PKU and Allied Metabolic Disorders Deutsche Interessengemeinschaft Phenylketonurie und verwandte angeborene Stoffwechselstörungen e 5 Fürth Germany

Hannover Medical School Department of Clinical Chemistry Hannover Germany

Hannover Medical School Department of Paediatrics Hannover Germany

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

Metabolic Screening Laboratory Screening Labor Hannover Hannover Germany

Pediatric Metabolic Unit Pediatrics Woman Mother Child Department Lausanne University Hospital and University of Lausanne Lausanne Switzerland

Zobrazit více v PubMed

Angileri F, Bergeron A, Morrow G, et al. Geographical and ethnic distribution of mutations of the fumarylacetoacetate hydrolase gene in hereditary tyrosinemia type 1. JIMD Rep. 2015;19:43‐58. doi:10.1007/8904_2014_363 PubMed DOI PMC

Arranz JA, Piñol F, Kozak L, et al. Splicing mutations, mainly IVS6‐1(G>T), account for 70% of fumarylacetoacetate hydrolase (FAH) gene alterations, including 7 novel mutations, in a survey of 29 tyrosinemia type I patients. Hum Mutat. 2002;20(3):180‐188. doi:10.1002/humu.10084 PubMed DOI

Poudrier J, St‐Louis M, Lettre F, et al. Frequency of the IVS12 + 5G‐‐>A splice mutation of the fumarylacetoacetate hydrolase gene in carriers of hereditary tyrosinaemia in the French Canadian population of Saguenay‐Lac‐St‐Jean. Prenat Diagn. 1996;16(1):59‐64. doi:10.1002/(SICI)1097-0223(199601)16:1<59::AID-PD810>3.0.CO;2-D PubMed DOI

Russo PA, Mitchell GA, Tanguay RM. Tyrosinemia: a review. Pediatr Dev Pathol. 2001;4(3):212‐221. doi:10.1007/s100240010146 PubMed DOI

Halac U, Dubois J, Mitchell GA. The liver in tyrosinemia type I: clinical management and course in Quebec. Adv Exp Med Biol. 2017;959:75‐83. doi:10.1007/978-3-319-55780-9_6 PubMed DOI

Maiorana A, Dionisi‐Vici C. NTBC and correction of renal dysfunction. Adv Exp Med Biol. 2017;959:93‐100. doi:10.1007/978-3-319-55780-9_8 PubMed DOI

Maiorana A, Malamisura M, Emma F, et al. Early effect of NTBC on renal tubular dysfunction in hereditary tyrosinemia type 1. Mol Genet Metab. 2014;113(3):188‐193. doi:10.1016/j.ymgme.2014.07.021 PubMed DOI

Mayorandan S, Meyer U, Gokcay G, et al. Cross‐sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice. Orphanet J Rare Dis. 2014;9:107. doi:10.1186/s13023-014-0107-7 PubMed DOI PMC

Koelink CJ, van Hasselt P, van der Ploeg A, et al. Tyrosinemia type I treated by NTBC: how does AFP predict liver cancer? Mol Genet Metab. 2006;89(4):310‐315. doi:10.1016/j.ymgme.2006.07.009 PubMed DOI

Paradis K, Weber A, Seidman EG, et al. Liver transplantation for hereditary tyrosinemia: the Quebec experience. Am J Hum Genet. 1990;47(2):338‐342. PubMed PMC

Schady DA, Roy A, Finegold MJ. Liver tumors in children with metabolic disorders. Transl Pediatr. 2015;4(4):290‐303. doi:10.3978/j.issn.2224-4336.2015.10.08 PubMed DOI PMC

van Spronsen FJ, Bijleveld CM, van Maldegem BT, Wijburg FA. Hepatocellular carcinoma in hereditary tyrosinemia type I despite 2‐(2 nitro‐4‐3 trifluoro‐ methylbenzoyl)‐1, 3‐cyclohexanedione treatment. J Pediatr Gastroenterol Nutr. 2005;40(1):90‐93. doi:10.1097/00005176-200501000-00017 PubMed DOI

Demers SI, Russo P, Lettre F, Tanguay RM. Frequent mutation reversion inversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia. Hum Pathol. 2003;34(12):1313‐1320. doi:10.1016/s0046-8177(03)00406-4 PubMed DOI

