The Pathophysiology and Treatment of Hereditary Tyrosinemia Type 1

 

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ABSTRACT

The topic of this review is hepatorenal tyrosinemia (hereditary tyrosinemia type 1 [HT1], or fumarylacetoacetate hydrolase deficiency; OMIM# 276700). HT1 is the most serious and common of the genetic defects in tyrosine degradation. In addition, this disorder has importance as a model of spontaneous self-correction of liver disease, as a model of liver repopulation by transplanted cells and gene therapy, and as a genetic cause of hepatocarcinoma. However, other forms of hypertyrosinemia exist; hence, the differential diagnosis also will be described briefly. Recent years have seen much progress in our understanding of the molecular basis, the pathophysiology, and especially the treatment of HT1. The current intervention with 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC) therapy has improved the outcome of this once devastating disorder. The successful repopulation of the HT1 liver with transplanted cells and positive results in the use of gene therapy in animal models may someday lead to therapy in humans that will obviate the need for life-long dietary and pharmacological therapy.

REFERENCES

• 1 Mitchell G A, Grompe M, Lambert M. Hypertyrosinemia. In: Scriver CR, Beaudet AL, Sly W, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease, 9th ed New York: McGraw-Hill 2001: 1777-1805
  Google Scholar
• 2 Levine S Z, Marples E, Gordon H H. A defect in the metabolism of aromatic amino acids in premature infants: The role of vitamin C.  Science . 1939;  90 620
  PubMedGoogle Scholar
• 3 Kvittingen E. Hereditary tyrosinemia type I-an overview.  Scand J Clin Lab Invest . 1986;  46 27-34
  PubMedGoogle Scholar
• 4 Russo P, O'Regan S. Visceral pathology of hereditary tyrosinemia type I.  Am J Hum Genet . 1990;  47 317-324
  PubMedGoogle Scholar
• 5 Mitchell G, Larochelle J, Lambert M. Neurologic crises in hereditary tyrosinemia.  N Engl J Med . 1990;  322 432-437
  CrossrefPubMedGoogle Scholar
• 6 Croffie J M, Gupta S K, Chong S K. Tyrosinemia type 1 should be suspected in infants with severe coagulopathy even in the absence of other signs of liver failure.  Pediatrics . 1999;  103 675-678
  CrossrefPubMedGoogle Scholar
• 7 De Braekeleer M, Larochelle J. Genetic epidemiology of hereditary tyrosinemia in Quebec and in Saguenay-Lac-St-Jean.  Am J Hum Genet . 1990;  47 302-307
  PubMedGoogle Scholar
• 8 Phaneuf D, Labelle Y, Bérubé D. Cloning and expression of the cDNA encoding human fumarylacetoacetae hydrolase, the enzyme deficient in hereditary tyrosinemia: assignment of the gene to chromosome 15.  Am J Hum Genet . 1991;  48 525-535
  PubMedGoogle Scholar
• 9 Labelle Y, Phaneuf D, Leclerc B. Characterization of the human fumarylacetoacetate hydrolase gene and identification of a missense mutation abolishing enzymatic activity.  Hum Mol Genet . 1993;  2 941-946
  PubMedGoogle Scholar
• 10 St-Louis M, Leclerc B, Laine J. Identification of a stop mutation in five Finnish patients suffering from hereditary tyrosinemia type I.  Hum Mol Genet . 1994;  3 69-72
  PubMedGoogle Scholar
• 11 Grompe M, St-Louis M, Demers S I. A single mutation of the fumarylacetoacetate hydrolase gene in French Canadians with hereditary tyrosinemia type I.  N Engl J Med . 1994;  331 353-357
  CrossrefPubMedGoogle Scholar
• 12 Jakobs C, Stellaard F, Kvittingen E A. First-trimester prenatal diagnosis of tyrosinemia type I by amniotic fluid succinylacetone determination.  Prenat Diagn . 1990;  10 133-134
