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.

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 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 Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone Discontinuation

Genes ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 3
Author(s):  
Haaike Colemonts-Vroninks ◽  
Jessie Neuckermans ◽  
Lionel Marcelis ◽  
Paul Claes ◽  
Steven Branson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Liver Regeneration ◽  
The Body ◽  
Glutathione Metabolism ◽  
Short Term ◽  
Therapeutic Regime ◽  
Tyrosinemia Type 1 ◽  
Hereditary Tyrosinemia

Hereditary tyrosinemia type 1 (HT1) is an inherited condition in which the body is unable to break down the amino acid tyrosine due to mutations in the fumarylacetoacetate hydrolase (FAH) gene, coding for the final enzyme of the tyrosine degradation pathway. As a consequence, HT1 patients accumulate toxic tyrosine derivatives causing severe liver damage. Since its introduction, the drug nitisinone (NTBC) has offered a life-saving treatment that inhibits the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD), thereby preventing production of downstream toxic metabolites. However, HT1 patients under NTBC therapy remain unable to degrade tyrosine. To control the disease and side-effects of the drug, HT1 patients need to take NTBC as an adjunct to a lifelong tyrosine and phenylalanine restricted diet. As a consequence of this strict therapeutic regime, drug compliance issues can arise with significant influence on patient health. In this study, we investigated the molecular impact of short-term NTBC therapy discontinuation on liver tissue of Fah-deficient mice. We found that after seven days of NTBC withdrawal, molecular pathways related to oxidative stress, glutathione metabolism, and liver regeneration were mostly affected. More specifically, NRF2-mediated oxidative stress response and several toxicological gene classes related to reactive oxygen species metabolism were significantly modulated. We observed that the expression of several key glutathione metabolism related genes including Slc7a11 and Ggt1 was highly increased after short-term NTBC therapy deprivation. This stress response was associated with the transcriptional activation of several markers of liver progenitor cells including Atf3, Cyr61, Ddr1, Epcam, Elovl7, and Glis3, indicating a concreted activation of liver regeneration early after NTBC withdrawal.

Characterisation of macular neovascularisation in geographic atrophy

2021 ◽  
pp. bjophthalmol-2021-318820
Author(s):  
Riccardo Sacconi ◽  
Maria Brambati ◽  
Alexandra Miere ◽  
Eliana Costanzo ◽  
Vittorio Capuano ◽  
...  
Keyword(s):  
Fundus Autofluorescence ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
First Year ◽  
Age Related ◽  
Treatment Naïve ◽  
Type 3 ◽  
Endothelial Growth Factor

AimTo characterise macular neovascularisation (MNV) developing in eyes affected by geographic atrophy (GA).MethodsIn this multicentric longitudinal study involving three retina referral centres, patients previously affected by GA who developed an active MNV were included. Patients were investigated using structural optical coherence tomography (OCT), fundus autofluorescence, OCT-angiography and dye angiographies. Patients were treated with ProReNata antivascular endothelial growth factor (VEGF) injections and were revaluated after treatment.ResultsAmong 512 patients previously diagnosed with GA, 40 eyes of 40 patients (mean age 80.8±7.9 years, mean GA area 8.73±7.39 mm2) presented with treatment-naïve exudative MNV (accounting for an estimated prevalence of 7.81%; 5.49 to 10.13, 95% CIs) and thus were included in the analysis. 67.5% of MNVs were classified as type 2 MNV, 25% as type 1, 2.5% as type 3 and 5% as mixed phenotype. In 92.5% of cases, active MNV in GA showed subretinal hyperreflective material with or without evidence of subretinal/intraretinal hyporeflective exudation. During a mean follow-up of 28±25 months, patients were treated with 6.6±6.3 anti-VEGF injections, with 2.9±1.4 injections in the first year of treatment. No patient developed GA enlargement in the area of MNV.ConclusionsMNVs in GA showed different features and therapeutic response in comparison to previously reported features of MNV in age-related macular degeneration (AMD) without GA. For these reasons, the combined phenotype (ie, GA with neovascular AMD) should be considered as a distinct entity in the research and clinical setting.

scholarly journals Pharmacological and clinical profile of nitisinone (Orfadin® Capsules): a therapeutic agent for hereditary tyrosinemia type 1

