507 results on '"Tyrosinemias"'
Search Results
2. Early Check: Expanded Screening in Newborns
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University of North Carolina, Chapel Hill, The John Merck Fund, Duke University, Wake Forest University, North Carolina Department of Health and Human Services, National Center for Advancing Translational Sciences (NCATS), Cure SMA, The National Fragile X Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Asuragen, Inc., Sarepta Therapeutics, Inc., Muscular Dystrophy Association, The Leona M. and Harry B. Helmsley Charitable Trust, Juvenile Diabetes Research Foundation, Janssen Pharmaceuticals, GeneDx, and Illumina, Inc.
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- 2024
3. Acceptability/Tolerance of Protein Substitutes in Tablet Form for the Dietary Management of Rare Aminoacidopathies (ZeroMinisMR)
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Birmingham Women's and Children's NHS Foundation Trust and Great Ormond Street Hospital for Children NHS Foundation Trust
- Published
- 2024
4. Evaluation of the Express Plus Range (express plus)
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- 2024
5. Evaluation of TYR Sphere
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- 2024
6. Evaluation of TYR Sphere in France (TYR sphere Fra)
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- 2024
7. A Non-interventional, Post-Marketing Study to Describe Outcome of Nitisinone Treatment in HT-1 Patients
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- 2024
8. GMP Case Studies of Tolerance, Safety and Acceptability in PKU and TYR
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- 2023
9. Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
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Zharmakhanova Gulmira, Head of Department of Natural Sciences disciplines (with course of Molecular Biology and Medical Genetic)
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- 2023
10. Biomarker for the Early Diagnosis and Monitoring in Tyrosinemia Type 1 (BioTyrosin) (BioTyrosin)
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- 2023
11. Características visuales en el albinismo: Revisión sistemática.
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Rodríguez, Selma and Maza Espinosa, Gabriela
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ONLINE information services ,SYSTEMATIC reviews ,OPTIC nerve diseases ,ALBINISM ,GENETIC disorders ,AMINO acid metabolism disorders ,NYSTAGMUS ,VISUAL acuity ,VISION disorders ,MEDLINE ,SYMPTOMS - Abstract
Copyright of Revista de Investigación en Salud VIVE is the property of Revista de Investigacion en Salud VIVE and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2023
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12. Long Term Safety Study of Orfadin Treatment in HT-1 Patients in Standard Clinical Care (OPAL)
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- 2020
13. Bio Equivalency 20 Mgm Orfadin and 20 Mgm of Nitisonine (Orfadin)
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- 2019
14. Hereditary Hepatorenal Tyrosinemia Natural History in Egypt and the Arab World (Multicenter Clinical Study)
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Society of Friends of Liver Patients in the Arab World (SLPAW) and Dr. Tawhida Yassin Abdel Ghaffar, Professor
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- 2019
15. Bioequivalence Study of Two Oral Nitisinone Formulations to Treat Hereditary Tyrosinemia (HT-1)
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Parexel
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- 2017
16. Bioequivalence Study of Two Nitisinone Formulations Compared to Orfadin
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Parexel
- Published
- 2017
17. Bioavailability Food-Effect Study of an Oral Nitisinone Formulation to Treat Hereditary Tyrosinemia (HT-1)
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Parexel
- Published
- 2017
18. Role of Delta-aminolevulinic Acid in the Symptoms of Acute Porphyria
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Bissell, D Montgomery, Lai, Jennifer C, Meister, Raymond K, and Blanc, Paul D
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Biomedical and Clinical Sciences ,Clinical Sciences ,Hematology ,Digestive Diseases ,Neurosciences ,Peripheral Neuropathy ,Chronic Pain ,Rare Diseases ,Neurodegenerative ,Pain Research ,Aetiology ,2.1 Biological and endogenous factors ,Abdominal Pain ,Adult ,Aminolevulinic Acid ,Chelation Therapy ,Diagnosis ,Differential ,Female ,Heme ,Humans ,Lead Poisoning ,Medicine ,Ayurvedic ,Neuralgia ,Porphyria ,Acute Intermittent ,Treatment Outcome ,Tyrosinemias ,Abdominal pain ,Acute porphyria ,Ayurveda ,Delta-aminolevulinic acid ,Lead poisoning ,Medical and Health Sciences ,General & Internal Medicine ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundAttacks of neuropathic pain, usually abdominal, are characteristic of the acute porphyrias and accompanied by overproduction of heme-precursor molecules, specifically delta-aminolevulinic acid and porphobilinogen. The basis for the acute symptoms in these diseases has been speculative.MethodsWe review genetic acute porphyria, hereditary tyrosinemia, and an acquired condition, lead poisoning. All perturb heme synthesis and present with a similar pain syndrome.ResultsAlthough each of these conditions has characteristic urine biochemistry, all exhibit excess delta-aminolevulinic acid. Moreover, in all, treatment with hemin reduces delta-aminolevulinic acid and relieves symptoms. In contrast, use of recombinant porphobilinogen deaminase to knock down porphobilinogen in acute porphyria was ineffective.ConclusionsThere is now convincing evidence that delta-aminolevulinic acid is the cause of pain in the acute porphyrias. The efficacy of hemin infusion is due mainly, if not entirely, to its inhibition of hepatic delta-aminolevulinic acid synthase-1, the enzyme that catalyzes delta-aminolevulinic acid formation. Delta-aminolevulinic acid synthase-1 is a rational target for additional therapies to control symptoms in acute porphyria.
