Consenso mexicano de tirosinemia tipo 1

INTRODUCTION: Tyrosinemia type 1 is a rare disease with autosomal recessive inheritance, featuring various clinical manifestations. These may encompass acute neonatal liver failure, neonatal cholestatic syndrome, chronic hepatitis, cirrhosis, hepatocellular carcinoma, and, alternatively, kidney disorders like renal tubular acidosis, Fanconi syndrome, hypophosphatemic rickets, among other alterations. Diagnosis relies on detecting toxic metabolites in the blood and urine, ideally confirmed through molecular testing. METHOD: A consensus was reached with experts in the field of inborn errors of metabolism (EIM), including eight pediatric gastroenterologists, two EIM specialists, two geneticists, three pediatric nutritionists specialized in EIM, and a pediatric surgeon specializing in transplants. Six working groups were tasked with formulating statements and justifications, and 32 statements were anonymously voted on using the Likert scale and the Delphi method. The first virtual vote achieved an 80% consensus, with the remaining 20% determined in person. RESULTS: The statements were categorized into epidemiology, clinical presentation, diagnosis, nutritional and medical treatment, and genetic counseling. CONCLUSIONS: This consensus serves as a valuable tool for primary care physicians, pediatricians, and pediatric gastroenterologists, aiding in the prompt diagnosis and treatment of this disease. Its impact on the morbidity and mortality of patients with tyrosinemia type 1 is substantial.

INTRODUCCIÓN: La tirosinemia tipo 1 es una enfermedad rara, con herencia autosómica recesiva, con múltiples manifestaciones clínicas, que pueden comprender desde falla hepática aguda neonatal, síndrome colestásico neonatal, hepatitis crónica, cirrosis o hepatocarcinoma, hasta alteraciones renales como acidosis tubular renal, síndrome de Fanconi o raquitismo hipofosfatémico, entre otras. El diagnóstico se basa en la presencia de metabolitos tóxicos en la sangre y la orina, idealmente con la confirmación molecular de la enfermedad. MÉTODO: Se realizó un consenso con expertos en el área de los errores innatos del metabolismo (EIM): ocho gastroenterólogos pediatras, dos médicos especialistas en EIM, dos genetistas, tres nutriólogas pediatras especializadas en EIM y un cirujano pediatra especialista en trasplantes. Se formaron seis mesas de trabajo encargadas de desarrollar los enunciados con sus justificaciones y fueron votados anónimamente 32 enunciados en una escala Likert con un método Delphi. La primera votación fue virtual, obteniendo consenso del 80% de los enunciados, y la segunda fue presencial, obteniendo el 20% restante. RESULTADOS: Los enunciados fueron divididos en epidemiología, cuadro clínico, diagnóstico, tratamiento nutricional y médico, y consejo genético. CONCLUSIONES: Este consenso constituye una valiosa herramienta para los médicos de atención primaria, pediatras y gastroenterólogos pediátricos, ya que ayuda a diagnosticar y tratar rápidamente esta enfermedad. Su impacto en la morbilidad y mortalidad de los pacientes con tirosinemia tipo 1 es sustancial.

A Lithuanian Case of Tyrosinemia Type 1 with a Literature Review: A Rare Cause of Acute Liver Failure in Childhood.

