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Current Strategies for the Treatment of Hereditary Tyrosinemia Type I

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Hereditary tyrosinemia type I (HT-I) is the most common of the three known diseases caused by defects in tyrosine metabolism. This type of tyrosinemia is caused by a mutation in the gene coding for fumarylacetoacetate hydrolase; several mutations in this gene have been identified. The main clinical features of HT-I are caused by hepatic involvement and renal tubular dysfunction.

Dietary intervention with restriction of phenylalanine and tyrosine together with supportive measures can ameliorate the symptoms, but given the high risk for hepatocellular carcinoma, a cure for these patients has so far been possible only with liver transplantation.

Pharmacologic treatment with nitisinone, a peroral inhibitor of the tyrosine catabolic pathway, offers an improved means of treatment for patients with HT-I. However, longer follow-up periods are needed to establish the role of this drug in ultimately protecting patients from end-stage organ involvement and hepatocellular carcinoma. Experimental work in mice has provided some promise for the future management of tyrosinemia with gene therapy.

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  1. 1.

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  1. 1.

    Lindblad B, Lindstedt S, Steen G. On the enzymatic defect in hereditary tyrosinemia. Proc Natl Acad Sci U S A 1977; 74: 4641–5

  2. 2.

    Russo PA, Mitchell GA, Tanguay RM. Tyrosinemia: a review. Pediatr Dev Pathol 2001; 4: 212–21

  3. 3.

    Nyhan WL, Ozand PT. Tyrosinemia. In: Nyhan WL, Ozand PT, editors. Atlas of metabolic diseases. London: Chapman and Hall Medical, 1998: 153–9

  4. 4.

    Tanguay RM, Valet JP, Duband JL, et al. Different molecular basis for fumarylacetoacetate hydrolase deficiency in the two clinical forms of hereditary tyrosinemia (type I). Am J Hum Genet 1990; 47: 308–16

  5. 5.

    Phaneuf D, Labelle Y, Berube D, et al. Cloning and expression of the cDNA encoding human fumarylacetoacetate hydrolase, the enzyme deficient in hereditary tyrosinemia: assignment of the gene to chromosome 15. Am J Hum Genet 1991; 48: 525–35

  6. 6.

    Labelle Y, Phaneuf D, Tanguay RM. Characterization of the human fumarylacetoacetate hydrolase gene and identification of a missense mutation abolishing enzymatic activity. Hum Mol Genet 1993; 2: 941–6

  7. 7.

    Awata H, Endo F, Tanoue A, et al. Structural organization and analysis of the human fumarylacetoacetate hydrolase gene in tyrosinemia type I. Biochim Biophys Acta 1994; 1226: 168–72

  8. 8.

    Phaneuf D, Lambert M, Laframboise R, et al. Type I hereditary tyrosinemia: evidence for molecular heterogeneity and identification of a causal mutation in a French Canadian patient. J Clin Invest 1992; 90: 1185–92

  9. 9.

    Grompe M, St-Louis M, Demers SI, et al. A single mutation of the fumarylacetoacetate hydrolase gene in French Canadians with hereditary tyrosinemia type I. N Engl J Med 1994; 331: 353–7

  10. 10.

    Rootwelt H, Chou J, Gahl WA, et al. Two missense mutations causing tyrosinemia type I with presence and absence of immunoreactive fumarylacetoacetase. Hum Genet 1994; 93: 615–9

  11. 11.

    Rootwelt H, Berger R, Gray G, et al. Novel splice, missense and nonsense mutations in the fumarylacetoacetase gene causing tyrosinemia type I. Am J Hum Genet 1994; 55: 653–8

  12. 12.

    Rootwelt H, Brodtkorb E, Kvittingen EA. Identification of a frequent pseudodeficiency mutation in the fumarylacetoacetase gene, with implications of diagnosis of tyrosinemia type I. Am J Genet 1994; 55: 1122–7

  13. 13.

    St-Louis M, Leclerc B, Laine J, et al. Identification of a stop mutation in five Finnish patients suffering from hereditary tyrosinemia type I. Hum Mol Genet 1994; 3: 69–72

  14. 14.

    Bergman AJIW, van den Berg IET, Brink W, et al. Spectrum of mutations in the fumarylacetoacetate hydrolase gene of tyrosinemia type I patients in Northwestern Europe and Mediterranean countries. Hum Mutat 1998; 12: 19–26

  15. 15.

