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Tyrosinemia
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.
Pathophysiology of metabolic disorders of phenylalanine and tyrosine
Inborn errors of metabolism of phenylalanine and tyrosine
Presentation
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 [1] [2] [3] [4] [5] [6] [7]:
- Tyrosinemia type 1 - Develops on the grounds of fumarylacetoacetase (FAH) deficiency, the enzyme involved in the final steps of converting tyrosine to fumarate [1] [5]. The pathogenesis stems from the generation of toxic metabolites that accumulate in various tissues, most notably in the liver and kidneys [1] [2]. 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 [1]. 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 [1] [2] [5]. 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 [5].
- 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 [3] [4]. 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 [3] [4].
- 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 [6] [7].
Entire Body System
Fatigue
- Tyrosinemia Type 1 Symptoms Bloody stools Cabbage like odor Diarrhea Fatigue Poor weight gain Failure to thrive Vomiting Tyrosinemia Type 2 Symptoms Painful lesions on the skin Red eyes and light sensitivity Corneal clouding Intellectual disability Behavioral[stlouischildrens.org]
Multiple Congenital Anomalies
- We have restudied a patient with typical symptoms of tyrosinemia II who in addition suffers from multiple congenital anomalies including severe mental retardation.[ncbi.nlm.nih.gov]
Respiratoric
Aspiration
- Of the remaining nine who survived the operation, one died at six months as a result of bronchial aspiration and aspiration pneumonia, and a second transplanted for hepatoma died five months later with metastases.[ncbi.nlm.nih.gov]
Tachypnea
- The report describes a male newborn who presented with tachypnea, lethargy, diarrhea and metabolic acidosis at 12 days old, with an elevated level of lactic acid.[ncbi.nlm.nih.gov]
Gastrointestinal
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]
- Main clinical findings were hepatomegaly, splenomegaly, cirrhosis, liver failure, tubulopathy, nephromegaly, Fanconi syndrome, seizures and failure to thrive. Histopathological findings were cirrhosis, fibrosis and steatosis.[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]
- Tyrosinemia Type 1 Symptoms Bloody stools Cabbage like odor Diarrhea Fatigue Poor weight gain Failure to thrive Vomiting Tyrosinemia Type 2 Symptoms Painful lesions on the skin Red eyes and light sensitivity Corneal clouding Intellectual disability Behavioral[stlouischildrens.org]
- 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]
Eyes
Corneal Deposit
- Corneal deposits can be one of the parameters in monitoring the efficacy of diet control.[ncbi.nlm.nih.gov]
- Reduction in the extent of corneal deposits was also confirmed with IVCM.[ncbi.nlm.nih.gov]
Musculoskeletal
Proximal Muscle Weakness
- We report a 27-month-old infant who presented with a sudden change in gait owing to proximal muscle weakness. The laboratory evaluation showed carnitine deficiency associated with Fanconi's tubulopathy. Eventually, tyrosinemia type I was diagnosed.[ncbi.nlm.nih.gov]
Skin
Formication
- METHODS: The 3.2 mm DBS were extracted by incubating at 45 C for 45 min with 100 μl of acetonitrile (ACN)-water-formic acid mixture containing hydrazine and stable-isotope labeled internal standards of AA, AC and SUAC.[ncbi.nlm.nih.gov]
- The solvent was acetonitrile-water (80:20 by volume) containing formic acid, hydrazine hydrate, and 100 nmol/L 5,7-dioxooctanoic acid as internal standard. Analysis was performed by tandem mass spectrometry in a separate run.[ncbi.nlm.nih.gov]
Petechiae
- On physical examination he presented petechiae and haematomas, and a slightly enlarged liver.[ncbi.nlm.nih.gov]
Urogenital
Renal Stone
- Four developed renal stones, two were in liver failure, and one developed a neurologic crisis that left him completely paralyzed. Hepatocellular carcinoma was found in one of the five at transplant.[ncbi.nlm.nih.gov]
Workup
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 [1] [3] [6], 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 [1] [5]. As a definitive diagnostic method, genetic studies, such as mutational analysis, can be used both prenatally and postnatally [1] [5].