Hereditary type 1 tyrosinemia (HT1) is a rare inherited autosomal recessive disorder of tyrosine metabolism, characterized by progressive liver damage, dysfunction of kidney tubules, and neurological crises. In the course of this disease, due to the deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), toxic intermediate metabolites of tyrosine breakdown, such as fumarylacetoacetate (FAA), succinylacetoacetate (SAA), and succinylacetone (SA), accumulate in liver and kidney cells, causing cellular damage. Because of this, an increased SA concentration in the blood or urine is pathognomonic of HT1. In the year 2000, HT1 was diagnosed in Lithuania for the first time, and this was the first time when a specific treatment for HT1 was administered in the country. Over two decades, four cases of this disease have been diagnosed in Lithuania. In the first of these patients, the disease was diagnosed in infancy, manifesting as liver damage with liver failure. Treatment with nitisinone was initiated, which continues to be administered, maintaining normal liver function. Liver transplantation was performed on two subsequent patients due to complications of HT1. It is crucial to diagnose HT1 as early as possible in order to reduce or completely eliminate complications related to the disease, including progressive liver failure and kidney dysfunction, among others. This can only be achieved by conducting a universal newborn screening for tyrosinemia and by starting treatment with nitisinone (NTBC) before the age of 1 month in all cases of HT1. However, in those countries where this screening is not being carried out, physicians must be aware of and consider this highly rare disorder. They should be vigilant, paying attention to even minimal changes in a few specific laboratory test results-such as unexplained anemia alongside neutropenia and thrombocytopenia-and should conduct more detailed examinations to determine the causes of these changes. In this article, we present the latest clinical case of HT1 in Lithuania, diagnosed at the Children's Diseases' Clinic of the Lithuanian University of Health Sciences (LUHS) Hospital Kaunas Clinics. The case manifested as life-threatening acute liver failure in early childhood. This article explores and discusses the peculiarities of diagnosing this condition in the absence of universal newborn screening for tyrosinemia in the country, as well as the course, treatment, and ongoing monitoring of patients with this disorder.

Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1.

Dried blood spot succinylacetone (SA) is often used as a biomarker for newborn screening (NBS) for tyrosinemia type 1 (TT1). However, false-positive SA results are often observed. Elevated SA may also be due to maleylacetoacetate isomerase deficiency (MAAI-D), which appears to be clinically insignificant. This study investigated whether urine organic acid (uOA) and quantitative urine maleic acid (Q-uMA) analyses can distinguish between TT1 and MAAI-D. We reevaluated/measured uOA (GC-MS) and/or Q-uMA (LC-MS/MS) in available urine samples of nine referred newborns (2 TT1, 7 false-positive), eight genetically confirmed MAAI-D children, and 66 controls. Maleic acid was elevated in uOA of 5/7 false-positive newborns and in the three available samples of confirmed MAAI-D children, but not in TT1 patients. Q-uMA ranged from not detectable to 1.16 mmol/mol creatinine in controls (n = 66) and from 0.95 to 192.06 mmol/mol creatinine in false-positive newborns and MAAI-D children (n = 10). MAAI-D was genetically confirmed in 4/7 false-positive newborns, all with elevated Q-uMA, and rejected in the two newborns with normal Q-uMA. No sample was available for genetic analysis of the last false-positive infant with elevated Q-uMA. Our study shows that MAAI-D is a recognizable cause of false-positive TT1 NBS results. Elevated urine maleic acid excretion seems highly effective in discriminating MAAI-D from TT1.

[Clinical features and genetic analysis of a child with acute form of Tyrosinemia type I due to a novel variant of FAH gene].

OBJECTIVE: To analyze the clinical phenotype and genetic basis for a child with acute form of tyrosinemia type I (TYRSN1). METHODS: A child with TYRSN1 who presented at the Gansu Provincial Maternal and Child Health Care Hospital in October 2020 was selected as the subject. The child was subjected to tandem mass spectrometry (MS-MS) and urine gas chromatography-mass spectrometry (GC-MS) for the detection of inherited metabolic disorders, in addition with whole exome sequencing (WES). Candidate variants were validated by Sanger sequencing. RESULTS: The child's clinical features included abdominal distension, hepatomegaly, anemia and tendency of bleeding. By mass spectrometry analysis, her serum and urine tyrosine and succinylacetone levels have both exceeded the normal ranges. WES and Sanger sequencing revealed that she has harbored c.1062+5G>A and c.943T>C (p.Cys315Arg) compound heterozygous variants of the FAH gene, which were inherited from her father and mother, respectively. Among these, the c.943T>C was unreported previously. CONCLUSION: Considering her clinical phenotype and result of genetic testing, the child was diagnosed with TYRSN1 (acute type). The compound heterozygous variants of the FAH gene probably underlay the disease in this child. Above finding has further expanded the spectrum of FAH gene variants, and provided a basis for accurate treatment, genetic counseling and prenatal diagnosis for her family.

