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Tyrosinemia
Published in Charles Theisler, Adjuvant Medical Care, 2023
Tyrosinemia is a genetic disorder that affects infants. The disorder is characterized by disruptions in the multistep process that breaks down the amino acid tyrosine. If untreated, tyrosine and its byproducts build up in tissues and organs, which can lead to serious health problems. There are three types of tyrosinemia, each distinguished by their symptoms and genetic cause. The presentation includes herpetiform corneal ulcers and hyperkeratotic (skin thickening) lesions of the digits, palms, and soles, as well as intellectual disability. About 10% of newborns have temporarily elevated levels of tyrosine (transient tyrosinemia). In these cases, the cause is not genetic. The most likely causes are vitamin C deficiency or immature liver enzymes due to premature birth.1
Oculocutaneous tyrosinemia/tyrosine aminotransferase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The treatment of oculocutaneous tyrosinemia consists of the institution of a diet low in tyrosine and phenylalanine. This effectively lowers concentrations of tyrosine in body fluids. Clinical symptomatology promptly resolves. Preparations (Tyrex (Ross) and Xphe XtyrAnalog, Maxamaid (SHS)) are available which are low in tyrosine and phenylalanine and simplify the preparation of formulas for the feeding of infants with tyrosinemia. Attention to compliance is important because treatment can prevent permanent ocular damage. The fact that symptoms of the disorder may be quite uncomfortable assists in the compliance of older patients. Whether early therapy prevents impaired mental development is not clear, but early dietary management is prudent. There is excellent correlation between the concentration of tyrosine in the plasma and the intake of the amino acid and its precursor (Figure 21.9). Reasonable levels of control and an absence of symptoms are readily achieved using acceptable diets in childhood, as well as in infancy.
Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Tyrosyluria and tyrosinemia are diseases of abnormal tyrosine metabolism. In tyrosyluria or tyrosinosis elevated amounts of tyrosine and its derivatives, particularly p-hydroxyphenylpyruvic acid, are excreted. If the diet contains large amounts of tyrosine, other tyrosyl metabolites, p-hydroxyphenyllactic and p-hydroxyphenylacetic acid, also occur in the urine. Tyrosyluria is characterized by cirrhosis of the liver, and the patient is dying from liver failure during the first week of life, but some cases have survived for months or years. In these cases, multiple renal tubular defects develop. The renal changes may affect to a greater or lesser extent the reabsorption of water, potassium, and bicarbonate ions, uric acid, glucose, amino acids, phosphate, and even protein. Other tubular functions are inconsistent and show variations.
The future of gene-targeted therapy for hereditary tyrosinemia type 1 as a lead indication among the inborn errors of metabolism
Published in Expert Opinion on Orphan Drugs, 2020
Whitney S. Thompson, Gourish Mondal, Caitlin J. Vanlith, Robert A. Kaiser, Joseph B. Lillegard
The need for gene therapy for IEMs is undeniable, but these indications are actually quite ideally suited to gene therapy development. Vector-born addition of a single functional transgene or successful correction of a single mutant allele (often in the context of compound heterozygosity) in the target hepatocyte is sufficient to cure most of these recessive diseases. Therefore, the goal can be simplified to be the safe and specific delivery of functional correction in a sufficient number of target cells to impact the phenotype. Of these four keys to the success of gene therapy, hereditary tyrosinemia eliminates one of these major obstacles by conferring a selective growth advantage to corrected cells, lowering the initial transduction threshold for phenotypic relevance. While it is estimated that curing PKU would require a minimum of 10% of hepatocytes to begin to produce PAH [75], initial transduction targets in HT1 could be substantially less while ultimately generating complete correction of the liver. Residual unconverted pockets of cells (if any) would ultimately be eliminated by the toxicity of aberrant metabolism while lacking the overall fibrotic environment needed to develop HCC in human patients.
Genetic Analysis of Tyrosinemia Type 1 and Fructose-1, 6 Bisphosphatase Deficiency Affected in Pakistani Cohorts
Published in Fetal and Pediatric Pathology, 2020
Muhammad Yasir Zahoor, Huma Arshad Cheema, Sadaqat Ijaz, Zafar Fayyaz
Hereditary tyrosinemia type 1 (HT1) is caused by deficiency or absence of the fumaryl acetoacetate hydrolase (FAH) enzyme, the last of the five enzymes responsible for tyrosine metabolism. FAH hydrolyzes fumaryl acetoacetate into fumarate and acetoacetate, which enters the Krebs cycle. FAH deficiency results in accumulation of fumarylacetoacetate, causing hepatorenal toxicity and subsequent dysfunction. The FAH encoding gene (FAH) has 14 coding exons and produces a protein of 419 amino acids [3–6]. To date, about 100 mutations causing HT1 have been reported in the FAH gene. Sixty-two of these are missense mutations, 24 are splicing defects, ten are small deletions, two are gross deletions and two are small indels (HT1; HGMD ® Professional 2017.2).
Bilateral recurrent pseudodendritic keratopathy as the initial manifestation of tyrosinemia type II
Published in Ophthalmic Genetics, 2022
Bruno Avelar Miranda, Anna Christina Higino Rocha, Rodrigo Rezende Arantes, Viviane de Cássia Kanufre, Sabrina Cavaglieri Silva, Daniel Vitor Vasconcelos-Santos
The variant c.707–2 A > G found in our patient has not been previously described in the literature. Taken together, the involved molecular mechanism, which possibly leads to changes in mRNA processing, the location of gene mutation, and the correlation of this gene with clinical symptoms, suggest that this variant is likely pathogenic hepatic cytosolic Tyrosine (TAT) (8) are responsible for Tyrosinemia type II.