Tyrosinemia is a term encompassing three disorders in which genetic mutations lead to various enzyme deficiencies and subsequent accumulation of tyrosine in organs and tissues. Type I is by far the most common, characterized by a severe, early-onset presentation of renal and liver failure that is frequently fatal in the first decade. Early recognition and proper treatment may significantly increase life-expectancy, but in order to make the diagnosis, a thorough clinical and biochemical workup is critical.
Tyrosinemia is a clinical entity describing abnormally high circulating concentrations of the amino acid tyrosine and may be seen due to various genetic mutations. Three distinct types of tyrosinemia are recognized       :
- Tyrosinemia type 1 - Develops on the grounds of fumarylacetoacetase (FAH) deficiency, the enzyme involved in the final steps of converting tyrosine to fumarate  . The pathogenesis stems from the generation of toxic metabolites that accumulate in various tissues, most notably in the liver and kidneys  . The clinical presentation of tyrosinemia type 1 starts in early infancy and childhood, with principal features being growth failure, coagulation deficits, and neurological crises consisting of neuropathy, abdominal pain, mental state changes and life-threatening respiratory insufficiency . Mortality rates are very high in the absence of an early diagnosis, usually from hepatic/respiratory failure or hepatocellular carcinoma, a well-known complication of tyrosinemia type 1   . The incidence rate of this autosomal recessive disorder is around 1 in 125,000 individuals, with more frequent cases observed in Turkey, India, and the Canadian province of Quebec .
- Tyrosinemia type 2 - Also known as Richner-Hanhart syndrome, tyrosinemia type 2 is a rare disorder of tyrosine metabolism, arising from tyrosine aminotransferase enzyme deficiency  . Very few reports of this disease exist, that mainly describe cutaneous (palmoplantar keratosis) and ocular symptoms (corneal lesions that are not responsive to commonly prescribed antiviral therapy), in addition to intellectual disability and other neurological signs  .
- Tyrosinemia type 3 - With only a few cases described in the literature and a poorly understood clinical presentation, tyrosinemia type 3 stems from 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) deficiency  .
Entire Body System
- Failure to Thrive
Similarities include failure to thrive with hypoproteinemia, micronodular cirrhosis, alpha-fetoprotein positive hepatocellular carcinoma, renal Fanconi syndrome with renal tubular ectasia, hypermethioninemia, and hypoglycemia associated with islet cell [ncbi.nlm.nih.gov]
At a Glance Approximate Incidence in Ontario 1 in 100, 000 Marker Measured Tyrosine and succinylacetone Screening can Prevent Liver and kidney damage and sequelae, failure to thrive, coagulopathy Treatment Special diet, medication Screening is Important [newbornscreening.on.ca]
The chronic form presents at about 1 year old with failure to thrive and delayed walking, possibly due to rickets. Signs Hepatomegaly is present in the first 3 months of life. [patient.info]
Affected individuals present with gastrointestinal problems leading to a failure to thrive, jaundice, and a cabbage-like odor to the body or urine. Kidney failure may lead to bleeding, ascites, and sepsis. Liver disease may occur. [sema4genomics.com]
Tyrosinemia type II should be suspected in patients demonstrating dermatologic signs, especially palmoplantar keratosis, associated with bilateral pseudodendritic corneal lesions unresponsive to antiviral therapy. [ncbi.nlm.nih.gov]
Very few reports of this disease exist, that mainly describe cutaneous (palmoplantar keratosis) and ocular symptoms (corneal lesions that are not responsive to commonly prescribed antiviral therapy), in addition to intellectual disability and other neurological [symptoma.com]
The palms and soles can have painful punctate keratosis which may extend to the digits. Developmental milestones such as walking are often delayed. The keratotic lesions may be up to 2 cm in size. [disorders.eyes.arizona.edu]
Deficiency of cytoplasmic tyrosine aminotransferase ( TAT) results in oculocutaneous tyrosinemia, characterized by palmoplantar keratosis and painful corneal erosions with photophobia (OMIM 276600). Half of reported patients have mental retardation. [web.archive.org]
Type II tyrosinemia, due to deficiency of tyrosine aminotransferase (TAT), is characterized by corneal ulcers and keratosis of digits, palms, and soles; caused by mutation in the TAT gene on 16q. [medical-dictionary.thefreedictionary.com]
On physical examination he presented petechiae and haematomas, and a slightly enlarged liver. [ncbi.nlm.nih.gov]
Because of the rare occurrence of tyrosinemia in clinical practice, the diagnosis might be difficult to attain. For this reason, the role of a detailed patient history and a proper physical examination are crucial in order to raise suspicion. The physician should obtain all information regarding the onset of symptoms, their progression, as well as severity and duration, either from the patient or from the parents (given the early onset of tyrosinemia type 1). The fact that autosomal recessive patterns of inheritance are confirmed for all tyrosinemias   , a family history (although not always informative) can provide vital clues into the etiology. The cornerstone of diagnosis, however, rests on the assessment of tyrosine and its metabolites (mainly succinylacetone) in blood and urine, which should be ordered as soon as sufficient evidence is gathered  . As a definitive diagnostic method, genetic studies, such as mutational analysis, can be used both prenatally and postnatally  .