Comprehensive Evaluation of the NeoBase 2 Non-derivatized MSMS Assay and Exploration of Analytes With Significantly Different Concentrations Between Term and Preterm Neonates.

Background: Despite the popularity of the NeoBase 2 Non-derivatized MSMS assay (PerkinElmer, Turku, Finland), there are no reports of its comprehensive evaluation, including the ability to distinguish transient tyrosinemia of the newborn (TTN) from tyrosinemia type 1 (TYR 1) using succinylacetone (SUAC). No newborn screening (NBS) cutoffs for preterm neonates in the Korean population have been suggested. We evaluated the NeoBase 2 assay and identified analytes requiring different cutoffs in preterm neonates. Methods: Residual NBS dried blood spot samples and proficiency testing (PT) materials of the Newborn Screening Quality Assurance Program and the Korean Association of External Quality Assessment Service were used. Precision, accuracy, limit of detection (LOD), lower limit of quantification (LLOQ), linearity, recovery, carryover, and performance of SUAC were evaluated. Cutoffs were determined, and analytes requiring different cutoffs in preterm neonates were investigated. Results: Mean CVs for within-run and between-day precision were within 15%. Accuracy analysis indicated high agreement with in-house derivatized assay results and results of other PT participants. All analytes demonstrated acceptable LOD, LLOQ, and linearity. Recoveries were acceptable, except for SUAC. Carryover was negligible. Cutoffs were established for all analytes; Tyr, adenosine, and C20:0-lysophosphatidylcholine required different cutoffs in preterm neonates. Differential diagnosis of TYR 1 and TTN was successful with simultaneous Tyr and SUAC measurement. Conclusions: The NeoBase 2 assay demonstrated satisfactory performance. The additional analytes provide a wider diagnostic coverage, and the simultaneous measurement of Tyr and SUAC is efficient in excluding TYR 1. The new cutoffs for preterm neonates may decrease false-positive rates, without compromising diagnostic sensitivity.

Coste-efectividad del cribado neonatal de la tirosinemia tipo I (actualización) / Cost-effectiveness of newborn screening for tyrosinemia type I (update)