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- 2015
19. Herediter Trozinemi Tip 1 ve Canlı Vericili Karaciğer Nakli: Zamanlama-Hasta Seçimi-Komplikasyonlar.
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ALİMA, Altan, DAL, Mehmet Burak, ERDOĞAN, Yalçın, KIYKIM, Ertuğrul, GÜLER, Necdet, AKTUĞLU ZEYBEK, Ayşe Çiğdem, and ACARLI, Koray
- Subjects
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SURVIVAL rate , *LIVER transplantation , *SURGICAL complications , *LIVER failure , *DIAGNOSIS , *TRANSPLANTATION of organs, tissues, etc. , *IMMUNOSUPPRESSION - Abstract
Objective: In this study, the importance of indication, preparation, process, results and liver transplant timing were rewieved in patients who underwent liver transplantation due to Tyrosinemia Type 1 (HT-1) and the suspicion of hepatocellular carcinoma (HCC). Material and Methods: All patients who underwent liver transplantations due to HT-1 in our clinic were included in the present study. The demographic findings, preoperative alpha-fetoprotein (AFP) levels and tomography/MRI findings of the patients and live donors were examined. Indications for surgery were questioned. The presence of HCC, tumor grade, extention and burden in the hepatectomy materials were recorded. The postoperative complications, the recurrences of HCC and the survival rates were investigated. Results: A total of 11 patients with Tyrosinemia Type1, 6 of whom were female and 5 were male, with an median age of 8.5±7 years and a median weight of 30.6±23.4 kg were included in this study. The mean AFP value before surgery was 10.682±22.612 U/ml (R: 8-76000). AFP value was within normal limits in only one patient. HCC was not detected in three patients transplanted due to liver failure. In seven (87%) of 8 patients who were transplanted with the diagnosis of HCC, HCC was determined. Multifocal lung metastases were detected in one at the postoperative sixth month. The average follow-up time after transplantation is 4.6±3.4 years and all patients are still alive. Conclusion: Living donor liver transplantation is a curative treatment method in HT-1 patients with liver failure findings or the diagnosis of clinical or radiological HCC. The patients should be carefully selected because of the possible complications and mortality of the liver transplantation, lifelong immunosuppression usage and the fact of requirement for a re-transplantation in a long-term period. [ABSTRACT FROM AUTHOR]
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- 2021
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20. Brief Report: Parthenogenetic Embryonic Stem Cells are an Effective Cell Source for Therapeutic Liver Repopulation
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Espejel, Silvia, Eckardt, Sigrid, Harbell, Jack, Roll, Garrett R, McLaughlin, K John, and Willenbring, Holger
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Medical Biotechnology ,Biomedical and Clinical Sciences ,Digestive Diseases ,Transplantation ,Stem Cell Research ,Regenerative Medicine ,Liver Disease ,Genetics ,Stem Cell Research - Embryonic - Non-Human ,5.2 Cellular and gene therapies ,Animals ,Cell Differentiation ,Embryonic Stem Cells ,Hepatocytes ,Humans ,Liver ,Liver Failure ,Liver Regeneration ,Mice ,129 Strain ,Mice ,Inbred C57BL ,Mice ,Knockout ,Parthenogenesis ,Tyrosinemias ,Liver regeneration ,Liver repopulation ,Liver cell therapy ,Embryonic stem cells ,Pluripotent stem cells ,Biological Sciences ,Technology ,Medical and Health Sciences ,Immunology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Parthenogenesis is the development of an oocyte without fertilization. Mammalian parthenogenetic (PG) embryos are not viable, but can develop into blastocysts from which embryonic stem cells (ESCs) have been derived in mouse and human. PG ESCs are frequently homozygous for alleles encoding major histocompatibility complex (MHC) molecules. MHC homozygosity permits much more efficient immune matching than MHC heterozygosity found in conventional ESCs, making PG ESCs a promising cell source for cell therapies requiring no or little immune suppression. However, findings of restricted differentiation and proliferation of PG cells in developmental chimeras have cast doubt on the potential of PG ESC derivatives for organ regeneration. To address this uncertainty, we determined whether PG ESC derivatives are effective in rescuing mice with lethal liver failure due to deficiency of fumarylacetoacetate hydrolase (Fah). In developmental chimeras generated by injecting wild-type PG ESCs into Fah-deficient blastocysts, PG ESCs differentiated into hepatocytes that could repopulate the liver, provide normal liver function, and facilitate long-term survival of adult mice. Moreover, after transplantation into adult Fah-deficient mice, PG ESC-derived hepatocytes efficiently engrafted and proliferated, leading to high-level liver repopulation. Our results show that--despite the absence of a paternal genome--PG ESCs can form therapeutically effective hepatocytes.
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- 2014
21. Efficacy and Safety of Once Daily Dosing Compared to Twice Daily Dosing of Nitisinone in HT-1 (HT-1)
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- 2015
22. Study of NTBC for Tyrosinemia I
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- 2015
23. Taste and Palatability of Orfadin Suspension
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- 2014
24. Current Landscape on Development of Phenylalanine and Toxicity of its Metabolites - A Review.
- Author
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Bose S, Mandal S, Khan R, Maji HS, and Ashique S
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- Humans, Phenylalanine metabolism, Amino Acids, Tyrosine metabolism, Phenylketonurias metabolism, Phenylalanine Hydroxylase chemistry, Phenylalanine Hydroxylase metabolism
- Abstract
Phenylalanine, an essential amino acid, is the "building block" of protein. It has a tremendous role in different aspects of metabolic events. The tyrosine pathway is the prime one and is typically used to degrade dietary phenylalanine. Phenylalanine exceeds its limit in bodily fluids and the brain when the enzyme, phenylalanine decarboxylase, phenylalanine transaminase, phenylalanine hydroxylase (PAH) or its cofactor tetrahydrobiopterin (BH4) is deficient causes phenylketonuria, schizophrenia, attentiondeficit/ hyperactivity disorder and another neuronal effect. Tyrosine, an amino acid necessary for synthesizing the pigments in melanin, is produced by its primary metabolic pathway. Deficiency/abnormality in metabolic enzymes responsible for the catabolism pathway of Phenylalanine causes an accumulation of the active intermediate metabolite, resulting in several abnormalities, such as developmental delay, tyrosinemias, alkaptonuria, albinism, hypotension and several other undesirable conditions. Dietary restriction of the amino acid(s) can be a therapeutic approach to avoid such undesirable conditions when the level of metabolic enzyme is unpredictable. After properly identifying the enzymatic level, specific pathophysiological conditions can be managed more efficiently., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
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- 2024
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25. The effects of phenylalanine and tyrosine levels on dopamine production in rat PC12 cells. Implications for treatment of phenylketonuria, tyrosinemia type 1 and comorbid neurodevelopmental disorders.
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Szigetvari PD, Patil S, Birkeland E, Kleppe R, and Haavik J
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- Rats, Animals, Dopamine metabolism, Tyrosine metabolism, Phenylalanine, PC12 Cells, Proteomics, Tyrosine 3-Monooxygenase metabolism, Tyrosinemias, Phenylketonurias metabolism, Neurodevelopmental Disorders
- Abstract
Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, resulting in phenylalanine accumulation and impaired tyrosine production. In Tyrosinemia type 1 (TYRSN1) mutations affect fumarylacetoacetate hydrolase, leading to accumulation of toxic intermediates of tyrosine catabolism. Treatment of TYRSN1 with nitisinone results in extreme tissue levels of tyrosine. Although PKU and TYRSN1 have opposite effects on tyrosine levels, both conditions have been associated with neuro-psychiatric symptoms typically present in ADHD, possibly indicating an impaired dopamine (DA) synthesis. However, concrete in vivo data on the possible molecular basis for disrupted DA production under disease mimicking conditions have been lacking. In pursuit to uncover associated molecular mechanisms, we exposed an established, DA producing cell line (PC12) to different concentrations of phenylalanine and tyrosine in culture media. We measured the effects on viability, proteomic composition, tyrosine, DA and tyrosine hydroxylase (TH) levels and TH phosphorylation. TH catalyzes the rate-limiting step in DA synthesis. High extracellular levels of phenylalanine depleted cells of intracellular tyrosine and DA. Compared to physiological levels (75 μM), either low (35 μM) or high concentrations of tyrosine (275 or 835 μM) decreased cellular DA, TH protein, and its phosphorylation levels. Using deep proteomic analysis, we identified multiple proteins, biological processes and pathways that were altered, including enzymes and transporters involved in amino acid metabolism. Using this information and published data, we developed a mathematical model to predict how extracellular levels of aromatic amino acids can affect the cellular synthesis of DA via different mechanisms. Together, these data provide new information about the normal regulation of neurotransmitter synthesis and how this may be altered in neurometabolic disorders, such as PKU and TYRSN1, with implications for the treatment of cognitive symptoms resulting from comorbid neurodevelopmental disorders., Competing Interests: Declaration of competing interest During the past three years JH has received speaker fees from Takeda and Medice, all unrelated to the present work. The other authors report no potential conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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26. Phase II Study of the Enzyme Inhibitor NTBC for Tyrosinemia Type I
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University of Michigan
- Published
- 2005
27. An Infant with Bilateral Keratitis: From Infectious to Genetic Diagnosis
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Louis-Philippe Thibault, Grant A. Mitchell, Brigitte Parisien, Patrick Hamel, and Ana C. Blanchard
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Male ,Tyrosinemias ,Child, Preschool ,Keratitis, Herpetic ,Infant ,Humans ,Acyclovir ,Administration, Intravenous ,General Medicine ,Corneal Ulcer - Abstract
BACKGROUND Tyrosinemia Type II (TYRII) is a rare autosomal recessive inborn error of metabolism caused by deficiency of tyrosine aminotransferase (TAT), leading to hypertyrosinemia. TYRII patients often present in the first year of life with ocular and cutaneous findings, including corneal ulcers, pseudodendritic keratitis, and palmoplantar hyperkeratosis. The corneal involvement is often mistaken for herpes simplex virus (HSV) keratitis, which is a much commoner condition. CASE REPORT A previously healthy 10-month-old male infant was referred to Ophthalmology for acute onset photophobia. Bilateral dendritiform corneal lesions raised the suspicion for herpetic keratitis. Additionally, a papular, crusted lesion was found on his thumb after a few days of hospitalization, also raising concerns about HSV. The patient's clinical condition seemed to improve under intravenous acyclovir and supportive treatment. A conjunctival swab and crusted lesion on the thumb were tested for HSV using a polymerase chain reaction (PCR) technique, and both were negative. Nevertheless, given the clinical presentation and the favorable course of signs and symptoms, hospital discharge was planned with oral acyclovir. It was halted by an alternative diagnosis of autosomal recessive inborn error of metabolism, tyrosinemia type II, confirmed by elevated plasma tyrosine level and later by molecular analysis requested as a confirmatory investigation by the genetics medical team. CONCLUSIONS The corneal involvement in TYRII is often mistaken for HSV keratitis, and clinical course alone should not halt further investigations to rule out TYRII. Clinicians should suspect TYRII clinically when its characteristic ocular dendritiform lesions are present, namely in infancy or early childhood, and even in the absence of its typical cutaneous palmoplantar hyperkeratosis plaques.
