Current management options for tyrosinemia

El‐Shabrawi, Mortada; Kamal, Naglaa M.

doi:10.2147/odrr.s31501

Cited by 5 publications

(5 citation statements)

References 72 publications

(72 reference statements)

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“…It is inherited as an autosomal recessive disorder caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH) (Kawabata, Kido, Yoshida, Matsumoto, & Nakamura, 2022;Morrow & Tanguay, 2017). The acute form of the disease is characterised by an early onset with severe multiorgan involvement affecting the liver and kidney functions, and the central nervous system due to the toxic accumulation of tyrosine metabolites, such as the succinyl acetone (El-Shabrawi & Kamal, 2013). Hence, elevated succinyl acetone, in DBS samples, or in plasma or urine, is the most reliable neonatal screening method and pathognomonic for inherited Tyrosinemia type 1.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, elevated succinyl acetone, in DBS samples, or in plasma or urine, is the most reliable neonatal screening method and pathognomonic for inherited Tyrosinemia type 1. Apart from liver transplants, drugs blocking the pathway upstream of FAH, such as the NTBC/Nitisone has been effectively used together with a diet low in tyrosine and phenylalanine in its management (El-Shabrawi & Kamal, 2013;Morrow & Tanguay, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Acquired hypertyrosinemia is notably more common than inherited types (Adnan & Puranik, 2022) and typically presents with a profile suggestive of secondary aetiology on biochemical testing. Acquired hypertyrosinemia may occur in several health conditions such as severe liver failure or hepatocellular dysfunction, nutritional deficiency such as vitamin B6, folate or vitamin C deficiency, medications that interfere with tyrosine metabolism, renal dysfunction leading to accumulation of tyrosine, hyperthyroidism and others (El-Shabrawi & Kamal, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Diagnostic pitfalls in neonatal hypertyrosinemia: a case report

Khalid,

Kamarudzaman,

Ahmad Ridzuan

et al. 2023

LSMB

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Hypertyrosinemia results from abnormality in tyrosine metabolism. Acquired hypertyrosinemia is notably more common than inherited types and typically presents with profile suggestive of secondary aetiology on biochemical testing. Herein, we present an unusual case of a day 16-of-life baby girl who was screened for inborn errors of metabolism (IEM). She presented with jaundice, hypotonia, lethargy and had hepatomegaly on examination. She was treated for sepsis with multiorgan involvement, requiring escalation of intravenous antibiotics and assisted ventilation. Her dried blood spot (DBS) showed moderate elevation of tyrosine (408umol/L, N:10-182) with low Phe:Tyr ratio (0.15mmol/L, N:0.32-3.45). Plasma amino acid showed isolated hypertyrosinemia at 807mmol/L (N:5-167) with mild, non-significant elevations of other liver metabolites. No succinylacetone peak seen with urine organic acids, making the diagnosis of inherited Tyrosinemia type I less likely despite the characteristic findings from DBS, plasma amino acids, and presenting clinical signs. Repeated IEM screening two weeks later revealed a non-diagnostic profile across both DBS and plasma amino acids in light of resolving sepsis and clinical improvement. This case highlights the challenges associated with incompatible biochemical testing in a child with a high index of suspicion for inherited Tyrosinemia. In our case, repeated screening ruled out inherited Tyrosinemia, suggesting the initial picture of hypertyrosinemia to be likely due to liver dysfunction and impaired activity of liver enzymes that are responsible for tyrosine catabolism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Diagnostic pitfalls in neonatal hypertyrosinemia: a case report

Khalid,

Kamarudzaman,

Ahmad Ridzuan

et al. 2023

LSMB

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“…In our study, the prescribed NP intake increased from a median of 5 g/day in children aged <12 months to 24 g/day by the age of 16 years. Over time NP tolerance varied both between and within the same individuals, and it was likely influenced by growth, adequacy of energy intake, protein substitute adherence and health status, particularly in those patients needing liver transplantation [8,22]. The continual re-appraisal of NP tolerance is essential in HTI patients.…”