2015 ◽  
Vol 146 (6) ◽  
pp. 342-348 ◽  
Author(s):  
Hideaki Minoura ◽  
Megumi Iwai ◽  
Yuta Taniuchi ◽  
Masataka Katashima ◽  
Hideyuki Takahashi
Keyword(s):  
Therapeutic Agent ◽  
Clinical Profile ◽  
Tyrosinemia Type 1 ◽  
Hereditary Tyrosinemia

scholarly journals Biomarkers of Micronutrients in Regular Follow-Up for Tyrosinemia Type 1 and Phenylketonuria Patients

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2011 ◽  
Author(s):  
Kimber van Vliet ◽  
Iris L. Rodenburg ◽  
Willem G. van Ginkel ◽  
Charlotte M.A. Lubout ◽  
Bruce H.R. Wolffenbuttel ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin B12 ◽  
Nutritional Deficiencies ◽  
Micronutrient Deficiencies ◽  
Dietary Restrictions ◽  
Normal Ranges ◽  
Correlation Tests ◽  
Tyrosinemia Type 1

Phenylketonuria (PKU) is treated with dietary restrictions and sometimes tetrahydrobiopterin (BH4). PKU patients are at risk for developing micronutrient deficiencies, such as vitamin B12 and folic acid, likely due to their diet. Tyrosinemia type 1 (TT1) is similar to PKU in both pathogenesis and treatment. TT1 patients follow a similar diet, but nutritional deficiencies have not been investigated yet. In this retrospective study, biomarkers of micronutrients in TT1 and PKU patients were investigated and outcomes were correlated to dietary intake and anthropometric measurements from regular follow-up measurements from patients attending the outpatient clinic. Data was analyzed using Kruskal–Wallis, Fisher’s exact and Spearman correlation tests. Furthermore, descriptive data were used. Overall, similar results for TT1 and PKU patients (with and without BH4) were observed. In all groups high vitamin B12 concentrations were seen rather than B12 deficiencies. Furthermore, all groups showed biochemical evidence of vitamin D deficiency. This study shows that micronutrients in TT1 and PKU patients are similar and often within the normal ranges and that vitamin D concentrations could be optimized.

Sustained NRF2 activation in hereditary leiomyomatosis and renal cell cancer (HLRCC) and in hereditary tyrosinemia type 1 (HT1)

2015 ◽  
Vol 43 (4) ◽  
pp. 650-656 ◽  
Author(s):  
Ivraj Singh Sandhu ◽  
Nicholas James Maksim ◽  
Eva Alice Amouzougan ◽  
Bryce Wilson Gallion ◽  
Anthony L.J. Raviele ◽  
...  
Keyword(s):  
Renal Cell Cancer ◽  
Renal Cell ◽  
Cell Cancer ◽  
Hereditary Syndromes ◽  
Nrf2 Activation ◽  
Tyrosinemia Type 1 ◽  
Hereditary Tyrosinemia ◽  
Hereditary Leiomyomatosis

The nuclear erythroid 2-like 2 transcription factor (NRF2), is a major regulator of cellular redox balance. Although NRF2 activation is generally regarded as beneficial to human health, recent studies have identified that sustained NRF2 activation is over-represented in many cancers. This raises the question regarding the role of NRF2 activation in the development and progression of those cancers. This review focuses on the mechanisms and the effects of NRF2 activation in two hereditary cancer predisposition syndromes: hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary tyrosinemia type 1 (HT1). Because the cancer initiating mutations in these hereditary syndromes are well defined, they offer a unique opportunity to explore the roles of NRF2 activation in the early stages of carcinogenesis. Over the years, a variety of approaches have been utilized to study the biology of HLRCC and HT1. In HLRCC, in vitro studies have demonstrated the importance of NRF2 activation in sustaining cancer cell proliferation. In the mouse model of HT1 however, NRF2 activation seems to protect cells from malignant transformation. In both HT1 and HLRCC, NRF2 activation promotes the clearance of electrophilic metabolites, enabling cells to survive cancer-initiating mutations. Biological insights gained from the hereditary syndromes’ studies may shed light on to the roles of NRF2 activation in sporadic tumours.

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