Final Diagnosis -- Hereditary Tyrosinemia Type 1




Hereditary tyrosinemia type 1 is the most severe of the hereditary tyrosinemias (1). It is caused by a deficiency in fumarylacetoacetate hydrolase (1, 2), an enzyme in the tyrosine metabolism pathway that is responsible for the conversion of the toxic metabolic product fumarylacetoacetate into fumaric acid and acetoacetic acid (3). In its absence, fumarylacetoacetate is converted into succinylacetone and succinylacetoacetate (3, 4), with detection of the former being pathognomonic for the diagnosis (1).

Fumarylacetoacetate is capable of causing both oxidative and mutagenic damage to cells (1). It typically accumulates in hepatocytes and proximal renal tubular cells, wherein many of its pathologic effects occur (1, 5). Liver manifestations of hereditary tyrosinemia type 1 include hepatomegaly, hypoglycemia, increases in PT and PTT (with decreases in the production of Factors II, VII, IX, XI, and XII), alpha fetal protein elevation (as was identified in this case), jaundice, and cirrhosis with progression to hepatocellular carcinoma (1, 2, 3, 6, 7). Renal manifestations present as a Fanconi syndrome, and include hypophosphatemia, aminoaciduria, and renal tubular acidosis (1, 2, 6). Other reported manifestations have included hypertrophic cardiomyopathy (8) and inhibition of aminolevulinate dehydratase, resulting in porphyria-like neurologic symptoms, such as pain, ileus, weakness, and even paralysis (1, 2, 7). In untreated patients, the most severe cases of hereditary tyrosinemia type 1 often result in death before two years of age (2).

It is a relatively rare disorder, with an autosomal recessive inheritance pattern (2), occurring in only 1 : 12,000 - 100,000 individuals (of Northern European descent) (9). The genetic mutations responsible have been mapped to chromosome 15q23-25 (2). One of the more well-described variants includes the Lac St Jean region of Quebec mutation, with a carrier rate of approximately 5% in that region's population (10).

As stated above, an elevation in succinylacetone is pathognomonic for hereditary tyrosinemia type 1. As such, in this case, a urine organic acid analysis was performed in addition to a serum amino acid analysis. Of note, a normal serum tyrosine level does not exclude hereditary tyrosinemia type 1. Conversely, an elevated tyrosine level may also be seen in an immature liver, which is much more common clinically (Steven Dobrowolski, Ph.D., personal communication). In this case, the initial urine organic acid analysis revealed elevated concentrations of 4-hydroxyphenylacetic acid, para hydroxyphenyllactic acid, and 4-hydroxyphenylpyruvate, all metabolic products of tyrosine metabolism, however, none specific for a diagnosis of hereditary tyrosinemia type 1. These compounds were so abundant relative to the internal standard that it was not possible to identify the succinylacetone signal, which was lost in the other peaks. A subsequent oxime derivatization of the specimen and repeat urine organic acid analysis resulted in the identification of succinylacetone, succinylacetoacetate, and fumarylacetoacetate, illustrating the entire pathway and leading to a definitive diagnosis. Other methodologies to aide in making a diagnosis of hereditary tyrosinemia type 1 include measuring fumarylacetoacetate hydrolase activity in cultured fibroblasts, as well as genetic mutational analysis (6).

The treatment for hereditary tyrosinemia type 1 is nitisinone [2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione]. It inhibits 4-hydroxy phenylpyruvate dioxygenase, an earlier enzyme in the tyrosine metabolism pathway, which prevents the initial generation of fumarylacetoacetate, and subsequently, succinylacetone (11). Patients typically experience a rapid clinical response after treatment is initiated, with succinylacetone levels and coagulation pathway deficiencies correcting in the days following drug administration (11). Nitisinone treatment is additionally coupled with dietary decreases in tyrosine and phenylalanine consumption (11). Liver transplantation may need to be considered in appropriate patients refractory to treatment, and routine imaging and follow up AFP measurements are important given the risk of cirrhosis and hepatocellular carcinoma in these patients (12).

In conclusion, hereditary tyrosinemia type 1 is a very rare, but potentially fatal disorder. Succinylacetone is the pathognomonic compound for diagnosis, which is important for prompt therapy administration. Treatment involves both dietary reduction of tyrosine and phenylalanine, as well as the drug nitisinone, which blocks the tyrosine metabolism pathway before fumarylacetoacetate and succinylacetone are generated.


  1. Grompe, M. Disorders of tyrosine metabolism. <> Accessed 2013 November 10.
  2. Scott, CR. The genetic tyrosinemias. Am Journal Medical Genetics, Part C. Semin Med Genetics. 2006; 142C:121-126.
  3. Kitagawa, T. Hepatorenal tyrosinemia. 2012; Proc. Jpn. Acad. Ser. B. 88: 192-200.
  4. Tanguay, RM, Jorquera, R, Poudrier, J, and St-Louis M. Tyrosine and its catabolites: from disease to cancer. Acta Biochimica Polonica. 1996; 43(1): 209-216.
  5. Endo, F, and Sun, MS. Tyrosinemia type 1 and apoptosis of hepatocytes and renal tubular cells. J Inherit Dis 2002; 25(3):227-34.
  6. Grompe, M. The Pathophysiology and treatment of Heredity Tyrosinemia Type 1. Seminars in Liver Disease 2001; 21(4): 563-571.
  7. Mitchell, G, Larochelle, J, Lambert, M, Michaud, J, Grenier, A, Ogier, H, Gauthier, M, Lacroix ,J, Vanasse, M, Larbrisseau, A, et al. Neurologic crises in hereditary tyrosinemia. N Engl J Med. 1990; 322(7):432-437.
  8. Mohamed, S, Kambal, M, Jurayyan, NA, Al-Nemn, A, Babiker, A, Hasanato, R, and Al-Jarallah, AS. Tyrosinemia type 1: a rare and forgotten cause of reversible hypertrophic cardiomyopathy in infancy. BMC Research Notes. 2013; 6:362.
  9. Kaye, CI, Committee on Genetics, Accurso, F, La Franchi, S, Lane, PA, Hope, N, Sonya, P, Bradley, S, Michelle, A. Newborn screening fact sheets. Pediatrics. 2006; 118(3): 934.
  10. De Braekeleer M, Larochelle, J. Genetic epidemiology of hereditary tyrosinemia in Quebec and in Saguenay-Lac-St-Jean. Am J Human Genetics. 1990; 47(2):302-307..
  11. De Laet ,C, Dionisi-Vici, C, Leonard ,,JV, and PMcKleman, P. Recommendations for the management of tyrosinemia type 1. Orphanet Journal of Rare Diseases. 2013; 8: 8.
  12. Shneider BL. Pediatric liver transplantation in metabolic disease: clinical decision making. Pediatric transplantation 2002; 6: 25-29.

Contributed by Tanner Bartholow, MD, MS and Steven Dobrowolski, PhD

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