Morrow G, Angileri F, Tanguay RM. Molecular aspects of the FAH mutations involved in HT1 disease. Adv Exp Med Biol. 2017;959:25‐48. doi:10.1007/978-3-319-55780-9_3 PubMed DOI

Morrow G, Tanguay RM. Biochemical and clinical aspects of hereditary tyrosinemia type 1. Adv Exp Med Biol. 2017;959:9‐21. doi:10.1007/978-3-319-55780-9_2 PubMed DOI

Tanguay RM, Valet JP, Lescault A, et al. Different molecular basis for fumarylacetoacetate hydrolase deficiency in the two clinical forms of hereditary tyrosinemia (type I). Am J Hum Genet. 1990;47(2):308‐316. PubMed PMC

van Spronsen FJ, Thomasse Y, Smit GP, et al. Hereditary tyrosinemia type I: a new clinical classification with difference in prognosis on dietary treatment. Hepatology. 1994;20(5):1187‐1191. PubMed

Das AM, Mayorandan S, Janzen N. Diagnosing hepatorenal tyrosinaemia in Europe: newborn mass screening versus selective screening. Adv Exp Med Biol. 2017;959:125‐132. doi:10.1007/978-3-319-55780-9_11 PubMed DOI

Lock EA. From weed killer to wonder drug. Adv Exp Med Biol. 2017;959:175‐185. doi:10.1007/978-3-319-55780-9_16 PubMed DOI

Holme E, Lindstedt S. Diagnosis and management of tyrosinemia type I. Curr Opin Pediatr. 1995;7(6):726‐732. doi:10.1097/00008480-199512000-00017 PubMed DOI

Lindstedt S, Holme E, Lock EA, Hjalmarson O, Strandvik B. Treatment of hereditary tyrosinaemia type I by inhibition of 4‐hydroxyphenylpyruvate dioxygenase. Lancet. 1992;340(8823):813‐817. doi:10.1016/0140-6736(92)92685-9 PubMed DOI

van Spronsen FJ, van Rijn M, Meyer U, Das AM. Dietary considerations in tyrosinemia type I. Adv Exp Med Biol. 2017;959:197‐204. doi:10.1007/978-3-319-55780-9_18 PubMed DOI

Bartlett DC, Lloyd C, McKiernan PJ, Newsome PN. Early nitisinone treatment reduces the need for liver transplantation in children with tyrosinaemia type 1 and improves post‐transplant renal function. J Inherit Metab Dis. 2014;37(5):745‐752. doi:10.1007/s10545-014-9683-x PubMed DOI

McKiernan PJ, Preece MA, Chakrapani A. Outcome of children with hereditary tyrosinaemia following newborn screening. Arch Dis Child. 2015;100(8):738‐741. doi:10.1136/archdischild-2014-306886 PubMed DOI

Bendadi F, de Koning TJ, Visser G, et al. Impaired cognitive functioning in patients with tyrosinemia type I receiving nitisinone. J Pediatr. 2014;164(2):398‐401. doi:10.1016/j.jpeds.2013.10.001 PubMed DOI

de Laet C, Munoz VT, Jaeken J, et al. Neuropsychological outcome of NTBC‐treated patients with tyrosinaemia type 1. Dev Med Child Neurol. 2011;53(10):962‐964. doi:10.1111/j.1469-8749.2011.04048.x PubMed DOI

Masurel‐Paulet A, Poggi‐Bach J, Rolland MO, et al. NTBC treatment in tyrosinaemia type I: long‐term outcome in French patients. J Inherit Metab Dis. 2008;31(1):81‐87. doi:10.1007/s10545-008-0793-1 PubMed DOI

Pohorecka M, Biernacka M, Jakubowska‐Winecka A, et al. Behavioral and intellectual functioning in patients with tyrosinemia type I. Pediatr Endocrinol Diabetes Metab. 2012;18(3):96‐100. PubMed