Section: Discussionmentioning

confidence: 99%

Natural Protein Tolerance and Metabolic Control in Patients with Hereditary Tyrosinaemia Type 1

et al. 2020

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In a longitudinal retrospective study, we aimed to assess natural protein (NP) tolerance and metabolic control in a cohort of 20 Hereditary Tyrosinaemia type I (HTI) patients. Their median age was 12 years ([3.2–17.7 years], n = 11 female, n = 8 Caucasian, n = 8 Asian origin, n = 2 Arabic and n = 2 Indian). All were on nitisinone (NTBC) with a median dose of 0.7 g/kg/day (range 0.4–1.5 g/kg/day) and were prescribed a tyrosine (Tyr)/phenylalanine (Phe)-restricted diet supplemented with Tyr/Phe-free L-amino acids. Data were collected on clinical signs at presentation, medical history, annual dietary prescriptions, and blood Phe and Tyr levels from diagnosis until transition to the adult service (aged 16–18 years) or liver transplantation (if it preceded transition). The median age of diagnosis was 2 months (range: 0 to 24 months), with n = 1 diagnosed by newborn screening, n = 3 following phenylketonuria (PKU) screening and n = 7 by sibling screening. Five patients were transplanted (median age 6.3 years), and one died due to liver cancer. The median follow-up was 10 years (3–16 years), and daily prescribed NP intake increased from a median of 5 to 24 g/day. Lifetime median blood Tyr (370 µmol/L, range 280–420 µmol/L) and Phe (50 µmol/L, 45–70 µmol/L) were maintained within the target recommended ranges. This cohort of HTI patients were able to increase the daily NP intake with age while maintaining good metabolic control. Extra NP may improve lifelong adherence to the diet.

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“…4‐Hydroxyphenylpyruvate dioxygenase (HPPD; http://www.chem.qmul.ac.uk/iubmb/enzyme/EC1/13/11/27.html), an Fe(II)‐dependent nonheme oxygenase, as a target, has shown great potential in drug discovery and crop protection due to its critical role in transforming 4‐hydroxyphenylpyruvate acid (HPPA) to homogentisate acid (HGA) in tyrosine metabolic pathway . In humans, abnormal tyrosine metabolism leads to diseases, including type I, type II, and type III tyrosinemia, hawkinsinuria, and alkaptonuria . In plants, HGA is an important aromatic precursor for the biosynthesis of plastoquinone and tocopherol, two essential cofactors for plant growth.…”

Section: Introductionmentioning

confidence: 99%

Molecular insights into the mechanism of 4‐hydroxyphenylpyruvate dioxygenase inhibition: enzyme kinetics, X‐ray crystallography and computational simulations

et al. 2019

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Slow‐binding inhibitors with long residence time on the target often display superior efficacy in vivo. Rationally designing inhibitors with low off‐target rates is restricted by a limited understanding of the structural basis of slow‐binding inhibition kinetics in enzyme–drug interactions. 4‐Hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for drug and herbicide development. Although the time‐dependent behavior of HPPD inhibitors has been studied for decades, its structural basis and mechanism remain unclear. Herein, we report a detailed experimental and computational study that explores structures for illustrating the slow‐binding inhibition kinetics of HPPD. We observed the conformational change of Phe428 at the C‐terminal α‐helix in the inhibitor‐bound structures and further identified that the inhibition kinetics of drugs are related to steric hindrance of Phe428. These detailed structural and mechanistic insights illustrate that steric hindrance is highly associated with the time‐dependent behavior of HPPD inhibitors. These findings may enable rational design of new potent HPPD‐targeted drugs or herbicides with longer target residence time and improved properties. Database Structure data are available in the PDB under the accession numbers (released), (released), and (released).

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Current management options for tyrosinemia

Cited by 5 publications

References 72 publications

Diagnostic pitfalls in neonatal hypertyrosinemia: a case report

Diagnostic pitfalls in neonatal hypertyrosinemia: a case report

Natural Protein Tolerance and Metabolic Control in Patients with Hereditary Tyrosinaemia Type 1

Molecular insights into the mechanism of 4‐hydroxyphenylpyruvate dioxygenase inhibition: enzyme kinetics, X‐ray crystallography and computational simulations

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