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.

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.

Tyrosinemia type iii: a case report of siblings and literature review / Tirosinemia tipo iii: descrição de caso clínico em irmãos e revisão da literatura

ABSTRACT Objective: Tyrosinemia type III (HT III) is the rarest form of tyrosinemia, and the full clinical spectrum of this disorder is still unknown. The neurological involvement varies, including intellectual impairment and attention deficit disorder with hyperactivity (ADHD). We report the case of two siblings diagnosed with HT III at different ages. Case description: The index case was diagnosed by newborn screening for endocrine and metabolic disorders, starting a low-protein diet immediately, with a consistent decrease in tyrosine levels. By the age of three, the child displayed a hyperactive behavior, starting treatment for ADHD two years later. At seven years of age, he shows a slight improvement in terms of behavior and attention span and has a cognitive performance slightly lower than his peers, despite maintaining acceptable tyrosine levels. His sister, who had a history of ADHD since age five, was diagnosed with HT III after family screening at the age of eight. Despite initiating a dietetic treatment, her behavior did not improve, and she has a mild intellectual impairment. Comments: This is the first case report describing siblings with HT III who underwent nutritional treatment with a low-protein diet in different phases of life, with a better neurological and behavioral evaluation in the patient who started treatment earlier.

RESUMO Objetivo: A tirosinemia tipo III (TT III) é a forma mais rara das tirosinemias e o espectro clínico desta entidade não está totalmente esclarecido. O envolvimento neurológico é variável, incluindo o atraso cognitivo ou transtorno do déficit de atenção com hiperatividade (TDAH). Descrevemos o caso de dois irmãos que foram diagnosticados com TT III em idades diferentes. Descrição dos casos: O caso índice foi diagnosticado no contexto do rastreio endócrino-metabólico neonatal, tendo iniciado imediatamente dieta hipoproteica, com redução consistente dos níveis de tirosina. Por volta dos três anos, foi detectado um comportamento hiperativo, tendo iniciado dois anos depois tratamento para o TDAH. Aos sete anos, apresenta leve melhora de comportamento e da atenção e avaliação cognitiva levemente inferior ou pouco abaixo quando comparado a crianças da mesma faixa etária, apesar de manter níveis aceitáveis de tirosina. A sua irmã, com história de TDAH desde os cinco anos, foi diagnosticada de TT III aos oito anos no contexto do rastreio de familiares. Apesar de iniciar tratamento dietético, nenhum efeito foi notado em termos de comportamento e a doente apresenta leve atraso cognitivo. Comentários: Este é o primeiro caso clínico descrito de irmãos com TT III que iniciaram terapêutica dietética com dieta hipoproteica em diferentes fases da vida, com melhor avaliação em termos neurológicos e comportamentais no doente que iniciou tratamento mais precocemente.

Cirrosis hepatiaa en lactante: una forma de presentacion de la tiroinnemia / Hepatic circosis in infant: a form of presentation of thyrosynemia

We present two documented cases of patients with Tyrosinemia type I (Hepatorenal Tyrosinemia) in infants. The most constant imaging findings in target organs: Liver (Hepatic Cirrhosis), Kidneys (Nefromegaly) are described and compared with pathological findings in one case. In the presence of confusing clinical manifestations, radiological findings of hepatic cirrhosis in infants associated with renal involvement are almost diagnostic of this entity.

Se presentan 2 casos documentados de lactantes portadores de Tirosinemia tipo I (Hepatorenal). Se describen los hallazgos imagenológicos principales de ella en los órganos blanco: Hígado (Cirrosis Hepática) y riñones (Nefromegalia) y se confrontan con los de la anatomía patológica en un caso. En un lactante, con un cuadro clínico poco claro, el hallazgo imagenológico de cirrosis hepática sumado a un compromiso renal, deben hacer plantear el diagnóstico de tirosinemia.

Crisis neurológica en Tirosinemia hereditaria / Neurological crisis in hereditary Tyrosinaemia

La Tirosinemia tipo I es el resultado de un error innato en la etapa final del metabolismo de la Tirosina. Sus manifestaciones clínicas son variables, las cuales pueden verse agravadas con la aparición de crisis neurológica. El objetivo del presente trabajo es reportar el caso de una preescolar portadora de la enfermedad, que desarrolló parálisis fláccida asociada a insuficiencia respiratoria y que requirió conexión a ventilación mecánica.