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- 2022
28. Determinants of tyrosinaemia during nitisinone therapy in alkaptonuria
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Ranganath, LR, Milan, AM, Hughes, AT, Davison, AS, M, Khedr, Norman, BP, Bou-Gharios, G, Gallagher, JA, Imrich, R, Arnoux, JB, Rudebeck, M, and Olsson, B
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Multidisciplinary ,Phenylpropionates ,Cyclohexanones ,Tyrosinemias ,Nitrobenzoates ,Phenylalanine ,Brain Diseases, Metabolic, Inborn ,Humans ,Tyrosine ,Alkaptonuria ,Homogentisic Acid - Abstract
Nitisinone (NIT) produces inevitable but varying degree of tyrosinaemia. However, the understanding of the dynamic adaptive relationships within the tyrosine catabolic pathway has not been investigated fully. The objective of the study was to assess the contribution of protein intake, serum NIT (sNIT) and tyrosine pathway metabolites to nitisinone-induced tyrosinaemia in alkaptonuria (AKU). Samples of serum and 24-h urine collected during SONIA 2 (Suitability Of Nitisinone In Alkaptonuria 2) at months 3 (V2), 12 (V3), 24 (V4), 36 (V5) and 48 (V6) were included in these analyses. Homogentisic acid (HGA), tyrosine (TYR), phenylalanine (PHE), hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and sNIT were analysed at all time-points in serum and urine. Total body water (TBW) metabolites were derived using 60% body weight. 24-h urine and TBW metabolites were summed to obtain combined values. All statistical analyses were post-hoc. 307 serum and 24-h urine sampling points were analysed. Serum TYR from V2 to V6, ranging from 478 to 1983 µmol/L were stratified (number of sampling points in brackets) into groups 1100 (59) µmol/L. The majority of sampling points had values greater than 900 µmol/L. sPHE increased with increasing sTYR (p p p
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- 2022
29. Biochemical and behavioural profile of NTBC treated Tyrosinemie type 1 mice
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van Ginkel, Willem G, Winn, Shelley R, Dudley, Sandra, Krenik, Destine, Perez, Ruby, Rimann, Nicole, Thöny, Beat, Raber, Jacob, Harding, Cary O, University of Zurich, and Harding, Cary O
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Male ,1303 Biochemistry ,Endocrinology, Diabetes and Metabolism ,610 Medicine & health ,Biochemistry ,Mice ,Endocrinology ,Cognition ,1311 Genetics ,1312 Molecular Biology ,Genetics ,Tyrosinemia type 1 ,Animals ,Behaviour ,Molecular Biology ,Cyclohexanones ,Tyrosinemias ,NTBC ,Neurotransmitters ,1310 Endocrinology ,Mice, Inbred C57BL ,2712 Endocrinology, Diabetes and Metabolism ,10036 Medical Clinic ,Nitrobenzoates ,Tyrosine ,Amino acids - Abstract
Background: Tyrosinemia type 1 (HT1) is a rare metabolic disorder caused by a defect in the tyrosine catabolic pathway. Since HT1 patients are treated with NTBC, outcome improved and life expectancy greatly increased. However extensive neurocognitive and behavioural problems have been described, which might be related to treatment with NTBC, the biochemical changes induced by NTBC, or metabolites accumulating due to the enzymatic defect characterizing the disease.Objective: To study the possible pathophysiological mechanisms of brain dysfunction in HT1, we assessed blood and brain LNAA, and brain monoamine neurotransmitter metabolite levels in relation to behavioural and cognitive performance of HT1 mice.Design: C57BL/6 littermates were divided in three different experimental groups: HT1, heterozygous and wild-type mice (n = 10; 5 male). All groups were treated with NTBC and underwent cognitive and behavioural testing. One week after behavioural testing, blood and brain material were collected to measure amino acid profiles and brain monoaminergic neurotransmitter levels.Results: Irrespective of the genetic background, NTBC treatment resulted in a clear increase in brain tyrosine levels, whereas all other brain LNAA levels tended to be lower than their reference values. Despite these changes in blood and brain biochemistry, no significant differences in brain monoamine neurotransmitter (metabolites) were found and all mice showed normal behaviour and learning and memory.Conclusion: Despite the biochemical changes, NTBC and genotype of the mice were not associated with poorer behavioural and cognitive function of the mice. Further research involving dietary treatment of FAH−/− are warranted to investigate whether this reveals the cognitive impairments that have been seen in treated HT1 patients.
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- 2022
30. The mutation spectrum and ethnic distribution of non-hepatorenal tyrosinemia (types II, III)
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Zahra Beyzaei, Sara Nabavizadeh, Sara Karimzadeh, and Bita Geramizadeh
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Tyrosinemias ,Mutation ,Ethnicity ,Mutation, Missense ,Humans ,Pharmacology (medical) ,General Medicine ,Exons ,Genetics (clinical) - Abstract
Background Different types of non-hepatorenal tyrosinemia are among the rare forms of tyrosinemia. Tyrosinemia type II and III are autosomal recessive disorders caused by pathogenic variants in the tyrosine aminotransferase (TAT), and 4-hydroxyphenyl-pyruvate dioxygenas (HPPD) genes, respectively. There are still unclarified aspects in their clinical presentations, mutational spectrum, and genotype–phenotype correlation. Main body In this study, we evaluated the spectrum of TAT and HHPD gene mutations in patients with tyrosinemia type II and III. Moreover, biochemical and clinical findings are evaluated to establish a genotype–phenotype relationship in the above-mentioned patients. Thirty-three TAT variants have been reported in 42 families, consisting of 21 missense variants, 5 frameshift variants, 4 nonsense variants, 2 variants that primarily cause splicing site, and 1 skipping complete exon (large deletion). The most common variant is p.Arg57Ter, causing a splicing defect, and resulting in premature termination of translation, which was found in 10 patients from 3 families. In HPPD gene, eleven variants in 16 patients have been reported including 7 missense variants, 2 nonsense variants, 1 splice defect, and 1 frameshift variant so far. All variants are unique, except for p.Tyr160Cys, which is a missense variant found in two different patients. Regarding genotype–phenotype correlations, in 90% of tyrosinemia type II patients, positive clinical and biochemical correlations with a detected variant are observed. In HPPD gene, due to the small number of patients, it is not possible to make a definite conclusion. Conclusion This is the first large review of variants in TAT and HPPD, highlighting the wide spectrum of disease-causing mutations. Such information is beneficial for the establishment of a privileged mutation screening process in a specific region or ethnic group.