Thimm E, Richter‐Werkle R, Kamp G, et al. Neurocognitive outcome in patients with hypertyrosinemia type I after long‐term treatment with NTBC. J Inherit Metab Dis. 2012;35(2):263‐268. doi:10.1007/s10545-011-9394-5 PubMed DOI

van Ginkel WG, Jahja R, Huijbregts SCJ, van Spronsen FJ. Neurological and neuropsychological problems in tyrosinemia type I patients. Adv Exp Med Biol. 2017a;959:111‐122. doi:10.1007/978-3-319-55780-9_10 PubMed DOI

van Ginkel WG, Pennings JP, van Spronsen FJ. Liver cancer in tyrosinemia type 1. Adv Exp Med Biol. 2017b;959:101‐109. doi:10.1007/978-3-319-55780-9_9 PubMed DOI

van Ginkel WG, van Vliet D, Burgerhof JGM, et al. Presumptive brain influx of large neutral amino acids and the effect of phenylalanine supplementation in patients with tyrosinemia type 1. PLoS One. 2017c;12(9):e0185342. doi:10.1371/journal.pone.0185342 PubMed DOI PMC

van Ginkel WG, Jahja R, Huijbregts SC, et al. Neurocognitive outcome in tyrosinemia type 1 patients compared to healthy controls. Orphanet J Rare Dis. 2016;11(1):87. doi:10.1186/s13023-016-0472-5 PubMed DOI PMC

Chinsky JM, Singh R, Ficicioglu C, et al. Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations. Genet Med. 2017;19(12):1380‐1395. doi:10.1038/gim.2017.101 PubMed DOI PMC

de Laet C, Dionisi‐Vici C, Leonard JV, et al. Recommendations for the management of tyrosinaemia type 1. Orphanet J Rare Dis. 2013;8. doi:10.1186/1750-1172-8-8 PubMed DOI PMC

Schiff M, Broue P, Chabrol B, et al. Heterogeneity of follow‐up procedures in French and Belgian patients with treated hereditary tyrosinemia type 1: results of a questionnaire and proposed guidelines. J Inherit Metab Dis. 2012;35(5):823‐829. doi:10.1007/s10545-011-9429-y PubMed DOI

de Jesús VR, Adam BW, Mandel D, Cuthbert CD, Matern D. Succinylacetone as primary marker to detect tyrosinemia type I in newborns and its measurement by newborn screening programs. Mol Genet Metab. 2014;113(1–2):67‐75. doi:10.1016/j.ymgme.2014.07.010 PubMed DOI PMC

la Marca G, Malvagia S, Pasquini E, et al. Newborn screening for tyrosinemia type I: further evidence that Succinylacetone determination on blood spot is essential. JIMD Rep. 2011;1:107‐109. doi:10.1007/8904_2011_24 PubMed DOI PMC

Morrissey MA, Sunny S, Fahim A, Lubowski C, Caggana M. Newborn screening for Tyr‐I: two years' experience of the New York State program. Mol Genet Metab. 2011;103(2):191‐192. doi:10.1016/j.ymgme.2011.02.017 PubMed DOI

Sander J, Janzen N, Peter M, et al. Newborn screening for hepatorenal tyrosinemia: tandem mass spectrometric quantification of succinylacetone. Clin Chem. 2006;52(3):482‐487. doi:10.1373/clinchem.2005.059790 PubMed DOI

Turgeon C, Magera MJ, Allard P, et al. Combined newborn screening for succinylacetone, amino acids, and acylcarnitines in dried blood spots. Clin Chem. 2008;54(4):657‐664. doi:10.1373/clinchem.2007.101949 PubMed DOI

Weigel JF, Janzen N, Pfäffle RW, Thiery J, Kiess W, Ceglarek U. Tandem mass spectrometric determination of succinylacetone in dried blood spots enables presymptomatic detection in a case of hepatorenal tyrosinaemia. J Inherit Metab Dis. 2007;30(4):610. doi:10.1007/s10545-007-0608-9 PubMed DOI

Allard P, Grenier A, Korson MS, Zytkovicz TH. Newborn screening for hepatorenal tyrosinemia by tandem mass spectrometry: analysis of succinylacetone extracted from dried blood spots. Clin Biochem. 2004;37(11):1010‐1015. doi:10.1016/j.clinbiochem.2004.07.006 PubMed DOI

Lund AM, Hougaard DM, Simonsen H, et al. Biochemical screening of 504,049 newborns in Denmark, The Faroe Islands and Greenland‐‐experience and development of a routine program for expanded newborn screening. Mol Genet Metab. 2012;107(3):281‐293. doi:10.1016/j.ymgme.2012.06.006 PubMed DOI

Metz TF, Mechtler TP, Merk M, et al. Evaluation of a novel, commercially available mass spectrometry kit for newborn screening including succinylacetone without hydrazine. Clin Chim Acta. 2012;413(15–16):1259‐1264. doi:10.1016/j.cca.2012.04.007 PubMed DOI