    Roth KS, Spencer PD, Higgins ES, et al. Effects of succinylacetone of methyl alpha-D-glucoside uptake by the rat renal tubule. Biochim Biophys Acta 1985; 820: 140–6

  16. 16.

    Sassa S, Kappas A. Hereditary tyrosinemia and the heme biosynthetic pathway: profound inhibition of delta-aminolevulinic acid dehydratase activity by succinylacetone. J Clin Invest 1983; 1: 625–34

  17. 17.

    Berger R, van Faassen H, Smith GPA. Biochemical studies on the enzymatic deficiencies in hereditary tyrosinemia. Clin Chim Acta 1983; 134: 129–41

  18. 18.

    Berger R, van Faassen H, Taanman JW, et al. Type I tyrosinemia: lack of immunologically detectable fumarylacetoacetase enzyme protein in tissue and cell extracts. Pediatr Res 1987; 22: 394–7

  19. 19.

    Laberge C, Lescault A, Tanguay RM. Hereditary tyrosinemias (type I): a new vista on tyrosine toxicity and cancer. In: Poirier LA, Newberne PM, Pariza MW, editors. Essential nutrients in carcinogenesis. New York: Plenum, 1986: 209–12

  20. 20.

    Hermes-Lima M, Valle VGR, Vercesi AE, et al. Damage to rat liver mithochondria promoted by delta-aminolevulinic acid-generated reactive oxygen species: connections with acute intermittent porphyria and lead poisoning. Biochim Biophys Acta 1991; 105: 57–63

  21. 21.

    Tanguay RM, Jorquera R, Poudrier J, et al. Tyrosine and its catabolites: from disease to cancer. Acta Biochim Pol 1996; 43: 209–16

  22. 22.

    Jorquera R, Tanguay RM. The mutagenicity of the tyrosine metabolite, fumarylacetoacetate, is enhanced by glutathione depletion. Biochem Biophys Res Commun 1997; 232: 42–8

  23. 23.

    Kubo S, Sun M, Miyahara M, et al. Hepatocyte injury in tyrosinemia type I is induced by fumarylacetoacetate and is inhibited by caspase inhibitors. Proc Natl Acad Sci U S A 1998; 4: 9552–7

  24. 24.

    Endo F, Kubo S, Awata H, et al. Complete rescue of lethal albino c14oS mice by null mutation of 4-hydroxyphenylpyruvate dioxygenase and induction of apoptosis of hepatocytes in these mice by in vivo retrieval of the tyrosine catabolic pathway. J Biol Chem 1997; 26: 24426–32

  25. 25.

    Kvittingen EA. Hereditary tyrosinemia type I: an overview. Scand J Clin Lab Invest 1986; 46: 27–34

  26. 26.

    Labergne C. Hereditary tyrosinemia in a French Canadian isolate. Am J Hum Genet 1969; 21: 36–45

  27. 27.

    De Braekeleer MJ, Larochelle J. Genetic epidemiology of hereditary tyrosinemia in Quebec and the Saguenay-Lac-St Jean. Am J Hum Genet 1990; 47: 302–7

  28. 28.

    Mustonen A, Ploos van Amstel HK, Berger R, et al. Mutation analysis for prenatal diagnosis of hereditary tyrosinemia type I. Prenat Diagn 1997; 17: 964–6

  29. 29.

    van Spronsen FJ, Thomasse Y, Smit GPA, et al. Hereditary tyrosinemia type I: a new clinical classification with difference in prognosis on dietary treatment. Hepatology 1994; 20: 1187–91

  30. 30.

    Kvittingen EA. Tyrosinemia type I: an update. J Inherit Metab Dis 1991; 14: 554–62

  31. 31.

    Kvittingen EA, Brodtkorb E. The pre- and post-natal diagnosis of tyrosinemia type I and the detection of the carrier state by assay of fumarylacetoacetase. Scand J Clin Lab Invest 1986; 184: 35–40

  32. 32.

    Kvittingen EA, Halvorsen S, Jellum E. Deficient fumaryacetoacetate fumarylhydrolase activity in lymphocytes and fibroblasts from patients with hereditary tyrosinemia. Pediatr Res 1983; 14: 541–4

  33. 33.