INTRODUCCIÓN La tirosinemia tipo I (TH1) es una enfermedad autosómica recesiva caracterizada por el déficit de la enzima fumaril acetoacetato hidrolasa. Los síntomas clínicos son variables e incluyen fallo hepático agudo, cirrosis, carcinoma hepatocelular (CHC), síndrome renal de Fanconi y neuropatía periférica. La TH1 es una enfermedad rara, de la que se calcula una frecuencia no mayor de 1 caso cada 100.000 recién nacidos vivos en la población mundial. La TH1, si no se trata, tiene pronóstico fatal, tanto en su forma aguda como crónica. Tradicionalmente el tratamiento ha consistido en una dieta con restricción de aminoácidos, fenilalanina y tirosina, y en el trasplante hepático. Actualmente existe un tratamiento farmacológico, la nitisinona, capaz de prevenir la degradación de la tirosina y la formación de metabolitos tóxicos. La introducción de la nitisinona como tratamiento de la TH1 se ha acompañado de un descenso considerable de la tasa de mortalidad. Actualmente, en España la TH1 no está incluida dentro del programa de cribado neonatal (PCN) de la cartera común de servicios del SNS. OBJETIVOS Evaluar y actualizar el coste-efectividad de la inclusión de la detección precoz de la TH1 mediante MS/MS en un PCN. • Estimar el impacto presupuestario que supondría para el SNS la inclusión de la detección precoz de la TH1 mediante MS/MS en el PCN actual. METODOLOGÍA Se realizó una revisión sistemática de la evidencia científica sobre el coste-efectividad del cribado neonatal de la TH1 para lo que se elaboró una estrategia de búsqueda en las bases de datos electrónicas: MEDLINE, EMBASE, Web of Science (WOS) y Cochrane desde 2013 hasta abril de 2021. Se ha desarrollado un modelo de coste-efectividad que compara dos alternativas: implantar el cribado neonatal de la tirosinemia tipo I o realizar la detección clínica de esta enfermedad. La perspectiva del análisis fue la del SNS, teniendo en cuenta los costes directos, expresados en euros de 2021. De manera adicional se tiene en cuenta la perspectiva social incluyendo los costes debidos a posibles pérdidas de productividad. La efectividad se midió empleando la medida Años de Vida Ajustados por Calidad (AVAC). Tanto los costes como la efectividad se descontaron al 3%. Por último, se realizó un análisis de impacto presupuestario para informar del coste que supondría la inclusión de la TH1 en el PCN del SNS. RESULTADOS Revisión sistemática de coste-efectividad Únicamente se pudo considerar un informe del Institute of Health Economics de Alberta (Canadá), localizado mediante búsqueda manual, publicado en 2016; cuyo objetivo fue evaluar la efectividad, seguridad y coste-efectividad de añadir siete condiciones al programa de cribado neonatal canadiense (incluyendo la TH1), mediante modelización tipo Markov. La calidad metodológica de la evaluación económica es alta. La perspectiva empleada es la del tercer pagador incluyendo exclusivamente los costes directos sanitarios; informando de un coste por niño cribado de 28,40 $CAD (21,20 € de 2021) frente a los 26,50 $CAD (19,78 € de 2021) por niño no cribado. La diferencia en años de vida entre ambas estrategias es de 0,00006 lo que resulta en una RCEI de 31.723,53 $CAD/AV (aproximadamente 23.666,66 €/AV en 2021). Aunque los autores no hacen mención al umbral coste-efectividad de referencia (y, por tanto, no especifican si la alternativa se considera coste-efectiva o no), declaran que, dado que la detección de una sola afección o una combinación de ellas produce un beneficio adicional para la salud, con costes adicionales para el sistema, su adopción depende de la disponibilidad de fondos. Análisis económico El análisis coste-efectividad muestra que el coste promedio por niño no cribado asciende a 33,03 €, mientras que el coste por niño cribado es de 35 €. Tanto los AVG como los AVAC promedio son más elevados con la estrategia de cribado neonatal lo que resulta en una RCEI de 30.034,32 €/AVAC desde la perspectiva del SNS y de 28.017,90 €/AVAC desde la perspectiva social. Ambos valores se encuentran por encima pero cercanos al umbral de coste-efectividad estimado para España en 25.000 €/AVAC. Al analizar diferentes escenarios variando los parámetros sobre los que existe mayor incertidumbre, se obtiene que la incorporación de la TH1 al programa de cribado neonatal sería una alternativa coste-efectiva si el precio del reactivo adicional para la detección de la TH1 mediante MS/MS no supera los 0,20 €/reactivo. El análisis de impacto presupuestario muestra que el coste incremental por niño cribado en el primer año se sitúa en torno a los 0,37 €, que equivale a 123.801 € para el conjunto de neonatos nacidos en España. CONCLUSIONES Existe muy escasa evidencia en la literatura científica sobre el coste-efectividad de un programa de cribado neonatal de la TH1 mediante MS/MS. Sólo se ha localizado un informe de ETS que concluye que la incorporación de la TH1 a un programa de cribado neonatal debe valorarse en función de la disponibilidad presupuestaria. • El análisis de coste-efectividad de novo realizado en este informe con datos actualizados de España concluye que la implantación del cribado neonatal de la TH1 no sería una opción coste-efectiva desde la perspectiva del SNS, ni desde la perspectiva social teniendo en cuenta una DAP de 25.000 €/AVAC. Sin embargo, si el coste del reactivo adicional necesario para la detección de la TH1 mediante MS/MS no supera los 0,20 €/reactivo, la inclusión de esta enfermedad dentro del programa de cribado neonatal mediante MS/MS sí sería una alternativa coste-efectiva. • De acuerdo al análisis de impacto presupuestario, cribar la TH1 tendría un coste incremental por neonato bajo, de aproximadamente 0,37 € el primer año.