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- 2022
31. Identification and functional characterization of a novel homozygous intronic variant in the fumarylacetoacetate hydrolase gene in a Chinese patient with tyrosinemia type 1
- Author
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Jiao Chen, Junhui Sun, Xuefang Li, and Mengmeng Du
- Subjects
China ,DNA, Complementary ,Tyrosinemias ,Hydrolases ,Homozygote ,Genetics ,Humans ,Child ,Genetics (clinical) - Abstract
Background Hereditary tyrosinemia type 1 (HT1; OMIM# 276700) is a genetic metabolism disorder caused by disease-causing variants in the fumarylacetoacetate hydrolase (FAH) gene encoding the last enzyme of the tyrosine catabolic pathway. Herein, we describe the clinical features and genetic characteristics of HT1 in a five years and seven months old Chinese patient. Methods After clinical diagnosis of the proband with HT1, genetic testing was performed by Sanger sequencing of the FAH gene in all family members. Functional analysis of the disease-causing variant was performed by cDNA sequencing to understand the effect of the variant on FAH transcript. To further predict the variant effect, we used Human Splicing Finder (HSF) and PyMol in silico analysis. Results We identified a novel previously undescribed intronic variant in the FAH gene (c.914-1G>A). It was detected in a child who was homozygous for the variant and had the clinical presentation of HT1. cDNA sequencing showed that this splice-junction variant affected the transcription of FAH by formation of two different transcripts. Our observations and laboratory experiments were in line with in silico methods. Conclusions Our study provides new insight into the HT1 variant spectrum and a better understanding of this disease in the Chinese population. This will be useful for molecular diagnosis in our country in cases where premarital screening, prenatal diagnosis and preimplantation genetic diagnosis are planned.
- Published
- 2022
32. Richner-Hanhart Syndrome (Tyrosinemia Type II) A Case Report of Delay Diagnosis with Hyperkeratotic Lesions of Palmes and Soles
- Author
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Zahra Alian
- Subjects
keratoderma ,palmoplantar ,tyrosinemias ,Medicine - Abstract
Introduction: Richner-Hanhart syndrome (tyrosinemia type II) is a rare autosomal recessive disease associated with high serum tyrosine levels caused by the deficiency of tyrosine ami-notransferase enzyme. Case Report: We report a 7-year-old female patient with complaints of hyperkeratosis lesions of palms and soles which started 3 years ago. Chromatography of serum amino acids showed a tyrosine level of 120micromole/L (normal range: 22-87). She had normal ophthalmologic examination and mild mental retardation was detected. One month after the tyrosine- and phenylalanine-restricted diet, her tyrosine level dropped to 42 micromol/L level, her keratotic lesions subsided, and a symptomatic relief in learning was achieved. Conclusion: Tyrosinemia type II should be suspected in patients demonstrating dermatologic signs, especially palmoplantar keratosis, associated with bilateral pseudodendritic corneal lesions unresponsive to antiviral therapy and mild to moderate mental retardation, although our patient without ophthalmic lesions is a very rare case of this syndrome.
- Published
- 2014
33. Long-term safety and outcomes in hereditary tyrosinaemia type 1 with nitisinone treatment: a 15-year non-interventional, multicentre study
- Author
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María L. Couce, Mattias Rudebeck, Marco Spada, Erik Sparve, Allan M. Lund, Corinne De Laet, Carlo Dionisi-Vici, Ute Spiekerkoetter, Johan Szamosi, Anibh M. Das, Roshni Vara, and Manuel Schiff
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Time Factors ,Adolescent ,Nitisinone ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,MEDLINE ,030209 endocrinology & metabolism ,Disease ,Liver transplantation ,03 medical and health sciences ,Neonatal Screening ,0302 clinical medicine ,Endocrinology ,Internal Medicine ,medicine ,Humans ,Longitudinal Studies ,Prospective Studies ,030212 general & internal medicine ,Enzyme Inhibitors ,Child ,Adverse effect ,Prospective cohort study ,Cyclohexanones ,Tyrosinemias ,business.industry ,Infant, Newborn ,Infant ,Clinical trial ,Treatment Outcome ,Child, Preschool ,Nitrobenzoates ,Female ,Kidney Diseases ,Observational study ,Chemical and Drug Induced Liver Injury ,business ,Follow-Up Studies ,medicine.drug - Abstract
Since the EU approval of nitisinone in 2005, prognosis for patients with hereditary tyrosinaemia type 1 has changed dramatically, with patients living with the disease now reaching adulthood for the first time in history. This study aimed to assess the long-term safety and outcomes of nitisinone treatment in patients with hereditary tyrosinaemia type 1.We did a non-interventional, non-comparative, multicentre study in 77 sites across 17 countries in Europe and collected retrospective and prospective longitudinal data in patients with hereditary tyrosinaemia type 1 who were treated with oral nitisinone during the study period (Feb 21, 2005, to Sept 30, 2019). There were no specific exclusion criteria. Patients were followed-up with an investigator at least annually for as long as they were treated, or until the end of the study. The primary endpoints, occurrence of adverse events related to hepatic, renal, ophthalmic, haematological, or cognitive or developmental function, were assessed in the complete set (all patients already receiving treatment at the index date [Feb 21, 2005] or starting treatment thereafter) and the index set (the subset of patients who had their first dose on the index date or later only).315 patients were enrolled during the study period (complete set). Additionally, data from 24 patients who had liver transplantation or died during the post-marketing surveillance programme were retrieved (extended analysis set; 339 patients). Median treatment duration was 11·2 years (range 0·7-28·4); cumulative nitisinone exposure was 3172·7 patient-years. Patients who were diagnosed by neonatal screening started nitisinone treatment at median age 0·8 months versus 8·5 months in those who presented clinically. Incidences of hepatic, renal, ophthalmic, haematological, or cognitive or developmental adverse events were low. Occurrence of liver transplantation or death was more frequent the later that treatment was initiated (none of 70 patients who started treatment at age28 days vs 35 [13%] of 268 patients who started treatment at age ≥28 days). 279 (89%) of 315 patients were assessed as having either very good or good nitisinone treatment compliance. Treatment and diet compliance declined as patients aged. Suboptimal plasma phenylalanine and tyrosine levels were observed. The majority of patients were reported to have good overall clinical condition throughout treatment; 176 (87%) of 203 during the entire study, 98% following 1 year of treatment.Long-term nitisinone treatment was well tolerated and no new safety signals were revealed. Life-limiting hepatic disease appears to have been prevented by early treatment start. Neonatal screening was the most effective way of ensuring early treatment. Standardised monitoring of blood tyrosine, phenylalanine, and nitisinone levels has potential to guide individualised therapy.Swedish Orphan Biovitrum (Sobi).