    Kvittingen EA, Steinmann B, Gitzelmann R, et al. Prenatal diagnosis of hereditary tyrosinemia by determination of fumarylacetoacetase in cultured amniotic fluid cells. Pediatr Res 1985; 19: 334–7

  34. 34.

    Kvittingen EA, Rootwelt H, Berger R, et al. Self-induced correction of the genetic defect in tyrosinemia type I. J Clin Invest 1994; 94: 1657–61

  35. 35.

    Poudrier J, Lettre F, Scriver CR, et al. Different clinical forms of hereditary tyrosinemia (type I) in patients with identical genotypes. Mol Genet Metab 1998; 64: 119–25

  36. 36.

    Crone J, Möslinger D, Bodamer OA, et al. Reversibility of cirrhotic regenerative liver nodules upon NTBC treatment in a child with tyrosinemia type I. Acta Paediatr 2003; 92: 625–8

  37. 37.

    Gagne R, Lescault A, Grenier A, et al. Prenatal diagnosis of hereditary tyrosinemia: measurement of succinylacetone in amniotic fluid. Prenatal Diagn 1982; 2: 185–8

  38. 38.

    Jakobs C, Lambertus D, Wikkerink B, et al. Stable isotope dilution analysis of succinylacetone using electron capture negative ion mass fragmentography: an accurate approach to the pre- and neonatal diagnosis of hereditary tyrosinemia type I. Clin Chim Acta 1988; 223: 223–32

  39. 39.

    McCormack MJ, Walker E, Gray AG, et al. Fumarylacetoacetase activity in cultured and non-cultured chorionic villus cells, and assay in two high-risk pregnancies. Prenat Diagn 1992; 12: 807–13

  40. 40.

    Goulden HK, Moss MA, Cole DEC, et al. Pitfalls in the initial diagnosis of tyrosinemia: three case reports and a review of the literature. Clin Biochem 1987; 20: 207–12

  41. 41.

    De Almieda IT, Leandro PP, Silva MFB, et al. Tyrosinemia type I with normal levels of plasma tyrosine. J Inherit Metab Dis 1990; 13: 305–7

  42. 42.

    Slordahl S, Lie SO, Jellum E, et al. Increased need for L-cysteine in hereditary tyrosinemia [abstract]. Pediatr Res 1979; 13: 74

  43. 43.

    Stoner E, Starkman H, Wellner VP, et al. Biochemical studies of a patient with hereditary hepatorenal tyrosinemia: evidence of glutathione deficiency. Pediatr Res 1984; 18: 1332–6

  44. 44.

    Lindstedt S, Holme E, Lock EA, et al. Treatment of hereditary tyrosinemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet 1992; 340: 813–7

  45. 45.

    Holme E, Lindstedt S. Tyrosinemia type I and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione). J Inherit Metab Dis 1998; 21: 507–17

  46. 46.

    Holme E, Lindstedt S. Diagnosis and management of tyrosinemia type I. Curr Opin Pediatr 1995; 7: 726–32

  47. 47.

    Holme E, Lindstedt S, Lock EA. Treatment of tyrosinemia type I with an enzyme inhibitor (NTBC). Int Pediatr 1995; 10: 41–3

  48. 48.

    Bird S, Miller NJ, Collins JE, et al. Plasma antioxidant capacity in two cases of tyrosinemia type I: one case treated with NTBC. J Inherit Metab Dis 1995; 18: 123–6

  49. 49.

    Kvittingen EA. Tyrosinemia: treatment and outcome. J Inherit Metab Dis 1995; 18: 375–9

  50. 50.

    Hanauske-Abel HM, Popwicz A, Remotti H, et al. Tyrosinemia I, a model for human diseases mediated by 2-oxoacid utilizing dioxygenases: hepatotoxin suppression by NTBC does not normalize hepatic collagen metabolism. J Pediatr Gastroenterol Nutr 2002; 35: 73–8

  51. 51.

    Luijerink MC, Jacobs SM, van Beurden EA, et al. Extensive changes in liver gene expression induced by hereditary tyrosinemia type I are not normalized by treatment with 2-(2-nitro-4-trifluoromethylbenzol)-1,3-cyclohexanedione (NTBC). J Hepatol 2003; 39(6): 901–9

  52. 52.

    Holme E, Lindstedt S. Nontransplant treatment of tyrosinemia. Clin Liver Dis 2000; 4: 805–14

  53. 53.