INTRODUCTION Tyrosinemia type I (TH1) is an autosomal recessive disease characterized by a deficiency of the enzyme fumaril acetoacetate hydrolase. Clinical symptoms are variable and include acute liver failure, cirrhosis, hepatocellular carcinoma (HCC), Fanconi renal syndrome, and peripheral neuropathy. TH1 is a rare disease, with an estimated frequency of not more than 1 case per 100,000 live newborns in the world population. If untreated, TH1 has a fatal prognosis, both in its acute and chronic forms. Traditionally, treatment has consisted of a diet with restriction of amino acids, phenylalanine and tyrosine, and liver transplantation. Currently there is a pharmacological treatment, nitisinone, capable of preventing the degradation of tyrosine and the formation of toxic metabolites. The introduction of nitisinone as a treatment for TH1 has been accompanied by a considerable decrease in the mortality rate. Currently, in Spain TH1 is not included in the newborn screening programme of the portfolio of common services of the National Health System (NHS). OBJECTIVES To evaluate the cost-effectiveness of newborn screening for TH1. • To determine the cost-effectiveness of including early detection of TH1 by MS/MS in a newborn screening programme. • To estimate the budget impact of implementation of early detection of TH1 through MS/MS in NHS. METHODS A systematic review of the scientific evidence on the cost-effectiveness of newborn screening for TH1 was carried out, for which a search strategy was developed in electronic databases: MEDLINE, EMBASE, Web of Science (WOS) and Cochrane since 2013 until April 2021. A cost-effectiveness model has been developed that compares two alternatives: implement newborn screening for type I tyrosinemia or carry out clinical detection of this disease. The perspective of the analysis was that of the SNS, taking into account direct healthcare costs, expressed in 2021 euros. Effectiveness was measured using the Quality-Adjusted Life Years (QALY) measure. Both costs and effectiveness were discounted at 3%. Finally, a budget impact analysis was carried out to report the cost of including newborn screening of TH1 in the NHS. RESULTS Cost-effectiveness systematic review Only a HTA-report from the Institute of Health Economics of Alberta (Canada), located by manual search and published in 2016, could be considered. The objective of this report was to evaluate the effectiveness, safety and cost-effectiveness of adding seven conditions (including TH1), to the Canadian newborn screening program using Markov-type modeling. The methodological quality of the economic evaluation was high. The perspective used is that of the third payer, including exclusively direct healthcare costs. The authors reported a cost per child screened of CAD $ 28.40 (€ 21.20 from 2021) compared to CAD $ 26.50 (€ 19.78 from 2021) per child not screened. The difference in life years between both strategies is 0.00006, which results in an ICER of CAD $ 31,723.53/LYs (approximately € 23,666.66/LYs in 2021). Although the authors do not mention a country willigness to pay (WTP) reference (and, therefore, do not specify whether the alternative is considered cost-effective or not), they declare that, since the detection of a single condition or a combination of them produces an additional benefit for health with additional costs for the system, its adoption depends on the availability of funds. Economic analysis The cost-effectiveness analysis shows that the mean cost per child not screened is € 33.03, while the cost per child screened is € 35. Both the LYs and QALYs are higher with the newborn screening strategy, which results in an ICER of 30,034.32 €/QALY from the NHS perspective and 28,017.90 €/LY from societal perspective. Both values are close to the cost-effectiveness threshold estimated for Spain at €25,000/QALY. When analyzing different scenarios varying the parameters about which there is greater uncertainty, it is obtained that the incorporation of TH1 to the neonatal screening program would be a cost-effective alternative if the price of the additional reagent used for the detection of TH1 by MS/MS does not exceeds €0.20/reagent. The budget impact analysis shows that the incremental cost per child screened in the first year is around € 0.37, which is equivalent to € 123,801 for all newborns born in Spain. CONCLUSIONS There is limited scientific literature evidence on the cost effectiveness of TH1 newborn screening using MS/MS. Only one HTA report has been located that concludes that the incorporation of TH1 into a newborn screening program should be assessed based on budget availability. • The cost-effectiveness analysis carried out in this report with updated data from Spain concludes that the implementation of TH1 newborn screening would be a cost-effective option from the NHS perspective if the price of the reagent used to detect the disease does not exceed €0.20/reagent. • According to the budget impact analysis, screening TH1 would have a low incremental cost per newborn, of approximately € 0.37 the first year.