Yang H, Al‐Hertani W, Cyr D, et al. Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency. J Med Genet. 2017a;54(4):241‐247. doi:10.1136/jmedgenet-2016-104289 PubMed DOI

Yang H, Rossignol F, Cyr D, et al. Mildly elevated succinylacetone and normal liver function in compound heterozygotes with pathogenic and pseudodeficient FAH alleles. Mol Genet Metab Rep. 2017b;14:55‐58. doi:10.1016/j.ymgmr.2017.12.002 PubMed DOI PMC

Spiekerkoetter U, Krude H. Target diseases for neonatal screening in Germany. Dtsch Arztebl Int. 2022;119(17):306‐316. doi:10.3238/arztebl.m2022.0075 PubMed DOI PMC

Bundesministerium für Gesundheit . Beschluss über eine Änderung der Richtlinie des Bundesausschusses der Ärzte und Krankenkassen über die Früherkennung von Krankheiten bei Kindern bis zur Vollendung des 6. Lebensjahres (Kinder‐Richtlinie) zur Einführung des erweiterten Neugeborenen‐Screenings vom. 2016. https://www.g‐ba.de/downloads/62‐492‐1333/RL_Kinder_2017‐11‐24_iK‐2017‐01‐28.pdf accessed 1.8,2924

de Braekeleer M, Lamarre V, Scriver CR, Larochelle J, Bouchard G. Fertility in couples heterozygous for the tyrosinemia gene in Saguenay Lac‐St‐Jean. Genet Couns. 1990;1(3–4):259‐264. PubMed

de Braekeleer M, Larochelle J. Genetic epidemiology of hereditary tyrosinemia in Quebec and in Saguenay‐Lac‐St‐Jean. Am J Hum Genet. 1990;47(2):302‐307. PubMed PMC

Rafati M, Mohamadhashem F, Hoseini A, Ramandi SD, Ghaffari SR. Prenatal diagnosis of tyrosinemia type 1 using next generation sequencing. Fetal Pediatr Pathol. 2016;35(4):282‐285. doi:10.3109/15513815.2016.1167149 PubMed DOI

Couce ML, Dalmau J, del Toro M, Pintos‐Morell G, Aldámiz‐Echevarría L. Spanish working group on tyrosinemia type 1. Tyrosinemia type 1 in Spain: mutational analysis, treatment and long‐term outcome. Pediatr Int. 2011;53(6):985‐989. doi:10.1111/j.1442-200X.2011.03427.x PubMed DOI

Cassiman D, Zeevaert R, Holme E, Kvittingen EA, Jaeken J. A novel mutation causing mild, atypical fumarylacetoacetase deficiency (Tyrosinemia type I): a case report. Orphanet J Rare Dis. 2009;4:28. doi:10.1186/1750-1172-4-28 PubMed DOI PMC

Morrow G, Dreumont N, Bourrelle‐Langlois M, Roy V, Tanguay RM. Presence of three mutations in the fumarylacetoacetate hydrolase gene in a patient with atypical symptoms of hereditary tyrosinemia type I. Mol Genet Metab. 2019;127(1):58‐63. doi:10.1016/j.ymgme.2019.01.019 PubMed DOI

Spiekerkoetter U, Couce ML, Das AM, et al. Long‐term safety and outcomes in hereditary tyrosinaemia type 1 with nitisinone treatment: a 15‐year non‐interventional, multicentre study. Lancet Diabetes Endocrinol. 2021;9(7):427‐435. doi:10.1016/S2213-8587(21)00092-9 PubMed DOI

Alvarez F, Mitchell GA. Tyrosinemia and liver transplantation: experience at CHU Sainte‐Justine. Adv Exp Med Biol. 2017;959:67‐73. doi:10.1007/978-3-319-55780-9_5 PubMed DOI

Larochelle J, Alvarez F, Bussières JF, et al. Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec. Mol Genet Metab. 2012;107(1–2):49‐54. doi:10.1016/j.ymgme.2012.05.022 PubMed DOI

Santra S, Baumann U. Experience of nitisinone for the pharmacological treatment of hereditary tyrosinaemia type 1. Expert Opin Pharmacother. 2008;9(7):1229‐1236. doi:10.1517/14656566.9.7.1229 PubMed DOI