  PubMedGoogle Scholar
• 13 Grenier A, Cederbaum S, Laberge C. A case of tyrosinaemia type I with normal level of succinylacetone in the amniotic fluid.  Prenat Diagn . 1996;  16 239-242
  CrossrefPubMedGoogle Scholar
• 14 Kvittingen E A, Steinmann B, Gitzelmann R. Prenatal diagnosis of hereditary tyrosinemia by determination of fumarylacetoacetase in cultured amniotic fluid cells.  Pediatr Res . 1985;  19 334-337
  PubMedGoogle Scholar
• 15 Demers S I, Phaneuf D, Tanguay R M. Hereditary tyrosinemia type I: strong association with haplotype 6 in French Canadians permits simple carrier detection and prenatal diagnosis.  Am J Hum Genet . 1994;  55 327-333
  PubMedGoogle Scholar
• 16 Rootwelt H, Kvittingen E A, Hoie K. The human fumarylacetoacetase gene: characterisation of restriction fragment length polymorphisms and identification of haplotypes in tyrosinemia type 1 and pseudodeficiency.  Hum Genet . 1992;  89 229-233
  PubMedGoogle Scholar
• 17 Demers S I, Phaneuf D, Tanguay R M. TaqI RFLP for the human fumarylacetoacetate hydrolase (FAH) gene.  Nucleic Acids Res . 1991;  19 1352
  PubMedGoogle Scholar
• 18 Demers S I, Tanguay R M. MspI RFLP in the human fumarylacetoacetate hydrolase (FAH) gene.  Nucleic Acids Res . 1991;  19 6971
  PubMedGoogle Scholar
• 19 Demers S I, Tanguay R M. Bg1II RFLP for the human fumarylacetoacetate hydrolase (FAH) gene.  Nucleic Acids Res . 1991;  19 1965
  PubMedGoogle Scholar
• 20 Hutchesson A C, Hall S K, Preece M A, Green A. Screening for tyrosinaemia type I.  Arch Dis Child Fetal Neonatal Ed . 1996;  74 F191-F194
  PubMedGoogle Scholar
• 21 Belanger M, Saint H B, Belanger L. A system of early screening for inborn errors of metabolism: methods and results for hereditary tyrosinemia.  Union Med Can . 1973;  102 294-302
  PubMedGoogle Scholar
• 22 Bain M D, Purkiss P, Jones M. Dietary treatment eliminates succinylacetone from the urine of a patient with tyrosinemia type I.  Eur J Pediatr . 1990;  149 637-639
  PubMedGoogle Scholar
• 23 Murcia F J, Vazquez J, Gamez M. Liver transplantation in type I tyrosinemia.  Transplant Proc . 1995;  27 2301-2302
  PubMedGoogle Scholar
• 24 Esquivel C O, Mieles L, Marino I R. Liver transplantation for hereditary tyrosinemia in the presence of hepatocellular carcinoma.  Transplant Proc . 1989;  21 2445-2446
  PubMedGoogle Scholar
• 25 van Thiel H D, Gartner L M, Thorp F K. Resolution of the clinical features of tyrosinemia following orthotopic liver transplantation for hepatoma.  J Hepatol . 1986;  3 42-48
  CrossrefPubMedGoogle Scholar
• 26 Horwich A L. Inherited hepatic enzyme defects as candidates for liver-directed gene therapy.  Curr Top Microbiol Immunol . 1991;  168 185-200
  PubMedGoogle Scholar
• 27 Lock E A, Ellis M K, Gaskin P. From toxicological problem to therapeutic use: the discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug.  J Inherit Metab Dis . 1998;  21 498-506
  CrossrefPubMedGoogle Scholar
• 28 Lindstedt S, Holme E, Lock E A. Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase.  Lancet . 1992;  340 813-817
  CrossrefPubMedGoogle Scholar
• 29 Holme E, Lindstedt S. Tyrosinaemia type I and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione).  J Inherit Metab Dis . 1998;  21 507-517
  CrossrefPubMedGoogle Scholar
• 30 Origuchi Y, Endo F, Kitano A. Sural nerve lesions in a case of hypertyrosinemia.  Brain Dev . 1982;  4 463
  PubMedGoogle Scholar
