Hereditary tyrosinaemia type I: from basics to progress in treatment.
ABSTRACT Hereditary tyrosinaemia type I is the most common of the diseases caused by defects in tyrosine metabolism. The underlying genetic defect is a mutation in the gene for fumarylacetate hydrolase (FAH), and more than 30 different mutations in this gene have been identified. The main clinical consequences of this defect include hepatic involvement, with a high risk for liver cancer, and renal tubular dysfunction. Restriction of phenylalanine and tyrosine from the diet along with supportive measures can ameliorate the symptoms, but cure has so far been possible only with liver transplantation. Recent discovery of a pharmacological treatment with a peroral inhibitor of tyrosine catabolic pathway, 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), offers a new promising tool for the treatment of patients with hereditary tyrosinaemia type I. Mouse models of FAH deficiency have been successfully used in experimental gene therapy, and these studies indicate that future management of tyrosinaemia with a gene therapeutic approach may become feasible.
- SourceAvailable from: Robert M Tanguay[show abstract] [hide abstract]
ABSTRACT: Current strategies for hepatic gene therapy are either quantitatively inefficient or suffer from lack of permanent gene expression. We have utilized an animal model of hereditary tyrosinaemia type I (HT1), a recessive liver disease caused by deficiency of fumarylacetoacetate hydrolase (FAH), to determine whether in vivo selection of corrected hepatocytes could improve the efficiency of liver gene transfer. As few as 1,000 transplanted wild-type hepatocytes were able to repopulate mutant liver, demonstrating their strong competitive growth advantage. Mutant hepatocytes corrected in situ by retroviral gene transfer were also positively selected. In mutant animals treated by multiple retrovirus injections >90% of hepatocytes became FAH positive and liver function was restored to normal. Our results demonstrate that in vivo selection is a useful strategy for hepatic gene therapy and may lead to effective treatment of human HT1 by retroviral gene transfer.Nature Genetics 03/1996; 12(3):266-73. · 35.21 Impact Factor
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ABSTRACT: Tyrosinemia type I is an autosomal recessive inborn error of metabolism caused by deficiency of the enzyme fumaryl acetoacetate hydrolase (FAH, EC 18.104.22.168). We have used reverse transcription and the polymerize chain reaction to amplify the peptide coding region of the FAH cDNA from four patients with tyrosinemia type I. Chemical mismatch cleavage analysis and DNA sequencing were utilized to determine mutant alleles in all cases. A French Canadian patient was homozygous for a splice error mutation in the 3' portion of the gene. A second patient, from a consanguineous pedigree in Iran, had the identical splice alteration. The third patient has a missense mutation, changing valine to glycine in codon 166. And finally two nonsense mutations in codons 357 and 364 were found in the fourth patient.Human Mutation 02/1993; 2(2):85-93. · 5.21 Impact Factor
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ABSTRACT: Succinylacetone, a catabolic end-product of tyrosine, is excreted in large quantities in urine from individuals with hereditary tyrosinemia and the Fanconi syndrome. Succinylacetone inhibits rat renal tubular concentrative uptake of the glucose transport analogue, methyl alpha-D-glucoside, in a noncompetitive and reversible fashion. This compound also depresses oxygen consumption by the rat renal tubule without fine structural damage to mitochondria. It is concluded that succinylacetone may be a useful probe in elucidation of the biochemical mechanism underlying the human Fanconi syndrome.Biochimica et Biophysica Acta 11/1985; 820(1):140-6. · 4.66 Impact Factor