Santra S, Preece MA, Hulton SA, McKiernan PJ. Renal tubular function in children with tyrosinaemia type I treated with nitisinone. J Inherit Metab Dis. 2008;31(3):399‐402. doi:10.1007/s10545-008-0817-x PubMed DOI

El‐Karaksy H, Fahmy M, El‐Raziky M, et al. Hereditary tyrosinemia type 1 from a single center in Egypt: clinical study of 22 cases. World J Pediatr. 2011;7(3):224‐231. doi:10.1007/s12519-011-0287-3 PubMed DOI

Hall MG, Wilks MF, Provan WM, Eksborg S, Lumholtz B. Pharmacokinetics and pharmacodynamics of NTBC (2‐(2‐nitro‐4‐fluoromethylbenzoyl)‐1,3‐cyclohexanedione) and mesotrione, inhibitors of 4‐hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteers. Br J Clin Pharmacol. 2001;52(2):169‐177. doi:10.1046/j.0306-5251.2001.01421.x PubMed DOI PMC

Schlune A, Thimm E, Herebian D, Spiekerkoetter U. Single dose NTBC‐treatment of hereditary tyrosinemia type I. J Inherit Metab Dis. 2012;35(5):831‐836. doi:10.1007/s10545-012-9450-9 PubMed DOI

Barchanska H, Rola R, Szczepankiewicz W, Mrachacz M. LC‐MS/MS study of the degradation processes of nitisinone and its by‐products. J Pharm Biomed Anal. 2019;171:15‐21. doi:10.1016/j.jpba.2019.03.046 PubMed DOI

Chakrapani A, Gissen P, McKiernan P. Disorders of tyrosine metabolism. In: Saudubray J‐M, van den Berghe G, Walter JH, eds. Inborn Metabolic Diseases, Chapter 18. 5th ed. Springer; 2012:275‐276.

DACH Deutsche Gesellschaft für Ernährung . Österreichische Gesellschaft für Ernährung, Schweizerische Gesellschaft für Ernährungsforschung, Schweizerische Vereinigung für Ernährung (Hrsg.): Referenzwerte für die Nährstoffzufuhr. Bonn, 2. Auflage, 5. aktualisierte Ausgabe. 2019.

Ney DM, Stroup BM, Clayton MK, et al. Glycomacropeptide for nutritional management of phenylketonuria: a randomized, controlled, crossover trial. Am J Clin Nutr. 2016;104(2):334‐345. doi:10.3945/ajcn.116.135293 PubMed DOI PMC

Daly A, Evans S, Pinto A, Ashmore C, MacDonald A. Casein glycomacropeptide: an alternative protein substitute in tyrosinemia type I. Nutrients. 2021;13(9):3224. doi:10.3390/nu13093224 PubMed DOI PMC

Bärhold F, Meyer U, Neugebauer AK, et al. Hepatorenal tyrosinaemia: impact of a simplified diet on metabolic control and clinical outcome. Nutrients. 2020;13(1):134. doi:10.3390/nu13010134 PubMed DOI PMC

Yilmaz O, Daly A, Pinto A, et al. Natural protein tolerance and metabolic control in patients with hereditary tyrosinaemia type 1. Nutrients. 2020;12(4):1148. doi:10.3390/nu12041148 PubMed DOI PMC

Adam BW, Hall EM, Meredith NK, et al. Performance of succinylacetone assays and their associated proficiency testing outcomes. Clin Biochem. 2012;45(18):1658‐1663. doi:10.1016/j.clinbiochem.2012.08.007 PubMed DOI PMC

Laeremans H, Turner C, Andersson T, et al. Inter‐laboratory analytical improvement of succinylacetone and nitisinone quantification from dried blood spot samples. JIMD Rep. 2020;53(1):90‐102. doi:10.1002/jmd2.12112 PubMed DOI PMC

Sander J, Janzen N, Terhardt M, et al. Monitoring tyrosinaemia type I: blood spot test for nitisinone (NTBC). Clin Chim Acta. 2011;412(1–2):134‐138. doi:10.1016/j.cca.2010.09.027 PubMed DOI