• 31 Giardini O, Cantani A, Kennaway N G. Chronic tyrosinemia associated with 4-hydroxyphenylpyruvate dioxygenase deficiency with acute intermittent ataxia and without visceral and bone involvement.  Pediatr Res . 1983;  17 25-29
  PubMedGoogle Scholar
• 32 Fois A, Borgogni P, Cioni M. Presentation of the data of the Italian registry for oculocutaneous tyrosinaemia.  J Inherit Metab Dis . 1986;  9 262
  CrossrefPubMedGoogle Scholar
• 33 Kvittingen E A, Rootwelt H, Brandtzaeg P. Hereditary tyrosinemia type I. Self-induced correction of the fumarylacetoacetase defect.  J Clin Invest . 1993;  91 1816-1821
  PubMedGoogle Scholar
• 34 Kvittingen E A, Rootwelt H, Berger R. Self-induced correction of the genetic defect in tyrosinemia type I.  J Clin Invest . 1994;  94 1657-1661
  PubMedGoogle Scholar
• 35 Poudrier J, Lettre F, Scriver C R. Different clinical forms of hereditary tyrosinemia (type I) in patients with identical genotypes.  Mol Genet Metab . 1998;  64 119-125
  CrossrefPubMedGoogle Scholar
• 36 Overturf K, Al-Dhalimy M, Tanguay R. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I.  Nat Genet . 1996;  12 266-273
  PubMedGoogle Scholar
• 37 Knox W E, Edwards S W. Enzymes involved in conversion of tyrosine to acetoacetate.  Methods Enzymol . 1955;  2 287-300
  PubMedGoogle Scholar
• 38 Edwards S W, Knox W E. Homogentisate metabolism: the isomerization of maleylacetoacetate by an enzyme which requires glutathione.  J Biol Chem . 1956;  220 79
  PubMedGoogle Scholar
• 39 Knox W E, Edwards S W. Homogentisate oxidase of liver.  J Biol Chem . 1955;  216 479-487
  PubMedGoogle Scholar
• 40 Timm D E, Mueller H A, Bhanumoorthy P. Crystal structure and mechanism of a carbon-carbon bond hydrolase.  Structure Fold Des . 1999;  7 1023-1033
  PubMedGoogle Scholar
• 41 Bateman R L, Bhanumoorthy P, Witte J F. Mechanistic inferences from the crystal structure of fumarylacetoacetate hydrolase with a bound phosphorus-based inhibitor.  J Biol Chem . 2001;  276 15284-15291
  CrossrefPubMedGoogle Scholar
• 42 Lindblad B, Lindstedt S, Steen G. On the enzymic defects in hereditary tyrosinemia.  Proc Natl Acad Sci USA . 1977;  74 4641-4645
  PubMedGoogle Scholar
• 43 La Du N B, Zannoni V G, Laster L. The nature of the defect in tyrosine metabolism in alkaptonuria.  J Biol Chem . 1958;  230 251-260
  CrossrefPubMedGoogle Scholar
• 44 Rehak A, Selim M M, Yadav G. Richner-Hanhart syndrome (tyrosinaemia-II) (report of four cases without ocular involvement).  Br J Dermatol . 1981;  104 469-475
  PubMedGoogle Scholar
• 45 Bienfang D C, Kuwabara T, Pueschel S M. The Richner-Hanhart syndrome: report of a case with associated tyrosinemia.  Arch Ophthalmol . 1976;  94 1133-1137
  CrossrefPubMedGoogle Scholar
• 46 Endo F, Katoh H, Matsuda I. Putative genetic deficiency of 4-hydroxyphenylpyruvic acid dioxygenase in mice: a murine model for hereditary tyrosinaemia type III.  J Inherit Metab Dis . 1990;  13 780-782
  CrossrefPubMedGoogle Scholar
• 47 Cerone R, Holme E, Schiaffino M C. Tyrosinemia type III: diagnosis and ten-year follow-up.  Acta Paediatr . 1997;  86 1013-1015
  PubMedGoogle Scholar
• 48 Ruppert S, Kelsey G, Schedl A. Deficiency of an enzyme of tyrosine metabolism underlies altered gene expression in newborn liver of lethal albino mice.  Genes Dev . 1992;  6 1430-1443
  PubMedGoogle Scholar
• 49 Kubo S, Sun M, Miyahara M. Hepatocyte injury in tyrosinemia type 1 is induced by fumarylacetoacetate and is inhibited by caspase inhibitors.  Proc Natl Acad Sci USA . 1998;  95 9552-9557
  CrossrefPubMedGoogle Scholar