    Gissen P, Preece MA, Willshaw HA, et al. Ophthalmic follow-up of patients with tyrosinaemia type I on NTBC. J Inherit Metab Dis 2003; 26(1): 13–6

  54. 54.

    Shaw V, Lawson M, editors. Tyrosinaemia type I, in clinical paediatric dietetics. 2nd ed. London: Blackwell Science, 2001: 241–62

  55. 55.

    Lahdenne P, Kuusela P, Siimes MA, et al. Biphasic reduction and concanavalin A binding properties of serum alpha-fetoprotein in preterm and term infants. J Pediatr 1991; 118: 272–6

  56. 56.

    Weinberg AG, Mize CE, Worten HG. The occurrence of hepatoma in the chronic form of hereditary tyrosinemia. J Pediatr 1976; 88: 434–8

  57. 57.

    Grenier A, Belanger L, Laberge C. Alpha-1-fetoprotein measurement in blood spotted on paper: discriminating test for hereditary tyrosinemia in neonatal mass screening. Clin Chem 1976; 22: 1001–4

  58. 58.

    Fisch RO, McCabe ERB, Doeden D, et al. Homotransplantation of the liver in a patient with hepatoma and hereditary tyrosinemia. J Pediatr 1978; 93: 542–96

  59. 59.

    Freese DK, Tuchman M, Schwarzenberger SJ, et al. Early liver transplantation is indicated for tyrosinemia type I. J Pediatr Gastroenterol Nutr 1991; 13: 10–5

  60. 60.

    Wu JT. Serum alpha-fetoprotein and its lectin reactivity in liver diseases: a review. Ann Clin Lab Sci 1990; 20: 98–105

  61. 61.

    Pitkänen S, Salo MK, Kuusela P, et al. Serum levels of oncofetal markers CA 125, CA 19-9 and alpha-fetoprotein in children with hereditary tyrosinemia type I. Pediatr Res 1994; 35: 205–8

  62. 62.

    Dehner LP, Snover DC, Sharp HL, et al. Hereditary tyrosinemia type I (chronic form): pathologic findings in the liver. Hum Pathol 1989; 20: 149–58

  63. 63.

    Mieles LA, Esquivel CO, Van Thiel DH, et al. Liver transplantation for tyrosinemia: a review of 10 cases from the University of Pittsburg. Dig Dis Sci 1990; 35: 153–7

  64. 64.

    Kvittingen EA, Jellum E, Stokke O, et al. Liver transplantation in a 23-year-old tyrosinemia patient: effects on the renal tubular dysfunction. J Inherit Metab Dis 1986; 9: 216–24

  65. 65.

    Tuchman M, Freese DK, Sharp HL, et al. Contribution of extrahepatic tissue to biochemical abnormalities in hereditary tyrosinemia type I: study of three patients after liver transplantation. J Pediatr 1987; 110: 399–404

  66. 66.

    Laine J, Salo MK, Krogerus L, et al. The nephropathy of type I tyrosinemia after liver transplantation. Pediatr Res 1995; 37: 640–5

  67. 67.

    Overturf K, Al-Dhalimy M, Manning K, et al. Ex vivo hepatic gene therapy of a mouse model of hereditary tyrosinemia type I. Hum Gene Ther 1998; 10: 295–304

  68. 68.

    Overturf K, Al-Dhalimy M, Tanguay R, et al. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinemia type I. Nat Genet 1996; 12: 266–73

  69. 69.

    Overturf K, Al-Dhalimy M, Ou CN, et al. Adenovirus-mediated gene therapy in mouse model of hereditary tyrosinemia type I. Hum Gene Ther 1997; 20: 513–21

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This work was supported by the Finnish Pediatric Foundation and the Helsinki University Central Hospital and Tampere University Hospital research funds. The authors have no conflicts of interest that are directly relevant to the content of this review.

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Correspondence to Dr Markku Heikinheimo.

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Ashorn, M., Pitkänen, S., Salo, M.K. et al. Current Strategies for the Treatment of Hereditary Tyrosinemia Type I. Pediatr-Drugs 8, 47–54 (2006).

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  • Liver Transplantation
  • Tyrosinemia
  • Nitisinone
  • Succinylacetone
  • Hereditary Tyrosinemia Type