Identification and functional characterization of a novel homozygous intronic variant in the fumarylacetoacetate hydrolase gene in a Chinese patient with tyrosinemia type 1.

BACKGROUND: Hereditary tyrosinemia type 1 (HT1; OMIM# 276700) is a genetic metabolism disorder caused by disease-causing variants in the fumarylacetoacetate hydrolase (FAH) gene encoding the last enzyme of the tyrosine catabolic pathway. Herein, we describe the clinical features and genetic characteristics of HT1 in a five years and seven months old Chinese patient. METHODS: After clinical diagnosis of the proband with HT1, genetic testing was performed by Sanger sequencing of the FAH gene in all family members. Functional analysis of the disease-causing variant was performed by cDNA sequencing to understand the effect of the variant on FAH transcript. To further predict the variant effect, we used Human Splicing Finder (HSF) and PyMol in silico analysis. RESULTS: We identified a novel previously undescribed intronic variant in the FAH gene (c.914-1G>A). It was detected in a child who was homozygous for the variant and had the clinical presentation of HT1. cDNA sequencing showed that this splice-junction variant affected the transcription of FAH by formation of two different transcripts. Our observations and laboratory experiments were in line with in silico methods. CONCLUSIONS: Our study provides new insight into the HT1 variant spectrum and a better understanding of this disease in the Chinese population. This will be useful for molecular diagnosis in our country in cases where premarital screening, prenatal diagnosis and preimplantation genetic diagnosis are planned.

An Infant with Bilateral Keratitis: From Infectious to Genetic Diagnosis.

BACKGROUND Tyrosinemia Type II (TYRII) is a rare autosomal recessive inborn error of metabolism caused by deficiency of tyrosine aminotransferase (TAT), leading to hypertyrosinemia. TYRII patients often present in the first year of life with ocular and cutaneous findings, including corneal ulcers, pseudodendritic keratitis, and palmoplantar hyperkeratosis. The corneal involvement is often mistaken for herpes simplex virus (HSV) keratitis, which is a much commoner condition. CASE REPORT A previously healthy 10-month-old male infant was referred to Ophthalmology for acute onset photophobia. Bilateral dendritiform corneal lesions raised the suspicion for herpetic keratitis. Additionally, a papular, crusted lesion was found on his thumb after a few days of hospitalization, also raising concerns about HSV. The patient's clinical condition seemed to improve under intravenous acyclovir and supportive treatment. A conjunctival swab and crusted lesion on the thumb were tested for HSV using a polymerase chain reaction (PCR) technique, and both were negative. Nevertheless, given the clinical presentation and the favorable course of signs and symptoms, hospital discharge was planned with oral acyclovir. It was halted by an alternative diagnosis of autosomal recessive inborn error of metabolism, tyrosinemia type II, confirmed by elevated plasma tyrosine level and later by molecular analysis requested as a confirmatory investigation by the genetics medical team. CONCLUSIONS The corneal involvement in TYRII is often mistaken for HSV keratitis, and clinical course alone should not halt further investigations to rule out TYRII. Clinicians should suspect TYRII clinically when its characteristic ocular dendritiform lesions are present, namely in infancy or early childhood, and even in the absence of its typical cutaneous palmoplantar hyperkeratosis plaques.

Hepatocellular carcinoma requiring liver transplantation in hereditary tyrosinemia type 1 despite nitisinone therapy and α1-fetoprotein normalization.