Sundberg J, Wibrand F, Lund AM, Christensen M. Simultaneous quantification of succinylacetone and nitisinone for therapeutic drug monitoring in the treatment of Tyrosinemia type 1. J Chromatogr B Analyt Technol Biomed Life Sci. 2018;1072:259‐266. doi:10.1016/j.jchromb.2017.11.031 PubMed DOI

la Marca G, Malvagia S, Materazzi S, et al. LC‐MS/MS method for simultaneous determination on a dried blood spot of multiple analytes relevant for treatment monitoring in patients with tyrosinemia type I. Anal Chem. 2012;84(2):1184‐1188. doi:10.1021/ac202695h PubMed DOI

Karall D, Scholl‐Bürgi S, Widmann G, et al. Stereotactic radiofrequency ablation for liver tumors in inherited metabolic disorders. Cardiovasc Intervent Radiol. 2014;37(4):1027‐1033. doi:10.1007/s00270-013-0756-2 PubMed DOI

Arnon R, Annunziato R, Miloh T, et al. Liver transplantation for hereditary tyrosinemia type I: analysis of the UNOS database. Pediatr Transplant. 2011;15(4):400‐405. doi:10.1111/j.1399-3046.2011.01497.x PubMed DOI

Pierik LJ, van Spronsen FJ, Bijleveld CM, van Dael CM. Renal function in tyrosinaemia type I after liver transplantation: a long‐term follow‐up. J Inherit Metab Dis. 2005;28(6):871‐876. doi:10.1007/s10545-005-0059-0 PubMed DOI

Ernst G, Lange K, Szczepanski R, Staab D, Ehrich J, Zinken K. How to train families to cope with lifelong health problems? J Pediatr. 2016;170:349‐350.e502. doi:10.1016/j.jpeds.2015.11.057 PubMed DOI

Meyer U, Das A, Ernst G, Lange K, Mit PKU gut leben . Schulungsprogramm und Curriculum für Eltern und betroffene Jugendliche. 2. überarbeitete Auflage, Pabst, Lengerich. 2017.

Phelan H, Lange K, Cengiz E, et al. ISPAD Clinical Practice Consensus Guidelines 2018: diabetes education in children and adolescents. Pediatr Diabetes. 2018;19(Suppl 27):75‐83. doi:10.1111/pedi.12762 PubMed DOI

Lange K, Kordonouri O. Setting the right course at type 1 diabetes diagnosis. Lancet Child Adolesc Health. 2019;3(3):138‐139. doi:10.1016/S2352-4642(19)30031-8 PubMed DOI

Skinner TC, Lange KS, Hoey H, et al. Targets and teamwork: understanding differences in pediatric diabetes centers treatment outcomes. Pediatr Diabetes. 2018;19(3):559‐565. doi:10.1111/pedi.12606 PubMed DOI

Gramer G, Haege G, Glahn EM, Hoffmann GF, Lindner M, Burgard P. Living with an inborn error of metabolism detected by newborn screening‐parents' perspectives on child development and impact on family life. J Inherit Metab Dis. 2014;37(2):189‐195. doi:10.1007/s10545-013-9639-6 PubMed DOI

Weber SL, Segal S, Packman W. Inborn errors of metabolism: psychosocial challenges and proposed family systems model of intervention. Mol Genet Metab. 2012;105(4):537‐541. doi:10.1016/j.ymgme.2012.01.014 PubMed DOI

Ernst G, Menrath I, Lange K, et al. Development and evaluation of a generic education program for chronic diseases in childhood. Patient Educ Couns. 2017;100(6):1153‐1160. doi:10.1016/j.pec.2017.01.001 PubMed DOI

Zeltner NA, Huemer M, Baumgartner MR, Landolt MA. Quality of life, psychological adjustment, and adaptive functioning of patients with intoxication‐type inborn errors of metabolism ‐ a systematic review. Orphanet J Rare Dis. 2014;9:159. doi:10.1186/s13023-014-0159-8 PubMed DOI PMC

Ernst G, Szczepanski R, eds. Hrsg) Modulares Schulungsprogramm für chronisch kranke Kinder und Jugendliche sowie deren Familien “ModuS”. 3. Auflage Pabst Publisher. 2020.

