scholarly journals Hepatocyte injury in tyrosinemia type 1 is induced by fumarylacetoacetate and is inhibited by caspase inhibitors

1998 ◽  
Vol 95 (16) ◽  
pp. 9552-9557 ◽  
Author(s):  
Shuji Kubo ◽  
Maosen Sun ◽  
Michio Miyahara ◽  
Kazuhiro Umeyama ◽  
Ken-ichi Urakami ◽  
...  
Keyword(s):  
Liver Failure ◽  
Double Mutant ◽  
Acute Onset ◽  
Mutant Mice ◽  
Free System ◽  
Caspase Inhibitors ◽  
Tyrosinemia Type 1 ◽  
Fumarylacetoacetate Hydrolase ◽  
Hereditary Tyrosinemia

Tyrosinemia type 1, caused by mutations in the fumarylacetoacetate hydrolase gene (Fah), is characterized by severe liver injury. We earlier developed a tyrosinemic mouse model with two genetic defects, Fah and 4-hydroxyphenylpyruvate dioxygenase (Hpd) deficiencies. Apoptosis of hepatocytes was induced and an acute onset of liver failure occurred after administration of homogentisic acid (HGA), the intermediate metabolite between the enzymes HPD and FAH. Cytochrome c was released from mitochondria prior to liver failure in the Fah−/−Hpd−/− double-mutant mice after the administration of HGA. In a cell-free system, the addition of fumarylacetoacetate induced the release of cytochrome c from the mitochondria. We also found that caspase inhibitors were highly effective in preventing the liver failure induced by HGA in the double-mutant mice. Therefore, fumarylacetoacetate apparently induces the release of cytochrome c, which in turn triggers activation of the caspase cascade in hepatocytes of subjects with hereditary tyrosinemia type 1.

Hereditary tyrosinemia type 1: novel missense, nonsense and splice consensus mutations in the human fumarylacetoacetate hydrolase gene; variability of the genotype-phenotype relationship

1996 ◽  
Vol 97 (1) ◽  
pp. 51-59 ◽  
Author(s):  
J. K. Ploos van Amstel ◽  
A. J. I. W. Bergman ◽  
E. A. C. M. van Beurden ◽  
J. F. M. Roijers ◽  
T. Peelen ◽  
...  
Keyword(s):  
Tyrosinemia Type 1 ◽  
Fumarylacetoacetate Hydrolase ◽  
Gene Variability ◽  
Hereditary Tyrosinemia

scholarly journals Fumarylacetoacetate Hydrolase Knock-out Rabbit Model for Hereditary Tyrosinemia Type 1

2017 ◽  
Vol 292 (11) ◽  
pp. 4755-4763 ◽  
Author(s):  
Li Li ◽  
Quanjun Zhang ◽  
Huaqiang Yang ◽  
Qingjian Zou ◽  
Chengdan Lai ◽  
...  
Keyword(s):  
Rabbit Model ◽  
Knock Out ◽  
Tyrosinemia Type 1 ◽  
Fumarylacetoacetate Hydrolase ◽  
Hereditary Tyrosinemia

scholarly journals Hereditary tyrosinemia type 1 in children

2019 ◽  
Vol 64 (5) ◽  
pp. 69-83
Author(s):  
G. V. Volynets ◽  
A. V. Nikitin ◽  
T. A. Skvortsova
Keyword(s):  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Laboratory Diagnostics ◽  
Low Protein ◽  
Current State ◽  
Tyrosine Metabolism ◽  
Tyrosinemia Type 1 ◽  
Fumarylacetoacetate Hydrolase ◽  
Hereditary Tyrosinemia

Hereditary metabolic disorders include a group of diseases (more than 400) when a defect of a particular gene changes the metabolic process leading either to the accumulation of unwanted metabolites, or to a deficiency of a substance. This group also includes hereditary tyrosinemia type 1, a severe defect of tyrosine metabolism caused by deficiency of fumarylacetoacetate hydrolase (FAH) – the last enzyme of tyrosine catabolic pathway. Tyrosinemia type 1 is an autosomal recessive disorder. This paper presents a review of literature on the current state of diagnosticis and approaches to treatment of tyrosinemia using nitisinone and a low-protein diet, as well as the analysis of clinical manifestations and laboratory diagnostics of hereditary tyrosinemia type 1 in 17 children.

Direct sequencing of FAH gene in Pakistani tyrosinemia type 1 families reveals a novel mutation

2016 ◽  
Vol 29 (3) ◽  
Author(s):  
Sadaqat Ijaz ◽  
Muhammad Yasir Zahoor ◽  
Muhammad Imran ◽  
Sibtain Afzal ◽  
Munir A. Bhinder ◽  
...  
Keyword(s):  
Screening Program ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Delayed Diagnosis ◽  
Recessive Mutations ◽  
Acute Form ◽  
Tyrosinemia Type 1 ◽  
Fumarylacetoacetate Hydrolase ◽  
Hereditary Tyrosinemia

