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Hepatorenal tyrosinemia/fumarylacetoacetate hydrolase 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
Hepatorenal tyrosinemia, which has been referred to as tyrosinemia type 1, tyrosinosis, or hereditary tyrosinemia, was first reported by Sakai and Kitagawa in 1957 [1–3]. The patient reported was the product of a consanguineous mating, who developed progressive liver disease, which led to death following hematemesis and hepatic coma at three years of age. In addition, the patient had rickets, which was resistant to vitamin D. The major metabolic products in the urine were p-hydroxyphenyllactic acid, p-hydroxyphenylpyruvic acid, and p-hydroxyphenylacetic acid, as well as tyrosine. Gentz and colleagues [4], in a report of seven patients with the disease, first characterized the renal component as Fanconi syndrome. It was noted that patients had neurologic crises reminiscent of porphyria [5, 6], and this led to the recognition that δ-aminolevulinic acid was excreted in large amounts [6–9]. Lindblad and colleagues [10] reported that succinylacetone, which they found in the urine of these patients, is an inhibitor of the synthesis of porphobilinogen from δ-aminolevulinic acid. They reasoned that the fundamental defect was in the activity of fumarylacetoacetate hydrolase (Figure 22.1). This was confirmed enzymatically by these investigators [11] and others [12–14].
Metabolic Disorders II
Published in John F. Pohl, Christopher Jolley, Daniel Gelfond, Pediatric Gastroenterology, 2014
Tyrosinemia type I is characterized by the following biochemical findings: Increased succinlyacetone excretion in the urine of a child with liver failure or severe renal disease is pathognomonic of tyrosinemia type 1. Many laboratories require that measurement of succinylacetone be specifically requested when ordering urine organic acids.Elevated urinary concentrations of tyrosine metabolites (p-hydroxyphenylpyruvate, p-hydroxyphenyllactate, and p-hydroxyphenylacetate) detected on urinary organic acids testing.Increased urinary excretion of the compound delta-aminolevulinic acid (δ-ALA) secondary to inhibition of the enzyme δ-ALA dehydratase by succinylacetone in liver and circulating RBCs.Elevated plasma concentration of tyrosine, methionine, and phenylalanine on plasma amino acid analysis; however, elevated plasma tyrosine concentration can also be a nonspecific indicator of liver damage or immaturity.Very low or undetectable FAH enzyme activity as measured in cultured skin fibroblasts or hepatocytes. Specific reference ranges vary among laboratories.
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
Inborn errors or metabolism are ideal candidates for gene therapy due to their recessive monogeneic nature.IEMs can be classified based on key characteristics that provide insight into the best-suited therapeutic approaches.Use of AAV or LV should be based on indication, target population, and severity of the disease being treated.Gene therapy is the undeniable future for treatment of IEMs, although demonstration of safety and cost mitigation barriers remain.Hereditary tyrosinemia type I is a perfect candidate for gene therapy based on an inherent growth advantage for corrected cells that overcomes current inefficiencies in gene therapy.
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).
The potential of nitisinone for the treatment of alkaptonuria
Published in Expert Opinion on Orphan Drugs, 2019
A drug under current investigation for use in AKU is nitisinone [1], an inhibitor of 4-hydroxyphenlypyruavte dioxygenase, which is also present in the tyrosine degradation pathway [36]. Although nitisinone is not routinely prescribed for AKU, it is administered to patients who are being treated at the National AKU center based in Liverpool [37]. This drug is licensed for the treatment of hereditary tyrosinemia type 1, another, more severe disorder of tyrosine metabolism [38].