Conijn T, Haverman L, Wijburg FA, De Roos C. Reducing posttraumatic stress in parents of patients with a rare inherited metabolic disorder using eye movement desensitization and reprocessing therapy: a case study. Orphanet J Rare Dis. 2021;16(1):126. doi:10.1186/s13023-021-01768-7 PubMed DOI PMC

Frankel LA, Pereira S, McGuire AL. Potential psychosocial risks of sequencing newborns. Pediatrics. 2016;137(Suppl 1):S24‐S29. doi:10.1542/peds.2015-3731F PubMed DOI PMC

Kenny T, Bogart K, Freedman A, et al. The importance of psychological support for parents and caregivers of children with a rare disease at diagnosis. Rare Dis Orphan Drugs J. 2022;1:7. doi:10.20517/rdodj.2022.04 DOI

Kißgen R, Carlitscheck J, Rapp C, Franke S. Die psychosoziale Versorgung in der Neonatologie in Deutschland: Eine quantitativ‐empirische Bestandsaufnahme aus ärztlicher Perspektive [Psychosocial care in institutional neonatology in Germany: a quantitative‐empirical inventory from the medical professionals' perspective]. Z Geburtshilfe Neonatol. 2012;216(6):259‐268. doi:10.1055/s-0032-1323795 PubMed DOI

Daly A, Gokmen‐Ozel H, MacDonald A, et al. Diurnal variation of phenylalanine concentrations in tyrosinaemia type 1: should we be concerned? J Hum Nutr Diet. 2012;25(2):111‐116. doi:10.1111/j.1365-277X.2011.01215.x PubMed DOI

van Dam E, Daly A, Venema‐Liefaard G, et al. What is the best blood sampling time for metabolic control of phenylalanine and tyrosine concentrations in tyrosinemia type 1 patients? JIMD Rep. 2017;36:49‐57. doi:10.1007/8904_2016_37 PubMed DOI PMC

Illsinger S, Lücke T, Meyer U, Vaske B, Das AM. Branched chain amino acids as a parameter for catabolism in treated phenylketonuria. Amino Acids. 2005;28(1):45‐50. doi:10.1007/s00726-004-0150-0 PubMed DOI

Schultz MJ, Netzel BC, Singh RH, et al. Laboratory monitoring of patients with hereditary tyrosinemia type I. Mol Genet Metab. 2020;130(4):247‐254. doi:10.1016/j.ymgme.2020.06.001 PubMed DOI

Nobili V, Jenkner A, Francalanci P, et al. Tyrosinemia type 1: metastatic hepatoblastoma with a favorable outcome. Pediatrics. 2010;126(1):e235‐e238. doi:10.1542/peds.2009-1639 PubMed DOI

van Ginkel WG, Gouw AS, van der Jagt EJ, et al. Hepatocellular carcinoma in tyrosinemia type 1 without clear increase of AFP. Pediatrics. 2015;135(3):e749‐e752. doi:10.1542/peds.2014-1913 PubMed DOI

Ayuso C, Rimola J, García‐Criado A. Imaging of HCC. Abdom Imaging. 2012;37(2):215‐230. doi:10.1007/s00261-011-9794-x PubMed DOI

Bolondi L. Screening for hepatocellular carcinoma in cirrhosis. J Hepatol. 2003a;39(6):1076‐1084. doi:10.1016/s0168-8278(03)00349-0 PubMed DOI

Bolondi L. Screening tests for hepatocellular carcinoma. Hepatology. 2003b;37(6):1493. doi:10.1053/jhep.2003.50215 PubMed DOI

Burrel M, Llovet JM, Ayuso C, et al. MRI angiography is superior to helical CT for detection of HCC prior to liver transplantation: an explant correlation. Hepatology. 2003;38(4):1034‐1042. doi:10.1053/jhep.2003.50409 PubMed DOI

Khanna R, Verma SK. Pediatric hepatocellular carcinoma. World J Gastroenterol. 2018;24(35):3980‐3999. doi:10.3748/wjg.v24.i35.3980 PubMed DOI PMC

Wisse RP, Wittebol‐Post D, Visser G, van der Lelij A. Corneal depositions in tyrosinaemia type I during treatment with Nitisinone. BMJ Case Rep. 2012;bcr2012006301. doi:10.1136/bcr-2012-006301 PubMed DOI PMC

Arora N, Stumper O, Wright J, Kelly DA, McKiernan PJ. Cardiomyopathy in tyrosinaemia type I is common but usually benign. J Inherit Metab Dis. 2006;29(1):54‐57. doi:10.1007/s10545-006-0203-5 PubMed DOI