AbstractHereditary tyrosinemia type 1 (HT1) is a rare inborn error of tyrosine catabolism with a worldwide prevalence of one out of 100,000 live births. HT1 is clinically characterized by hepatic and renal dysfunction resulting from the deficiency of fumarylacetoacetate hydrolase (FAH) enzyme, caused by recessive mutations in theThree Pakistani families, each having one child affected with HT1, were enrolled over a period of 1.5 years. Two of the affected children had died as they were presented late with acute form. All regions of theThree differentMost of the HT1 patients die before they present to hospitals in Pakistan, as is indicated by enrollment of only three families in 1.5 years. Most of those with late clinical presentation do not survive due to delayed diagnosis followed by untimely treatment. This tragic condition advocates the establishment of expanded newborn screening program for HT1 within Pakistan.

scholarly journals In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions

2021 ◽  
Author(s):  
Clara T Nicolas ◽  
Caitlin J VanLith ◽  
Kari L Allen ◽  
Raymond D Hickey ◽  
Zeji Du ◽  
...  
Keyword(s):  
Lentiviral Vector ◽  
Ex Vivo ◽  
Expression Patterns ◽  
Tyrosinemia Type 1 ◽  
Vector Targeting ◽  
Fumarylacetoacetate Hydrolase ◽  
Hereditary Tyrosinemia ◽  
First Time

AbstractConventional therapy for hereditary tyrosinemia type-1 (HT1) with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) delays but in some cases fails to prevent disease progression to liver fibrosis, liver failure, and activation of tumorigenic pathways. Here we demonstrate for the first time a complete cure of HT1 by direct, in vivo administration of a therapeutic lentiviral vector targeting the expression of a human fumarylacetoacetate hydrolase (FAH) transgene in the porcine model of HT1. This therapy was well tolerated and provided stable long-term expression of FAH in pigs with HT1. Genomic integration displayed a benign profile, with subsequent fibrosis and tumorigenicity gene expression patterns similar to wild-type animals as compared to NTBC-treated or diseased untreated animals. Indeed, the phenotypic and genomic data following in vivo lentiviral vector administration demonstrate comparative superiority over other therapies including ex vivo cell therapy and therefore support clinical application of this approach.

scholarly journals Hereditary Tyrosinemia Type 1—A Rare Disease with Typical Radiological Features: Case Report and Review of Literature

2020 ◽  
Vol 3 (S 01) ◽  
pp. S58-S64
Author(s):  
Somesh Singh ◽  
Rana Vishwadeep Mall ◽  
Pragya Chaturvedi ◽  
Rajnikant R. Yadav
Keyword(s):  
Liver Failure ◽  
Rare Disease ◽  
Imaging Features ◽  
Biochemical Tests ◽  
Inborn Errors ◽  
Radiological Features ◽  
Tyrosinemia Type 1 ◽  
The Many ◽  
Hereditary Tyrosinemia

AbstractHereditary tyrosinemia type 1 is one of the many inborn errors of metabolism associated with tyrosine catabolism. It is a rare disease with its incidence or prevalence in India unknown. The cascading alternate metabolism results in characteristic injury patterns to the liver, kidneys, and the central nervous system, with resultant classical radiological findings. Identifying this constellation of imaging features by a radiologist may help in arriving at a diagnosis and help referring physicians in performing appropriate biochemical tests and instituting early treatment. These usually present with chronic liver failure and are extensively evaluated for other causes of liver failure. We present a case type 1 hereditary tyrosinemia with characteristic radiological features and highlight its pathophysiology to understand the basis of these imaging findings.

scholarly journals Hereditary Tyrosinemia Type 1 in Jordan: A Retrospective Study

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Noor A. Megdadi ◽  
Ahmad K. Almigdad ◽  
Mo’men O. Alakil ◽  
Shahrazad M. Alqiam ◽  
Sumaia G. Rababah ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Clinical Features ◽  
Positive Family History ◽  
Laboratory Data ◽  
Acute Onset ◽  
Increased Risk ◽  
The Mean ◽  
Tyrosinemia Type 1 ◽  
Hereditary Tyrosinemia

Background. Hereditary tyrosinemia type 1 (HT1) is a recessively inherited inborn error of metabolism affecting the final step of tyrosine catabolism. The accumulation of tyrosine toxic metabolites leads to progressive hepatic, renal, and neurological manifestations. Treatment of HT1 consists of tyrosine-restricted diets and nitisinone. The untreated disease progresses into life-threatening liver failure with an increased risk of hepatocellular carcinoma. Methods. From April 2010 to March 2021, eighteen patients were diagnosed with HT1 in the metabolic department at Queen Rania Al Abdullah Hospital for Children in Jordan. Patients were reviewed retrospectively regarding their clinical features, laboratory data, and sociodemographic history. Results. The mean age of nine boys and nine girls was 6.03 years ( SD ± 3.85 ). The mean age for symptom onset was 5.61 months ( SD ± 6.02 ). However, the diagnosis was belated from the onset by 10.50 months (±10.42). Nitisinone treatment was delayed from diagnosis around 12.28 months ( SD ± 25.36 ). Most of the patients (66.7%) had acute onset of the disease. Two children (11.1%) died due to hepatic complications. Positive family history was identified in 61.1% of patients, and a similar percentage were born to parents with consanguineous marriage. The most common presentation was abdominal pain, vomiting, and fever. Hepatomegaly and abdominal distention were the most common findings. Six patients’ (42.9%) first presentation was rickets. Conclusion. HT1 diagnosis is usually delayed because it is not part of newborn screening and nonfamiliarity with the clinical features of the disease. Therefore, nationwide newborn screening should be expanded to include HT1.

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