• 50 Sun M S, Hattori S, Kubo S. A mouse model of renal tubular injury of tyrosinemia type 1: development of de Toni Fanconi syndrome and apoptosis of renal tubular cells in Fah/Hpd double mutant mice.  J Am Soc Nephrol . 2000;  11 291-300
  PubMedGoogle Scholar
• 51 Jorquera R, Tanguay R M. Cyclin B-dependent kinase and caspase-1 activation precedes mitochondrial dysfunction in fumarylacetoacetate-induced apoptosis.  FASEB J . 1999;  13 2284-2298
  PubMedGoogle Scholar
• 52 Schmid W, Müller G, Schütz G. Deletions near the albino locus on chromosome 7 of the mouse affect the level of tyrosine aminotransferase mRNA.  Proc Natl Acad Sci USA . 1985;  82 2866-2869
  PubMedGoogle Scholar
• 53 Gluecksohn-Waelsch S. Genetic control of morphogenetic and biochemical differentiation: lethal albino deletions in the mouse.  Cell . 1979;  16 225-237
  CrossrefPubMedGoogle Scholar
• 54 Loose D S, Shaw P A, Krauter K S. Trans regulation of the phosphoenolpyruvate carboxykinase (GTP) gene, identified by deletions in chromosome 7 of the mouse.  Proc Natl Acad Sci USA . 1986;  83 5184-5188
  PubMedGoogle Scholar
• 55 Sala-Trepat J M, Poiret M, Sellem C H, Bessada R. A lethal deletion on mouse chromosome 7 affects regulation of liver cell-specific functions: posttranscriptional control of serum protein and transcriptional control of aldolase B synthesis.  Proc Natl Acad Sci USA . 1985;  82 2442-2446
  PubMedGoogle Scholar
• 56 Ruppert S, Boshart M, Bosch F X. Two genetically defined trans-acting loci coordinately regulate overlapping sets of liver-specific genes.  Cell . 1990;  61 895-904
  CrossrefPubMedGoogle Scholar
• 57 Fornace Jr J A, Nebert D W, Hollander M C. Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents.  Mol Cell Biol . 1989;  9 4196-203
  PubMedGoogle Scholar
• 58 Petersen D D, Gonzalez F J, Rapic V. Marked increases in hepatic NAD(P)H: oxidoreductase gene transcription and mRNA levels correlated with a mouse chromosome 7 deletion.  Proc Natl Acad Sci USA . 1989;  86 6699-6703
  PubMedGoogle Scholar
• 59 Nebert D W, Roe A L, Dieter M Z. Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis.  Biochem Pharmacol . 2000;  59 65-85
  CrossrefPubMedGoogle Scholar
• 60 Vasiliou V, Puga A, Chang C Y. Interaction between the Ah receptor and proteins binding to the AP-1-like electrophile response element (EpRE) during murine phase II [Ah] battery gene expression.  Biochem Pharmacol . 1995;  50 2057-2068
  CrossrefPubMedGoogle Scholar
• 61 Spencer P D, Roth K S. Effects of succinylacetone on amino acid uptake in the rat kidney.  Biochem Med Metab Biol . 1987;  37 101-109
  CrossrefPubMedGoogle Scholar
• 62 Spencer P D, Medow M S, Moses L C. Effects of succinylacetone on the uptake of sugars and amino acids by brush border vesicles.  Kidney Int . 1988;  34 671-677
  PubMedGoogle Scholar
• 63 Jorquera R, Tanguay R M. The mutagenicity of the tyrosine metabolite, fumarylacetoacetate, is enhanced by glutathione depletion.  Biochem Biophys Res Commun . 1997;  232 42-48
  CrossrefPubMedGoogle Scholar
• 64 Manning K, Al-Dhalimy M, Finegold M. In vivo suppressor mutations correct a murine model of hereditary tyrosinemia type I.  Proc Natl Acad Sci USA . 1999;  96 11928-11933
  CrossrefPubMedGoogle Scholar
• 65 Sassa S, Kappas A. Succinylacetone inhibits delta-aminolevulinate dehydratase and potentiates the drug and steroid induction of delta-aminolevulinate synthase in liver.  Trans Assoc Am Physicians . 1982;  95 42-52
  PubMedGoogle Scholar