André N, Roquelaure B, Jubin V, Ovaert C. Successful treatment of severe cardiomyopathy with NTBC in a child with tyrosinaemia type I. J Inherit Metab Dis. 2005;28(1):103‐106. doi:10.1007/s10545-005-5085-4 PubMed DOI

Bergman AJ, van den Berg IE, Brink W, Poll‐The BT, Ploos van Amstel J, Berger R. Spectrum of mutations in the fumarylacetoacetate hydrolase gene of tyrosinemia type 1 patients in northwestern Europe and Mediterranean countries. Hum Mutat. 1998;12(1):19‐26. doi:10.1002/(SICI)1098-1004(1998)12:1<19::AID-HUMU3>3.0.CO;2-3C PubMed DOI

García MI, de la Parra A, Arias C, Arredondo M, Cabello JF. Long‐term cognitive functioning in individuals with tyrosinemia type 1 treated with nitisinone and protein‐restricted diet. Mol Genet Metab Rep. 2017;11:12‐16. doi:10.1016/j.ymgmr.2017.01.016 PubMed DOI PMC

van Ginkel WG, Rodenburg IL, Harding CO, Hollak CEM, Heiner‐Fokkema MR, van Spronsen FJ. Long‐term outcomes and practical considerations in the pharmacological management of tyrosinemia type 1. Paediatr Drugs. 2019a;21(6):413‐426. doi:10.1007/s40272-019-00364-4 PubMed DOI PMC

van Ginkel WG, van Reemst HE, Kienstra NS, et al. The effect of various doses of phenylalanine supplementation on blood phenylalanine and tyrosine concentrations in tyrosinemia type 1 patients. Nutrients. 2019b;11(11):2816. doi:10.3390/nu11112816 PubMed DOI PMC

González‐Lamuño D, Sánchez‐Pintos P, Andrade F, Couce ML, Aldámiz‐Echevarría L. Treatment adherence in tyrosinemia type 1 patients. Orphanet J Rare Dis. 2021;16(1):256. doi:10.1186/s13023-021-01879-1 PubMed DOI PMC

Malik S, NiMhurchadha S, Jackson C, et al. Treatment adherence in type 1 hereditary Tyrosinaemia (HT1): a mixed‐method investigation into the beliefs, attitudes and behaviour of adolescent patients, their families and their health‐care team. JIMD Rep. 2015;18:13‐22. doi:10.1007/8904_2014_337 PubMed DOI PMC

Das AM, Goedecke K, Meyer U, et al. Dietary habits and metabolic control in adolescents and young adults with phenylketonuria: self‐imposed protein restriction may be harmful. JIMD Rep. 2014;13:149‐158. doi:10.1007/8904_2013_273 PubMed DOI PMC

Äärelä L, Nevalainen PI, Kurppa K, Hiltunen P. First Scandinavian case of successful pregnancy during nitisinone treatment for type 1 tyrosinemia. J Pediatr Endocrinol Metab. 2020;33(5):661‐664. doi:10.1515/jpem-2019-0540 PubMed DOI

Garcia Segarra N, Roche S, Imbard A, et al. Maternal and fetal tyrosinemia type I. J Inherit Metab Dis. 2010;33(suppl 3):S507‐S510. doi:10.1007/s10545-012-9569-8 PubMed DOI

Kassel R, Sprietsma L, Rudnick DA. Pregnancy in an NTBC‐treated patient with hereditary tyrosinemia type I. J Pediatr Gastroenterol Nutr. 2015;60(1):e5‐e7. doi:10.1097/MPG.0b013e3182a27463 PubMed DOI

Vanclooster A, Devlieger R, Meersseman W, et al. Pregnancy during nitisinone treatment for tyrosinaemia type I: first human experience. JIMD Rep. 2012;5:27‐33. doi:10.1007/8904_2011_88 PubMed DOI PMC

Zöggeler T, Ramoser G, Höller A, et al. Nitisinone treatment during two pregnancies and breastfeeding in a woman with tyrosinemia type 1—a case report. J Pediatr Endocrinol Metab. 2021;35(2):259‐265. doi:10.1515/jpem-2021-0465 PubMed DOI

Pichler K, Michel M, Zlamy M, et al. Breast milk feeding in infants with inherited metabolic disorders other than phenylketonuria—a 10‐year single‐center experience. J Perinat Med. 2017;45(3):375‐382. doi:10.1515/jpm-2016-0205 PubMed DOI