In developed countries, expanded newborn screening, based on succinylacetone quantification by tandem mass spectrometry, has been very valuable in the early detection of hepatorenal tyrosinemia, providing the opportunity for rapid treatment of affected [ncbi.nlm.nih.gov]
Prognosis in types II and III is relatively good. © 2014 Japan Pediatric Society. KEYWORDS: liver cancer; liver transplantation; nitisinone; succinylacetone; tyrosine [ncbi.nlm.nih.gov]
317 ) Chronic form is milder, with chronic liver disease, renal tubular dysfunction, hypophosphatemia with rickets and increased risk for hepatocellular carcinoma 80% of patients have reversion of mutant alleles in hepatocytes, associated with better prognosis [pathologyoutlines.com]
Hereditary tyrosinemia type I: a new clinical classification with difference in prognosis on dietary treatment. Hepatology. 1994;20:1187-90. FROM THE INTERNET King LS, Trahms C, and Scott CR. (Updated 10/21/08). Tyrosinemia Type I. [rarediseases.org]
The fact that autosomal recessive patterns of inheritance are confirmed for all tyrosinemias, a family history (although not always informative) can provide vital clues into the etiology. [symptoma.com]
Etiology Tyrosinemia type 2 is caused by mutations in the TAT gene (16q22.1) encoding tyrosine aminotransferase (TAT). [orpha.net]
Ongoing controversies regarding etiology, diagnosis, treatment N/A Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved. [clinicaladvisor.com]
Scant information has been published on the etiology of TNT in the last 20 years; therefore, recent epidemiological figures, both nationally and internationally, remain unknown. [doi.org]
Summary Epidemiology Prevalence is unknown but less than 150 cases have been reported in the literature so far. The disease appears to be more common in Arab and Mediterranean populations. [orpha.net]
Epidemiology Tyrosinaemia I is much more common than type II. Type III is very rare. The incidence of type I is about 1 in 100,000 births. It is inherited as an autosomal recessive. Incidence and clinical pattern shows no sex difference. [patient.info]
Genetic epidemiology of hereditary tyrosinemia in Quebec and in Saguenay-Lac-St-Jean. American journal of human genetics. 1990;47(2):302-7. 5. Herbst DA, Reddy KR. Risk factors for hepatocellular carcinoma. [ijp.mums.ac.ir]
Tyrosinemia Epidemiology Tyrosinemia is a rare condition, occurring in almost 1 in every 100000 individuals. Type II of this disease affects less than one in every 250000 individuals. [hxbenefit.com]
Unfortunately the exact neuropsychological profile of these HTI patients is not known yet, neither are the exact pathophysiological mechanisms underlying these impairments. [ncbi.nlm.nih.gov]
Pathophysiology of metabolic disorders of tyrosine, resulting in elevated levels of tyrosine in blood. Diagnosis [ edit ] This section is empty. [en.wikipedia.org]
Khazal Paradis, Pediatric GastroenterologyNutrition, Hôpital Sainte-Justine, 3175 Côte Ste-Catherine, Montreal QC H3T 1C5; fax 514 345-4999 Contents Abstract Résumé Introduction Clinical presentation Pathophysiology Management options Conclusions Acknowledgements [nlc-bnc.ca]
Available treatments have potential complications, including liver transplantation (risks of surgery and of immunosuppression to prevent rejection), nitisinone and diet therapy (hypertyrosinemia, corneal opacities, nutritional imbalances and possibly [ncbi.nlm.nih.gov]
Nityr treatment requires restriction of the dietary intake of tyrosine and phenylalanine to prevent the toxicity associated with elevated plasma levels of tyrosine. [empr.com]
- Sniderman King L, Trahms C, Scott CR. Tyrosinemia Type I. 2006 Jul 24 [Updated 2017 May 25]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
- Fernández-Lainez C, Ibarra-González I, Belmont-Martínez L, Monroy-Santoyo S, Guillén-López S, Vela-Amieva M. Tyrosinemia type I: clinical and biochemical analysis of patients in Mexico. Ann Hepatol. 2014;13(2):265-272.
- Peña-Quintana L, Scherer G, Curbelo-Estévez ML, et al. Tyrosinemia type II: Mutation update, 11 novel mutations and description of 5 independent subjects with a novel founder mutation. Clin Genet. Mar 3, 2017.
- Iskeleli G, Bilgeç MD, Arici C, Atalay E, Oğreden T, Aydin A. Richner-Hanhart syndrome (tyrosinemia type II): a case report of delayed diagnosis with pseudodendritic corneal lesion. Turk J Pediatr. 2011;53(6):692-694.
- Mayorandan S, Meyer U, Gokcay G, et al. Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice. Orphanet J Rare Dis. 2014;9:107.
- Heylen E1, Scherer G, Vincent MF, Marie S, Fischer J, Nassogne MC. Tyrosinemia Type III detected via neonatal screening: management and outcome. Mol Genet Metab. 2012;107(3):605-607.
- Rüetschi U, Cerone R, Pérez-Cerda C, et al. Mutations in the 4-hydroxyphenylpyruvate dioxygenase gene (HPD) in patients with tyrosinemia type III. Hum Genet. 2000;106(6):654-662.