- Published
- 2021
34. [Update on pathogenesis, diagnosis and treatment of hereditary tyrosinemia type Ⅰ]
- Author
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S J, Jin, C Q, Du, and X P, Luo
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Tyrosinemias ,Humans ,Tyrosine ,Amino Acid Metabolism, Inborn Errors - Abstract
遗传性酪氨酸血症Ⅰ型(HT-1)是一种罕见的常染色体隐性遗传病,因延胡索酰乙酰乙酸水解酶缺陷,引起体内酪氨酸分解代谢受阻,毒性代谢物蓄积,从而导致严重的肝、肾功能障碍及神经危象,且有较高的肝细胞癌风险。本病多见于2岁内婴儿,临床表现缺乏特异性,血琥珀酰丙酮检测有助于早期识别。尼替西农联合低酪氨酸饮食治疗可显著改善预后。对于肝功能严重衰竭且尼替西农治疗无效或疑有肝细胞癌患者,推荐肝移植。酶替代疗法及基因治疗仍处于临床研究阶段。.
- Published
- 2022
35. Clinical and biochemical footprints of inherited metabolic diseases. VIII. Neoplasias
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Teodoro Jerves, Nenad Blau, and Carlos R. Ferreira
- Subjects
Diagnosis, Differential ,Endocrinology ,Carcinoma, Hepatocellular ,Tyrosinemias ,Endocrinology, Diabetes and Metabolism ,Liver Neoplasms ,Genetics ,Humans ,Glycogen Storage Disease ,Molecular Biology ,Biochemistry ,Article - Abstract
Cancer, caused by multiple cumulative pathogenic variants in tumor suppressor genes and proto-oncogenes, is a leading cause of mortality worldwide. The uncontrolled and rapid cell growth of the tumors requires a reprogramming of the complex cellular metabolic network to favor anabolism. Adequate management and treatment of certain inherited metabolic diseases might prevent the development of certain neoplasias, such as hepatocellular carcinoma in tyrosinemia type 1 or hepatocellular adenomas in glycogen storage disorder type 1a. We reviewed and updated the list of known metabolic etiologies associated with various types of benign and malignant neoplasias, finding 64 relevant inborn errors of metabolism. This is the eighth article of the series attempting to create a comprehensive list of clinical and metabolic differential diagnosis by system involvement.
- Published
- 2022
36. Bilateral recurrent pseudodendritic keratopathy as the initial manifestation of tyrosinemia type II
- Author
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Bruno Avelar Miranda, Anna Christina Higino Rocha, Rodrigo Rezende Arantes, Viviane de Cássia Kanufre, Sabrina Cavaglieri Silva, and Daniel Vitor Vasconcelos-Santos
- Subjects
Cornea ,Ophthalmology ,Tyrosinemias ,Pediatrics, Perinatology and Child Health ,Humans ,Tyrosine ,Genetics (clinical) ,Corneal Diseases - Published
- 2022
37. Comprehensive Evaluation of the NeoBase 2 Non-derivatized MSMS Assay and Exploration of Analytes With Significantly Different Concentrations Between Term and Preterm Neonates
- Author
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Beomki Lee, Won Young Heo, Jee Ah Kim, Hyun-Seung Lee, Narae Hwang, Hyung-Doo Park, Se In Sung, Yun Sil Chang, Won Soon Park, and Soo-Youn Lee
- Subjects
Neonatal Screening ,Adenosine ,Tandem Mass Spectrometry ,Tyrosinemias ,Biochemistry (medical) ,Clinical Biochemistry ,Infant, Newborn ,Humans ,Lysophosphatidylcholines ,General Medicine - Abstract
Despite the popularity of the NeoBase 2 Non-derivatized MSMS assay (PerkinElmer, Turku, Finland), there are no reports of its comprehensive evaluation, including the ability to distinguish transient tyrosinemia of the newborn (TTN) from tyrosinemia type 1 (TYR 1) using succinylacetone (SUAC). No newborn screening (NBS) cutoffs for preterm neonates in the Korean population have been suggested. We evaluated the NeoBase 2 assay and identified analytes requiring different cutoffs in preterm neonates.Residual NBS dried blood spot samples and proficiency testing (PT) materials of the Newborn Screening Quality Assurance Program and the Korean Association of External Quality Assessment Service were used. Precision, accuracy, limit of detection (LOD), lower limit of quantification (LLOQ), linearity, recovery, carryover, and performance of SUAC were evaluated. Cutoffs were determined, and analytes requiring different cutoffs in preterm neonates were investigated.Mean CVs for within-run and between-day precision were within 15%. Accuracy analysis indicated high agreement with in-house derivatized assay results and results of other PT participants. All analytes demonstrated acceptable LOD, LLOQ, and linearity. Recoveries were acceptable, except for SUAC. Carryover was negligible. Cutoffs were established for all analytes; Tyr, adenosine, and C20:0-lysophosphatidylcholine required different cutoffs in preterm neonates. Differential diagnosis of TYR 1 and TTN was successful with simultaneous Tyr and SUAC measurement.The NeoBase 2 assay demonstrated satisfactory performance. The additional analytes provide a wider diagnostic coverage, and the simultaneous measurement of Tyr and SUAC is efficient in excluding TYR 1. The new cutoffs for preterm neonates may decrease false-positive rates, without compromising diagnostic sensitivity.
- Published
- 2022
38. Application of machine learning tools and integrated OMICS for screening and diagnosis of inborn errors of metabolism.