• 66 Russell L B, Russell W L, Kelly E M. Analysis of the albino-locus region of the mouse. Origin and viability.  Genetics . 1979;  91 127-139
  PubMedGoogle Scholar
• 67 Niswander L, Kelsey G, Schedl A. Molecular mapping of albino deletions associated with early embryonic lethality in the mouse.  Genomics . 1991;  9 162-169
  CrossrefPubMedGoogle Scholar
• 68 Grompe M, Al-Dhalimy M, Finegold M. Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice.  Genes Dev . 1993;  7 2298-2307
  CrossrefPubMedGoogle Scholar
• 69 Grompe M, Lindstedt S, al-Dhalimy M. Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I.  Nat Genet . 1995;  10 453-460
  PubMedGoogle Scholar
• 70 Grompe M, Overturf K, Al-Dhalimy M. Therapeutic trials in the murine model of hereditary tyrosinemia type I: a progress report.  J Inher Metab Dis . 1998;  21 518-531
  PubMedGoogle Scholar
• 71 Overturf K, al-Dhalimy M, Ou C N. Adenovirus-mediated gene therapy in a mouse model of hereditary tyrosinemia type I.  Hum Gene Ther . 1997;  8 513-521
  PubMedGoogle Scholar
• 72 Overturf K, Al-Dhalimy M, Manning K. Ex vivo hepatic gene therapy of a mouse model of hereditary tyrosinemia type I.  Hum Gene Ther . 1998;  9 295-304
  PubMedGoogle Scholar
• 73 Chen S J, Tazelaar J, Moscioni A D. In vivo selection of hepatocytes transduced with adeno-associated viral vectors.  Mol Ther . 2000;  1 414-422
  CrossrefPubMedGoogle Scholar
• 74 Overturf K, Al-Dhalimy M, Finegold M. The repop- ulation potential of hepatocyte populations differing in size and prior mitotic expansion.  Am J Pathol . 1999;  155 2135-2143
  CrossrefPubMedGoogle Scholar
• 75 Grompe M, Al-Dhalimy M, Overturf K. Hepatic repopulation by adult murine pancreatic liver stem cells.  Am J Hum Genet . 1998;  63 9
  PubMedGoogle Scholar
• 76 Overturf K, Al-Dhalimy M, Ou C N. Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes.  Am J Pathol . 1997;  151 1273-1280
  PubMedGoogle Scholar
• 77 Wang X, Al-Dhalimy M, Lagasse E. Liver repopulation and correction of metabolic liver disease by transplanted adult mouse pancreatic cells.  Am J Pathol . 2001;  158 571-579
  CrossrefPubMedGoogle Scholar
• 78 Lagasse E, Connors H, Al-Dhalimy M. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo.  Nat Med . 2000;  6 1229-1234
  CrossrefPubMedGoogle Scholar
• 79 Grompe M. Liver repopulation for the treatment of metabolic diseases.  J Inherit Metab Dis . 2001;  24 231-244
  CrossrefPubMedGoogle Scholar
• 80 Grompe M, Laconi E, Shafritz D A. Principles of therapeutic liver repopulation.  Semin Liver Dis . 1999;  19 7-14
  PubMedGoogle Scholar
• 81 Fernandez-Canon J M, Penalva M A. Fungal metabolic model for human type I hereditary tyrosinaemia.  Proc Natl Acad Sci USA . 1995;  92 9132-9136
  PubMedGoogle Scholar
• 82 Fernandez-Canon J M, Penalva M A. Molecular characterization of a gene encoding a homogentisate dioxygenase from Aspergillus nidulans and identification of its human and plant homologues.  J Biol Chem . 1995;  270 21199-21205
  CrossrefPubMedGoogle Scholar
• 83 Fernandez-Canon J M, Penalva M A. Characterization of a fungal maleylacetoacetate isomerase gene and identification of its human homologue.  J Biol Chem . 1998;  273 329-337
  CrossrefPubMedGoogle Scholar
• 84 Garrod A E. The incidence of alkaptonuria: a study in chemical individuality.  Lancet . 1902;  2 1616-1620
  PubMedGoogle Scholar
• 85 Fernandez-Canon J M, Granadino B, Beltran-Valero de Bernabe D. The molecular basis of alkaptonuria.  Nat Genet . 1996;  14 19-24
  PubMedGoogle Scholar