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.

The outcome of seven patients with hereditary tyrosinemia type 1

2016 ◽  
Vol 29 (10) ◽  
Author(s):  
Songul Gokay ◽  
Pembe Soylu Ustkoyuncu ◽  
Fatih Kardas ◽  
Mustafa Kendirci
Keyword(s):  
Clinical Symptoms ◽  
Age At Onset ◽  
Nodule Formation ◽  
First Year ◽  
Tyrosine Metabolism ◽  
Tyrosinemia Type 1 ◽  
Hereditary Tyrosinemia ◽  
Biochemical Imaging

AbstractBackground:Hereditary tyrosinemia type 1 (HT1) is a rare, inborn error of tyrosine metabolism. It is a fatal disorder without treatment. Early treatment may prevent acute liver failure, renal dysfunction, liver cirrhosis, hepatocellular carcinoma (HCC) and improves survival. The aim of the present study is to describe the clinical, biochemical, imaging and follow-up of seven patients with HT1 and to define the consequences of the late and interrupted treatment.Methods:A retrospective study was carried out with seven HT1 patients.Results:The median age at onset of clinical symptoms was 11.2 months (range, 3–28 months) and the median age at diagnosis was 22 months (range, 6–58 months). Liver enzymes and coagulation parameters were back to normal in all symptomatic patients in about 2 weeks. Alfa-fetoprotein (AFP) levels were normalized within the first year of therapy. Hypoechoic nodule formation was detected in two of the seven patients despite drug treatment without an increase of AFP and any dysplastic changes in the biopsies. One patient died due to metastatic HCC because of the late diagnosis and the poor compliance of the follow-up.Conclusions:This study showed once again that adherence to the treatment and a follow-up schedule of the patients are very important. Also it should not be forgotten that nodule formation can occur despite nitisinone treatment without an increase of AFP. Despite nitisinone treatment, HT1 patients still carry the risk of HCC. HCC must be detected before metastasis to other organs otherwise, patients may lose the chance for liver transplantation.

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

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 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 NTBC Treatment Monitoring in Chilean Patients with Tyrosinemia Type 1 and Its Association with Biochemical Parameters and Liver Biomarkers

2021 ◽  
Vol 10 (24) ◽  
pp. 5832
Author(s):  
Karen Fuenzalida ◽  
María Jesús Leal-Witt ◽  
Patricio Guerrero ◽  
Valerie Hamilton ◽  
María Florencia Salazar ◽  
...  
Keyword(s):  
Amino Acids ◽  
Clinical Manifestations ◽  
Dietary Treatment ◽  
Laboratory Parameters ◽  
Paired Samples ◽  
Tyrosinemia Type 1 ◽  
One Year ◽  
Hereditary Tyrosinemia

Treatment and follow-up in Hereditary Tyrosinemia type 1 (HT-1) patients require comprehensive clinical and dietary management, which involves drug therapy with NTBC and the laboratory monitoring of parameters, including NTBC levels, succinylacetone (SA), amino acids, and various biomarkers of liver and kidney function. Good adherence to treatment and optimal adjustment of the NTBC dose, according to clinical manifestations and laboratory parameters, can prevent severe liver complications such as hepatocarcinogenesis (HCC). We analyzed several laboratory parameters for 15 HT-1 patients over one year of follow-up in a cohort that included long-term NTBC-treated patients (more than 20 years), as well as short-term patients (one year). Based on this analysis, we described the overall adherence by our cohort of 70% adherence to drug and dietary treatment. A positive correlation was found between blood and plasma NTBC concentration with a conversion factor of 2.57. Nonetheless, there was no correlation of the NTBC level with SA levels, αFP, liver biomarkers, and amino acids in paired samples analysis. By separating according to the range of the NTBC concentration, we therefore determined the mean concentration of each biochemical marker, for NTBC ranges above 15–25 μmol/L. SA in urine and αFP showed mean levels within controlled parameters in our group of patients. Future studies analyzing a longer follow-up period, as well as SA determination in the blood, are encouraged to confirm the present findings.

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.

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