- Author
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Usha Rani G, Kadali S, Kurma Reddy B, Shaheena D, and Naushad SM
- Subjects
- Infant, Newborn, Humans, Neonatal Screening methods, Metabolomics, Machine Learning, Propionic Acidemia, Tyrosinemias
- Abstract
Introduction: Tandem mass spectrometry (TMS) has emerged an important screening tool for various metabolic disorders in newborns. However, there is inherent risk of false positive outcomes. Objective To establish analyte-specific cutoffs in TMS by integrating metabolomics and genomics data to avoid false positivity and false negativity and improve its clinical utility., Methods: TMS was performed on 572 healthy and 3000 referred newborns. Urine organic acid analysis identified 23 types of inborn errors in 99 referred newborns. Whole exome sequencing was performed in 30 positive cases. The impact of physiological changes such as age, gender, and birthweight on various analytes was explored in healthy newborns. Machine learning tools were used to integrate demographic data with metabolomics and genomics data to establish disease-specific cut-offs; identify primary and secondary markers; build classification and regression trees (CART) for better differential diagnosis; for pathway modeling., Results: This integration helped in differentiating B12 deficiency from methylmalonic acidemia (MMA) and propionic acidemia (Phi coefficient=0.93); differentiating transient tyrosinemia from tyrosinemia type 1 (Phi coefficient=1.00); getting clues about the possible molecular defect in MMA to initiate appropriate intervention (Phi coefficient=1.00); to link pathogenicity scores with metabolomics profile in tyrosinemia (r2=0.92). CART model helped in establishing differential diagnosis of urea cycle disorders (Phi coefficient=1.00)., Conclusion: Calibrated cut-offs of different analytes in TMS and machine learning-based establishment of disease-specific thresholds of these markers through integrated OMICS have helped in improved differential diagnosis with significant reduction of the false positivity and false negativity rates., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
- Full Text
- View/download PDF
39. Nitisinone: two decades treating hereditary tyrosinaemia type 1
- Author
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Wendy J. Introne
- Subjects
Pediatrics ,medicine.medical_specialty ,Nitisinone ,Cyclohexanones ,Tyrosinemias ,business.industry ,Endocrinology, Diabetes and Metabolism ,MEDLINE ,Endocrinology ,Nitrobenzoates ,Internal Medicine ,medicine ,Humans ,business ,medicine.drug - Published
- 2021
40. Clinical utilization of dried blood spot nitisinone (NTBC) and succinylacetone (SA) concentrations in hereditary tyrosinaemia type 1 – A UK centre experience
- Author
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Neil Dalton, Mildrid Yeo, Roshni Vara, Yusof Rahman, and Charles Turner
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Nitisinone ,Clinical Biochemistry ,030105 genetics & heredity ,Gastroenterology ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Child ,Retrospective Studies ,Cyclohexanones ,Tyrosinemias ,business.industry ,Infant, Newborn ,Infant ,General Medicine ,United Kingdom ,Heptanoates ,Dried blood spot ,030104 developmental biology ,Succinylacetone ,Child, Preschool ,Nitrobenzoates ,Female ,Dried Blood Spot Testing ,business ,medicine.drug - Abstract
Background Dried blood spot monitoring of nitisinone and succinylacetone in hereditary tyrosinaemia type 1 patients is not widely available in the United Kingdom. Currently, biochemical monitoring utilizes urinary succinylacetone, blood spot tyrosine and phenylalanine monitoring, which can lack in convenience and accuracy, respectively. Methods We report the development of a dried blood spot assay for nitisinone and succinylacetone and analysed retrospective clinical and biochemical data for hereditary tyrosinaemia type 1 patients from a single UK centre. Results A total of 13 hereditary tyrosinaemia type 1 patients were evaluated. Eleven presented with liver dysfunction (two with associated renal tubulopathy) and two were detected by early sibling screening. All patients (age 0.03–22 months) were commenced on a tyrosine-/phenylalanine-restricted diet and nitisinone at diagnosis. Ten patients were on twice daily dosing and three were on single daily dosing at the start of monitoring. One patient from each dosing group swapped between dosing regimens at 20 years of age and 8 months of age, respectively. A total of 684 dried blood spot samples were analysed; 80% of nitisinone concentrations were between 9.2 and 27 µmol/L when succinylacetone was Conclusions Dried blood spot monitoring for nitisinone and succinylacetone concentrations in hereditary tyrosinaemia type 1 patients is a rapid and convenient method which allows physicians to individualize treatment plans and observe adherence to treatment.
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- 2020
41. Laboratory monitoring of patients with hereditary tyrosinemia type I
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Rani H. Singh, Matthew J. Schultz, Gisele Pino, Piero Rinaldo, Brian C. Netzel, Kimiyo Raymond, Silvia Tortorelli, Devin Oglesbee, Dietrich Matern, Wendy E. Smith, and Dimitar Gavrilov
- Subjects
Adult ,Male ,0301 basic medicine ,Analyte ,Adolescent ,Nitisinone ,Endocrinology, Diabetes and Metabolism ,030105 genetics & heredity ,Biochemistry ,Specimen Handling ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Liquid chromatography–mass spectrometry ,Genetics ,medicine ,Humans ,Amino Acids ,Child ,Molecular Biology ,Aged ,Aged, 80 and over ,Newborn screening ,Chromatography ,Cyclohexanones ,Tyrosinemias ,business.industry ,Selected reaction monitoring ,Infant, Newborn ,Infant ,Middle Aged ,Reference Standards ,Prognosis ,Heptanoates ,Hereditary tyrosinemia ,Specimen collection ,Succinylacetone ,Case-Control Studies ,Child, Preschool ,Nitrobenzoates ,Female ,Laboratories ,business ,Biomarkers ,030217 neurology & neurosurgery ,Follow-Up Studies ,medicine.drug - Abstract
Background The prognosis of patients with Hereditary Tyrosinemia Type 1 (HT-1) has greatly improved with early detection through newborn screening and the introduction of nitisinone (NTBC) therapy. A recent guideline calls for periodic monitoring of biochemical markers and NTBC levels to tailor treatment; however, this is currently only achieved through a combination of clinical laboratory tests. We developed a multiplexed assay measuring relevant amino acids, succinylacetone (SUAC), and NTBC in dried blood spots (DBS) to facilitate treatment monitoring. Methods Tyrosine, phenylalanine, methionine, NTBC and SUAC were eluted from DBS with methanol containing internal standards for each analyte and analyzed by liquid chromatography tandem mass spectrometry over 6.5 min in the multiple reaction monitoring positive mode. Results Pre-analytical and analytical factors were studied and demonstrated a reliable assay. Chromatography resolved an unknown substance that falsely elevates SUAC concentrations and was present in all samples. To establish control and disease ranges, the method was applied to DBS collected from controls (n = 284) and affected patients before (n = 2) and after initiation of treatment (n = 29). In the treated patients SUAC concentrations were within the normal range over a wide range of NTBC levels. Conclusions This assay enables combined, accurate measurement of revelevant metabolites and NTBC in order to simplify treatment monitoring of patients with HT-1. In addition, the use of DBS allows for specimen collection at home to facilitate more standardization in relation to drug and dietary treatment.
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- 2020
42. Amelioration of an Inherited Metabolic Liver Disease through Creation of a De Novo Start Codon by Cytidine Base Editing
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Shuming Yin, Yaqiang Hu, Meizhen Liu, Xueyun Ma, Honghui Han, Haibo Li, Dali Li, Liren Wang, Yanan Huo, Jun Wang, Mingyao Liu, Lei Yang, Hongquan Geng, Rui Zheng, Zhang Xiaohui, Chen Xi, and Weishi Yu
- Subjects
Hydrolases ,Genetic enhancement ,Genetic Vectors ,Codon, Initiator ,Cytidine ,Biology ,medicine.disease_cause ,Inteins ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Start codon ,Drug Discovery ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Gene ,030304 developmental biology ,Gene Editing ,Pharmacology ,0303 health sciences ,Mutation ,Tyrosinemias ,Translation (biology) ,Genetic Therapy ,Dependovirus ,Disease Models, Animal ,HEK293 Cells ,chemistry ,030220 oncology & carcinogenesis ,Feasibility Studies ,Molecular Medicine ,Fumarylacetoacetate hydrolase ,Original Article ,Cytosine - Abstract
Base editing technology efficiently generates nucleotide conversions without inducing excessive double-strand breaks (DSBs), which makes it a promising approach for genetic disease therapy. In this study, we generated a novel hereditary tyrosinemia type 1 (HT1) mouse model, which contains a start codon mutation in the fumarylacetoacetate hydrolase (Fah) gene by using an adenine base editor (ABE7.10). To investigate the feasibility of base editing for recombinant adeno-associated virus (rAAV)-mediated gene therapy, an intein-split cytosine base editor (BE4max) was developed. BE4max efficiently induced C-to-T conversion and restored the start codon to ameliorate HT1 in mice, but an undesired bystander mutation abolished the effect of on-target editing. To solve this problem, an upstream sequence was targeted to generate a de novo in-frame start codon to initiate the translation of FAH. After treatment, almost all C-to-T conversions created a start codon and restored Fah expression, which efficiently ameliorated the disease without inducing off-target mutations. Our study demonstrated that base editing-mediated creation of de novo functional elements would be an applicable new strategy for genetic disease therapy.