Serum
Tyrosine Increased
- Serum tyrosine increases due to tyrosine aminotransferase deficiency resulting in the deposition of tyrosine crystals in the cornea and in corneal inflammation. Patients are often misdiagnosed as having herpes simplex keratitis.[ncbi.nlm.nih.gov]
Biopsy
Hepatocellular Carcinoma
- Hepatocellular carcinoma (HCC) was found either preoperatively or incidentally in five patients, all older than 2 years at the time of their transplant.[ncbi.nlm.nih.gov]
- Two patients also had elevated alpha-fetoprotein but no evidence of hepatocellular carcinoma. All patients are on low tyrosine-phenylalanine diet and on regular follow up.[ncbi.nlm.nih.gov]
- One child received NTBC for only 3 months after which he was diagnosed to have hepatocellular carcinoma and underwent a living-related liver transplantation. The child is doing well post-transplant.[ncbi.nlm.nih.gov]
- Autopsy of a 4-year-old girl with hereditary tyrosinemia type I revealed a hepatocellular carcinoma in addition to cirrhosis and renal tubular dysplasia.[ncbi.nlm.nih.gov]
- Characteristic to HT1 is the development of hepatocellular carcinoma, irrespective of dietary intervention or pharmacological treatment.[ncbi.nlm.nih.gov]
Treatment
- FINDINGS: No hospitalizations for acute complications of HT1 occurred during 5731 months of nitisinone treatment, versus 184 during 1312 months without treatment (p INTERPRETATION: Nitisinone treatment abolishes the acute complications of HT1.[ncbi.nlm.nih.gov]
- Treatment adherence is variable, causing concern about long term outcome for some patients. Around the world, there are great disparities in the diagnosis and treatment of HT1.[ncbi.nlm.nih.gov]
- The patient had been placed on topical acyclovir treatment with the diagnosis of recurrent bilateral herpetic keratitis during the previous 12 months.[ncbi.nlm.nih.gov]
- In fact, single dose treatment may increase patients' compliance with the drug treatment and improve metabolic control.[ncbi.nlm.nih.gov]
- Since the introduction of NTBC [2-(2-nitro-4-trifluoromethyl benzoyl)-1-3-cyclohexanedione] (nitisinone R ) in the treatment of tyrosinemia, no liver disease has been observed when started in the first weeks of life.[ncbi.nlm.nih.gov]
Prognosis
- 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]
- Early liver transplantation should be considered as an option for infants with certain inherited metabolic disorders with poor prognosis, such as tyrosinemia type I, who fail to respond to medical therapy.[ncbi.nlm.nih.gov]
- Thus, the elucidation of the pathogenesis of this disease has led to the possibility that, if a reliable newborn screening method could be developed, the prognosis of these patients would be improved.[ncbi.nlm.nih.gov]
- Prognosis The controlled diet results in lowering of plasma tyrosine levels and rapid resolution of the oculocutaneous manifestations. However, the extent to which this controlled diet prevents the CNS involvement is unclear.[orpha.net]
- 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]
Etiology
- 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]
- Such data more firmly establish an etiologic relationship between the pathway intermediates and the mutational events they cause.[emedicine.medscape.com]
Epidemiology
- 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]
- 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]
- 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]
- 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]
- 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]
Sex distribution
Age distribution
Pathophysiology
- 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]
- This could play a role in the pathophysiology of the neuropsychological impairments in HT1 patients and may have therapeutic implications.[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]
- Type III tyrosinemia can be diagnosed by detection of a mutation in HPD in cultured fibroblasts. [3] Pathophysiology of metabolic disorders of tyrosine, resulting in elevated levels of tyrosine in blood.[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]
Prevention
- Initiation of a tyrosine-restricted and phenylalanine-restricted diet in infancy is most effective in preventing cognitive impairment.[ncbi.nlm.nih.gov]
- Programmatic and methodological barriers were identified that prevent widespread adoption of SUAC measurements in NBS laboratories.[ncbi.nlm.nih.gov]
- 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]
- The inability to predict or prevent significant complications of tyrosinemia and the favorable outcome from transplantation lead us to recommend liver transplant for all patients with tyrosinemia type I by 12 months of age.[ncbi.nlm.nih.gov]
- Early diagnosis and intervention with diet control are crucial for preventing permanent visual and developmental deficits. Corneal deposits can be one of the parameters in monitoring the efficacy of diet control.[ncbi.nlm.nih.gov]
References
Article
- 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.