BACKGROUND: Hereditary tyrosinemia type 1 is a rare metabolic condition associated with an increased risk of hepatocellular carcinoma. Nitisinone (2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione, NTBC) treatment has reduced but not eliminated the risk. The delayed initiation of nitisinone treatment, and persistently abnormal α1-fetoprotein (AFP) levels are recognized to be risk factors for late-onset hepatocellular carcinoma. We report three children diagnosed and treated with nitisinone since infancy who developed hepatocellular carcinoma despite long-term normalization of AFP. METHODS: A retrospective review of all patients with tyrosinemia on nitisinone managed at our center was undertaken. Patient demographics, age at diagnosis, duration of therapy, timing of AFP normalization, and radiographic imaging findings were noted. RESULTS: Three patients at our center with tyrosinemia type 1 developed hepatocellular carcinoma 9-13 years after diagnosis despite long-term nitisinone therapy and normalization of AFP. Two patients developed new nodules on imaging with an elevation of AFP leading to the diagnosis and subsequent liver transplant. The third patient proceeded with liver transplant because of a very nodular liver and increasing splenomegaly despite normal AFP and no change in surveillance gadoxetate magnetic resonance imaging. Early hepatocellular carcinoma was found in her liver explant. All three patients were cirrhotic at diagnosis. CONCLUSIONS: Patients with hereditary tyrosinemia type 1, especially those already cirrhotic at diagnosis, remain at high risk of developing hepatocellular carcinoma despite long-term nitisinone therapy and AFP normalization, and warrant close monitoring and surveillance.

Clinical experience with hepatorenal tyrosinemia from a single Egyptian center.

Although very recently, in Egypt, sick newborn screening has included screening for hepatorenal tyrosinemia, yet, it is not yet included in nationwide neonatal screening and hence diagnosis may be delayed. The aim of this study was to analyze data of all cases presenting with hepatorenal tyrosinemia to the Pediatric Hepatology Unit, Cairo University, Egypt from 2006 to 2019. Data were retrieved from patients' files including age of onset of symptoms, clinical signs, blood counts, liver functions, serum phosphorous, alpha-fetoprotein, succinylacetone and abdominal ultrasound. During this period, 76 patients were diagnosed with hepatorenal tyrosinemia if succinylacetone in dry blood spot was elevated above 1 µmol/L. These 76 cases came from 70 families; consanguinity was reported in 61 families. In our cohort we reported 30 affected siblings with a similar clinical presentation, who died undiagnosed. Presentation was acute in 26%, subacute in 30% and chronic in 43%. Abdominal distention was the commonest presenting symptom (52.6%). Coagulopathy was the commonest derangement in liver functions; hyperbilirubinemia and raised transaminases were less common. Ultrasound findings included hepatic focal lesions in 47% and enlarged echogenic kidneys in 39% and 45.3% respectively. Only 20 children were treated with Nitisinone because of unavailability and high costs; seven out of them underwent liver transplantation. In conclusion, although hepatorenal tyrosinemia is a rare inborn error of metabolism, in a large population country with high rate of consanguinity; this disease is not uncommonly diagnosed. The current treatment is not readily available because of the costs in a resource-limited country. Neonatal screening and subsidization of the costly medication need to be considered.

Clinical and biochemical footprints of inherited metabolic diseases. VIII. Neoplasias.

Cancer, caused by multiple cumulative pathogenic variants in tumor suppressor genes and proto-oncogenes, is a leading cause of mortality worldwide. The uncontrolled and rapid cell growth of the tumors requires a reprogramming of the complex cellular metabolic network to favor anabolism. Adequate management and treatment of certain inherited metabolic diseases might prevent the development of certain neoplasias, such as hepatocellular carcinoma in tyrosinemia type 1 or hepatocellular adenomas in glycogen storage disorder type 1a. We reviewed and updated the list of known metabolic etiologies associated with various types of benign and malignant neoplasias, finding 64 relevant inborn errors of metabolism. This is the eighth article of the series attempting to create a comprehensive list of clinical and metabolic differential diagnosis by system involvement.

Evaluation of dynamic thiol/disulfide homeostasis in hereditary tyrosinemia type 1 patients.

