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.

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 Neurofibromatosis Type 1 in a Pediatric Population: Ste-Justine's Experience

2005 ◽  
Vol 32 (2) ◽  
pp. 225-231 ◽  
Author(s):  
J.M. Boulanger ◽  
A. Larbrisseau
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Attention Deficit Disorder ◽  
Pediatric Population ◽  
Laboratory Data ◽  
Neurofibromatosis Type ◽  
Optic Glioma ◽  
Increased Risk ◽  
The Mean

ABSTRACT:Background:To date, few pediatric series of neurofibromatosis type 1 (NF-1) have been described in the literature even though it is the most frequently encountered phakomatosis.Methods:We reviewed 987 charts of pediatric patients with a presumptive diagnosis of NF-1 who were evaluated at Ste-Justine hospital from January 1, 1991 to July 31, 2002. Patients who presented with two or more cardinal criteria were diagnosed with NF-1. Clinical and laboratory data were retrospectively collected, including: demographics, neuroimaging and presence or absence of associated symptoms or signs of NF-1.Results:A total of 279 patients were diagnosed with NF-1. The mean age at diagnosis was 3.4 years. Ninety-nine percent of the patients had café au lait spots and 47% had a first degree relative with NF-1. Almost 60 percent (59.6%) of those seen by an ophthalmologist had Lisch nodules. Optic glioma was found in in 14.7%, cutaneous neurofibromas in 38.4%, plexiform neurofibromas in 24.7%, neurofibrosarcoma in 1.8%, learning disabilities in 39%, attention deficit disorder in 40.5%, osseous dysplasias in 7.2%, pseudoarthrosis in 3.6%, precocious puberty in 3.2% and short stature in 17.9%. Magnetic resonance, when performed, showed hyperintense T2 lesions in 87.1% of cases. The mean period of follow-up was 7.4 years.Conclusion:Neurofibromatosis type 1 is a multisystemic disorder associated with increased risk of malignancy. It can be diagnosed at a very young age and clinical follow-up is advised. To our knowledge, this is the largest single center study of NF-1 in a pediatric population.

The effect of insulin pump therapy in retinal vasculature in type 1 diabetic patients

2021 ◽  
pp. 112067212199057
Author(s):  
Tomás de Oliveira Loureiro ◽  
João Nobre Cardoso ◽  
Carlos Diogo Pinheiro Lima Lopes ◽  
Ana Rita Carreira ◽  
Sandra Rodrigues-Barros ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Metabolic Control ◽  
Insulin Pump Therapy ◽  
Vascular Density ◽  
Diabetic Patients ◽  
Retinal Vasculature ◽  
Increased Risk ◽  
The Mean ◽  
Type 1 Diabetic Patients

Background/objectives: Continuous subcutaneous insulin infusion (CSII) is a treatment for type 1 diabetes that improves metabolic control and reduces micro and macrovascular complications. The aim of this study was to compare the effect of CSII versus traditional multiple daily injections (MDI) therapy on retinal vasculature. Methods: We performed a prospective study with type 1 diabetic patients with no prior history of ocular pathology other than mild diabetic retinopathy. The patients were divided into two groups according to their therapeutic modality (CSII vs MDI). The retinal nerve fiber layers thickness and vascular densities were compared between groups in both macula and optic disc. The correlations between vascular density and clinical features were also determined. Statistical significance was defined as p < 0.05. Results: The study included 52 eyes, 28 in the insulin CSII group. The mean age was 36.66 ± 12.97 years, with no difference between groups ( p = 0.49). The mean glycated hemoglobin (HbA1c) was found to be lower in the CSII group (7.1% ± 0.7 vs 7.5% ± 0.7 p < 0.01). The parafoveal vascular density was found to be higher in the CSII group (42.5% ± 0.4 vs 37.7% ± 0.6, p < 0.01). We found an inverse correlation between HbA1c value and parafoveal vascular densities ( p < 0.01, r = −0.50). Conclusion: We found that CSII provided better metabolic control than MDI and this seemed to result in higher parafoveal vascular density. As lower vascular density is associated with an increased risk of diabetic retinopathy, these results suggest that CSII could be the safest therapeutic option to prevent retinopathy.

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.

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 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 Pathological fracture of non-ossifying fibroma associated with neurofibromatosis type 1

2019 ◽  
Vol 12 (7) ◽  
pp. e228170 ◽  
Author(s):  
James Ritchie Gill ◽  
Tamer Magid EL Nakhal ◽  
Soo-Mi Park ◽  
Mariusz Chomicki
Keyword(s):  
Clinical Features ◽  
Neurofibromatosis Type 1 ◽  
Pathological Fracture ◽  
Neurofibromatosis Type ◽  
Ossifying Fibroma ◽  
Pathological Fractures ◽  
Cast Immobilisation ◽  
Increased Risk ◽  
Operative Fixation

We report the management of a pathological fracture through a proximal tibial non-ossifying fibroma (NOF) in a 13-year-old girl with neurofibromatosis type 1 (NF1). The fracture was minimally displaced, and the lesion had clinical features of a NOF, and therefore biopsy was not required. Operative fixation has been the preferred method of treatment for pathological fractures through NOF associated with NF1. Multiple NOFs associated with NF1 are rare but can coalesce resulting in large lesions with an increased risk of pathological fracture. In cases which permit, non-operative treatment with cast immobilisation can yield satisfactory results.

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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