- Published
- 2020
43. Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria
- Author
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Juliette H. Hughes, James A. Gallagher, Jonathan C. Jarvis, S Judd, Anna M. Milan, Andrew T. Hughes, Peter Wilson, George Bou-Gharios, Lakshminarayan R. Ranganath, and Hazel Sutherland
- Subjects
Male ,medicine.medical_specialty ,Nitisinone ,phenylalanine ,Phenylalanine ,nitisinone ,Alkaptonuria ,Tyrosinemia ,Mice ,QH301 ,03 medical and health sciences ,chemistry.chemical_compound ,RA0421 ,Internal medicine ,Diet, Protein-Restricted ,Genetics ,Animals ,Humans ,Medicine ,Homogentisic acid ,Tyrosine ,QH426 ,Genetics (clinical) ,030304 developmental biology ,Homogentisate 1,2-dioxygenase ,chemistry.chemical_classification ,alkaptonuria ,0303 health sciences ,Cyclohexanones ,Tyrosinemias ,business.industry ,030305 genetics & heredity ,Original Articles ,medicine.disease ,tyrosinemia ,QP ,Amino acid ,Endocrinology ,chemistry ,Nitrobenzoates ,Female ,Original Article ,protein ,business ,medicine.drug - Abstract
BACKGROUND: Alkaptonuria (AKU) is caused by homogentisate 1,2-dioxygenase deficiency that leads to homogentisic acid (HGA) accumulation, ochronosis and severe osteoarthropathy. Recently, nitisinone treatment, which blocks HGA formation, has been effective in AKU patients. However, a consequence of nitisinone is elevated tyrosine that can cause keratopathy. The effect of tyrosine and phenylalanine dietary restriction was investigated in nitisinone-treated AKU mice, and in an observational study of dietary intervention in AKU patients. METHODS: Nitisinone-treated AKU mice were fed tyrosine/phenylalanine-free and phenylalanine-free diets with phenylalanine supplementation in drinking water. Tyrosine metabolites were measured pre-nitisinone, post-nitisinone, and after dietary restriction. Subsequently an observational study was undertaken in 10 patients attending the National Alkaptonuria Centre (NAC), with tyrosine >700μmol/L who had been advised to restrict dietary protein intake and where necessary, to use tyrosine/phenylalanine-free amino acid supplements. RESULTS: Elevated tyrosine (813μmol/L) was significantly reduced in nitisinone-treated AKU mice fed a tyrosine/phenylalanine-free diet in a dose responsive manner. At 3 days of restriction, tyrosine was 389.3μmol/L, 274.8μmol/L and 144.3μmol/L with decreasing phenylalanine doses. In contrast, tyrosine was not effectively reduced in mice by a phenylalanine-free diet; at 3 days tyrosine was 757.3μmol/L, 530.2μmol/L and 656.2μmol/L, with no dose response to phenylalanine supplementation. In NAC patients, tyrosine was significantly reduced (p=0.002) when restricting dietary protein alone, and when combined with tyrosine/phenylalanine-free amino acid supplementation; 4 out of 10 patients achieved tyrosine
- Published
- 2020
44. Liver Transplantation for Tyrosinemia Type 1 in the Developing World: Is It Really the Best We Can Offer?
- Author
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Rishi Bolia and Anshu Srivastava
- Subjects
Tyrosinemias ,Pediatrics, Perinatology and Child Health ,Humans ,Amino Acid Metabolism, Inborn Errors ,Liver Transplantation - Published
- 2022
45. Neurocognitive outcome and mental health in children with tyrosinemia type 1 and phenylketonuria: A comparison between two genetic disorders affecting the same metabolic pathway
- Author
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Kimber van Vliet, Willem G. van Ginkel, Rianne Jahja, Anne Daly, Anita MacDonald, Saikat Santra, Corinne De Laet, Philippe J. Goyens, Roshni Vara, Yusof Rahman, David Cassiman, Francois Eyskens, Corrie Timmer, Nicky Mumford, Paul Gissen, Jörgen Bierau, Peter M. van Hasselt, Gisela Wilcox, Andrew A. M. Morris, Elisabeth A. Jameson, Alicia de la Parra, Carolina Arias, Maria I. Garcia, Veronica Cornejo, Annet M. Bosch, Carla E. M. Hollak, M. Estela Rubio‐Gozalbo, Martijn C. G. J. Brouwers, Floris C. Hofstede, Maaike C. de Vries, Mirian C. H. Janssen, Ans T. van der Ploeg, Janneke G. Langendonk, Stephan C. J. Huijbregts, Francjan J. van Spronsen, Pediatrics, Internal Medicine, Endocrinology, Paediatric Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Reproduction & Development (AR&D), Center for Liver, Digestive and Metabolic Diseases (CLDM), MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Kindergeneeskunde, MUMC+: MA Medische Staf Kindergeneeskunde (9), Interne Geneeskunde, MUMC+: MA Endocrinologie (9), and RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,NTBC TREATMENT ,phenylketonuria ,INHIBITION ,social cognition ,Neuropsychological Tests ,neurocognitive outcome ,PROFILE ,Amsterdam Neuropsychological Tasks ,TREATED PHENYLKETONURIA ,SDG 3 - Good Health and Well-being ,Phenylketonurias ,Genetics ,Tyrosinemia type 1 ,MANAGEMENT ,Phenylketonuria ,Humans ,Child ,Genetics (clinical) ,Tyrosinemias ,PHENYLALANINE ,nutritional and metabolic diseases ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,executive functions ,Mental Health ,NITISINONE ,Human medicine ,ADULT PHENYLKETONURIA ,tyrosinemia type 1 ,Metabolic Networks and Pathways - Abstract
Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p values
- Published
- 2022
46. Self-inactivating, all-in-one AAV vectors for precision Cas9 genome editing via homology-directed repair in vivo
- Author
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Nida Javeed, Yueying Cao, Esther Mintzer, Samantha J. Nelson, Zexiang Chen, Athma A. Pai, Phillip W. L. Tai, Suk Namkung, Scot A. Wolfe, Aamir Mir, Erik J. Sontheimer, Stacy Maitland, Eraj Khokhar, Dan Wang, Jiaming Wang, Raed Ibraheim, Guangping Gao, Wen Xue, Tomás Rodríguez, and Emmanouela Tsagkaraki
- Subjects
CRISPR-Cas9 genome editing ,Male ,Computer science ,Science ,Genetic Vectors ,General Physics and Astronomy ,Computational biology ,Genome ,Article ,General Biochemistry, Genetics and Molecular Biology ,Homology directed repair ,Mice ,Mucopolysaccharidosis type I ,Genome editing ,CRISPR-Associated Protein 9 ,Animals ,Humans ,Vector (molecular biology) ,Mucopolysaccharidosis II ,Subgenomic mRNA ,Gene Editing ,Multidisciplinary ,Tyrosinemias ,Cas9 ,Targeted Gene Repair ,Recombinational DNA Repair ,Genetic Therapy ,General Chemistry ,Dependovirus ,Targeted gene repair ,Female - Abstract
Adeno-associated virus (AAV) vectors are important delivery platforms for therapeutic genome editing but are severely constrained by cargo limits. Simultaneous delivery of multiple vectors can limit dose and efficacy and increase safety risks. Here, we describe single-vector, ~4.8-kb AAV platforms that express Nme2Cas9 and either two sgRNAs for segmental deletions, or a single sgRNA with a homology-directed repair (HDR) template. We also use anti-CRISPR proteins to enable production of vectors that self-inactivate via Nme2Cas9 cleavage. We further introduce a nanopore-based sequencing platform that is designed to profile rAAV genomes and serves as a quality control measure for vector homogeneity. We demonstrate that these platforms can effectively treat two disease models [type I hereditary tyrosinemia (HT-I) and mucopolysaccharidosis type I (MPS-I)] in mice by HDR-based correction of the disease allele. These results will enable the engineering of single-vector AAVs that can achieve diverse therapeutic genome editing outcomes., Long-term expression of Cas9 following precision genome editing in vivo may lead to undesirable consequences. Here we show that a single-vector, self-inactivating AAV system containing Cas9 nuclease, guide, and DNA donor can use homology-directed repair to correct disease mutations in vivo.