BACKGROUND: Despite successful treatment with nitisinone, the pathophysiology of long-term complications, including hepatocellular carcinoma and mental decline in tyrosinemia type 1 patients, is still obscure. Oxidative stress may play a role in these complications. While increased fumarylacetoacetate and maleylacetoacetate cause oxidative stress in the liver, increased tyrosine causes oxidative stress in the brain. The aim of this study is to evaluate dynamic thiol/disulfide homeostasis as an indicator of oxidative stress in late-diagnosed tyrosinemia type 1 patients. METHODS: Twenty-four late-diagnosed (age of diagnosis; 14.43 ± 26.35 months) tyrosinemia type 1 patients (19 under nitisinone treatment and 5 with liver transplantation) and 25 healthy subjects were enrolled in the study. Serum native thiol, total thiol, and disulfide levels were measured, and disulfide/native, disulfide/total, and native thiol/total thiol ratios were calculated from these values. RESULTS: No significant difference was observed in native, total, and disulfide thiol levels between the groups and no increase in disulfide/native, disulfide/total, and native/total thiol ratios was detected, despite significantly higher plasma tyrosine levels in the nitisinone-treated group. CONCLUSIONS: We suggest that providing sufficient metabolic control with good compliance to nitisinone treatment can help to prevent oxidative stress in late-diagnosed tyrosinemia type 1 patients. IMPACT: Despite successful nitisinone (NTBC) treatment, the underlying mechanisms of long-term complications in hereditary tyrosinemia type 1 (HT1), including hepatocellular carcinoma and mental decline, are still obscure. Oxidative stress may play a role in these complications. Thiol/disulfide homeostasis, which is an indicator of oxidative stress, is not disturbed in hereditary tyrosinemia patients under NTBC treatment, despite higher plasma tyrosine levels and patients who had liver transplantation. This is the first study evaluating dynamic thiol/disulfide homeostasis as an indicator of oxidative stress in late-diagnosed HT1 patients.

Liver Transplantation: A Safe and Definitive Alternative to Lifelong Nitisinone for Tyrosinemia Type 1.

OBJECTIVES: To report the experience of liver transplantation (LT) for tyrosinemia type 1 (TT-1). METHODS: Clinical data of children with TT-1 who underwent living donor LT between July 2009 and May 2020 were retrospectively analyzed. Data included pre-LT nitisinone therapy, graft type, post-LT complications, HCC incidence, and graft/patient survival. RESULTS: Nine children were diagnosed with TT-1 at a median age of 12 mo (6-54 mo). Nitisinone was started in 6 patients at a median age of 15 mo (6-42 mo), but all had frequent interruption of therapy due to logistics with drug procurement including its cost. Median age at transplantation was 5 y (2-11 y). Explant liver showed HCC in 5 patients (55% of total cohort). The graft and patient survival are 100% with median follow-up of 58 mo (24-84 mo). CONCLUSION: LT is curative for TT-1 and excellent results can be obtained in experienced centers. This is especially favorable in countries with limited resources where the cost of medical therapy is highly prohibitive, with lifelong diet restrictions and unclear long-term risk of HCC.

Hereditary tyrosinemia type â : newborn screening, diagnosis and treatment.

Hereditary tyrosinemia type Ⅰ (HT-1) is a severe autosomal recessive inherited metabolic disease. Due to the deficiency of fumarylacetoacetase hydrolase (FAH), the toxic metabolites are accumulated in the body, resulting in severe liver dysfunction, renal tubular dysfunctions, neurological crises, and the increased risk of hepatocellular carcinoma. Clinical symptoms typically begin at after the birth; the prognosis of patients is poor if they are not treated timely. Succinylacetone is a specific and sensitive marker for HT-1, and the screening in newborns can make early diagnosis of HT-1 at the asymptomatic stage. The diagnosis of HT-1 can be confirmed based on the characteristic biochemical findings and molecular testing of mutations in both alleles of gene. Combined treatment with nitisinone and a low tyrosine diet may significantly improve outcomes for patients. Liver transplantation is an effective treatment in cases where nitisinone is not available. Some novel HT-1 treatments are in clinical trials, including enzyme replacement therapy, hepatocyte transplantation and gene-targeted therapy.