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.

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.

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.

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 First Macedonian child with tyrosinemia type 1 successfully treated with nitisinone and report of a novel mutation in the FAH gene

2017 ◽  
Vol 145 (9-10) ◽  
pp. 530-533
Author(s):  
Aco Kostovski ◽  
Nikolina Zdraveska ◽  
Marketa Tesarova ◽  
Jiři Zeman
Keyword(s):  
Novel Mutation ◽  
Molecular Genetic ◽  
Failure To Thrive ◽  
In Silico Analysis ◽  
Normal Growth ◽  
Psychomotor Development ◽  
Focal Lesions ◽  
Tyrosinemia Type 1 ◽  
Hereditary Tyrosinemia

Introduction. Hereditary tyrosinemia type 1 (HT1) is a severe hereditary metabolic disorder of tyrosine metabolism due to fumarylacetoacetate hydrolase (FAH) deficiency and accumulation of toxic products in tissues. More than 80 mutations in the FAH gene are presently reported on the Human Genome Mutation Database. To date, no molecular genetic defects of HT1 in Macedonia have been described. Case outline. A female infant two and a half months old presented with failure to thrive, anemia, edemas, and severe coagulation disturbances. The diagnosis of HT1 was based on high levels of serum ?-fetoprotein, increased serum tyrosine, and positive succinylacetone in urine. Nitisinone treatment with tyrosine-restriction diet was immediately introduced. The patient, currently aged five years, has normal growth, psychomotor development, and no focal lesions on abdominal MRI. A screening of the FAH gene revealed two heterozygous mutations ? c.[1A>G];[784T>A]. The mutation c.784T>A is a novel one (p.Trp262Arg), and was predicted to be the cause of the disease by an in silico analysis. Conclusion. To date, this case is the first and only child with HT1 successfully treated with nitisinone in our country. Also, this is the first report of an HT1 patient caused by the c.784T>A mutation.

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