- Published
- 2021
47. Physical Growth of Patients with Hereditary Tyrosinaemia Type I: A Single-Centre Retrospective Study
- Author
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Catherine Ashmore, Ozlem Yilmaz, Nurcan Yabanci Ayhan, Richard J. Jackson, Girish Gupte, Alex Pinto, Sharon Evans, Anne Daly, and Anita MacDonald
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,phenylalanine ,growth ,Age at diagnosis ,Comorbidity ,Overweight ,Article ,Body Mass Index ,tyrosinaemia ,Young Adult ,physical outcomes ,BMI ,Child Development ,medicine ,Humans ,TX341-641 ,Longitudinal Studies ,Child ,Retrospective Studies ,Retrospective review ,Nutrition and Dietetics ,business.industry ,Tyrosinemias ,Nutrition. Foods and food supply ,Body Weight ,Retrospective cohort study ,weight ,medicine.disease ,Obesity ,Early life ,Body Height ,United Kingdom ,Single centre ,Child, Preschool ,Hereditary tyrosinaemia type I ,Female ,medicine.symptom ,business ,diet ,tyrosine ,Food Science ,height - Abstract
In a retrospective review, we aimed to assess long-term growth in 17 patients (n = 11 males) with hereditary tyrosinaemia type I (HTI). Median age at assessment was 15.6 years (5.7–26.6 years) and median age at diagnosis was 1 month (range: 0–16 months), with 35% (n = 6/17) symptomatic on presentation. From the age of 8 years, there was a noticeable change in median height, weight, and body-mass-index [BMI]-z-scores. Median height-for-age z-scores were consistently ≤ −1 (IQR −1.6, −0.5) during the first 8 years of life but increased with age. Weight-for-age z-scores ranged between −1 to 0 (IQR −1.2, 0.1) in the first 8 years, then increased to >, 0.5 (IQR −0.3, 1.3) by age 16 years, and BMI-for-age z-scores ranged from 0 to 1 (IQR −0.7, 1.3) up to 8 years, and >, 1 (IQR −0.2, 1.9) until 16 years. The percentage of overweight and obesity was lowest in children aged <, 5 years, and consistently >, 40% in patients aged between 7 to 16 years. The prescribed total protein intake was associated with improved height growth (p <, 0.01). Impaired growth in early life improved with age achieving normal population standards. Further studies are needed to investigate factors that influence growth outcome in HTI patients.
- Published
- 2021
48. Nutritional interventions for patients with alkaptonuria: A minireview.
- Author
-
Imrich R, Zatkova A, Lukacova O, Sedlakova J, Zanova E, Vlcek M, Penesova A, Radikova Z, Havranova A, and Ranganath L
- Subjects
- Humans, Tyrosine therapeutic use, Homogentisic Acid metabolism, Alkaptonuria drug therapy, Alkaptonuria metabolism, Ochronosis drug therapy, Tyrosinemias
- Abstract
Alkaptonuria (AKU, OMIM, No. 203500) is a rare, slow-progressing, irreversible, multisystemic disease resulting from a deficiency of the homogentisate 1,2-dioxygenase enzyme, which leads to the accumulation of homogentisic acid (HGA) and subsequent deposition as pigment in connective tissues called ochronosis. As a result, severe arthropathy of large joints and spondyloarthropathy with frequent fractures, ligament ruptures, and osteoporosis develops in AKU patients. Since 2020, the first-time treatment with nitisinone has become available in the European Union. Nitisinone significantly reduces HGA production and arrests ochronosis in AKU patients. However, blocking of the tyrosine metabolic pathway by the drug leads to tyrosine plasma and tissue concentrations increase. The nitisinone-induced hypertyrosinemia can lead to the development of corneal keratopathy, and once it develops, the treatment needs to be interrupted. A decrease in overall protein intake reduces the risk of the keratopathy during nitisinone-induced hypertyrosinemia in AKU patients. The low-protein diet is not only poorly tolerated by patients, but over longer periods, leads to a severe muscle loss and weight gain due to increased energy intake from carbohydrates and fats. Therefore, the development of novel nutritional approaches is required to prevent the adverse events due to nitisinone-induced hypertyrosinemia and the negative impact on skeletal muscle metabolism in AKU patients., (© 2023 Richard Imrich et al., published by Sciendo.)
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- 2023
- Full Text
- View/download PDF
49. Simultaneous newborn screening for sickle cell disease, biotinidase deficiency, and hereditary tyrosinemia type 1 with an optimized tandem mass spectrometry protocol
- Author
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Stephan Lobitz, Claudia Frömmel, Annemarie Brose, Oliver Blankenstein, Charles Turner, R. Neil Dalton, Yvonne Daniel, and Jeannette Klein
- Subjects
Biotinidase Deficiency ,Neonatal Screening ,Tandem Mass Spectrometry ,Tyrosinemias ,Infant, Newborn ,Humans ,Anemia, Sickle Cell ,Hematology ,General Medicine - Published
- 2022
50. A split prime editor with untethered reverse transcriptase and circular RNA template
- Author
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Bin Liu, Xiaolong Dong, Haoyang Cheng, Chunwei Zheng, Zexiang Chen, Tomás C. Rodríguez, Shun-Qing Liang, Wen Xue, and Erik J. Sontheimer
- Subjects
Gene Editing ,Tyrosinemias ,Biomedical Engineering ,Bioengineering ,RNA-Directed DNA Polymerase ,RNA, Circular ,Applied Microbiology and Biotechnology ,Mice ,Molecular Medicine ,Animals ,Deoxyribonuclease I ,CRISPR-Cas Systems ,Biotechnology ,RNA, Guide, Kinetoplastida - Abstract
Delivery and optimization of prime editors (PEs) have been hampered by their large size and complexity. Although split versions of genome-editing tools can reduce construct size, they require special engineering to tether the binding and catalytic domains. Here we report a split PE (sPE) in which the Cas9 nickase (nCas9) remains untethered from the reverse transcriptase (RT). The sPE showed similar efficiencies in installing precise edits as the parental unsplit PE3 and no increase in insertion-deletion (indel) byproducts. Delivery of sPE to the mouse liver with hydrodynamic injection to modify β-catenin drove tumor formation with similar efficiency as PE3. Delivery with two adeno-associated virus (AAV) vectors corrected the disease-causing mutation in a mouse model of type I tyrosinemia. Similarly, prime editing guide RNAs (pegRNAs) can be split into a single guide RNA (sgRNA) and a circular RNA RT template to increase flexibility and stability. Compared to previous sPEs, ours lacks inteins, protein-protein affinity modules and nuclease-sensitive pegRNA extensions, which increase construct complexity and might reduce efficiency. Our modular system will facilitate the delivery and optimization of PEs.
- Published
- 2021
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