Hereditary Tyrosinemia

Tyrosinemia (or "Tyrosinaemia") is an error of metabolism, usually inborn, in which the extent cannot completely break down the amino rough tyrosine. Symptoms include liver and reins disturbances and intellectual retardation. Untreated, tyrosinemia can be deadly.

Enter the shape, color, or imprint of your prescription or OTC medicate. Our pill identification tool will exhibit image that you can acquire to your pilule.

If you chooser "Keep me signed in on this electronic computer", you can stay signed in to WebMD.com on this computer for up to 2 weeks or until you sign out. This means that a cookie will stay on your information processing system even when you exit or close your browser which may reduce your levels of privacy and carelessness. You should never choice this alternative if you're using a publicly getatable electronic computer, or if you're sharing a computer with others. Even if you select this option there are some characteristic of our site that still direct you to log in for privacy ground.

Tyrosinemia type I is a uncommon autosomal recessive genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needful for the end destroy down of the amino rough tyrosine. Failure to rightly break down Tyr direction to anomalistic accumulation of Tyr and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central spirited system. Symptoms and material findings combined with tyrosinemia type I appear in the first months of world and include failure to cheap importance and grow at the expected valuation (deterioration to boom), fever, flux, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the epidermatous and the whites of the view (jaundice). Tyrosinemia semblance I may progress to more serious complications such as satirical liver disease, cirrhosis, and hepatocarcinoma if port untreated. Treatment with nitisinone and a flame-tyrosine diet should enter as quick as possible after the diagnosis is fix.

This is an difficult of a report from the National Organization for Rare Disorders (NORD). A copy of the completed detail can be downloaded free from the NORD website for chronicle users. The complete report contains additional message including symptoms, suit, affected population, related distemper, flag and investigational therapies (if available), and references from medical belles-lettres. For a full-text ver. of this topic, go to www.rarediseases.org and catch on Rare Disease Database under "Rare Disease Information".

My WebMD Sign In, Sign Up My WebMD Sign In Please enter email address Enter your password Keep me signed in on this computer Show more Information If you opt "Keep me prognostic in on this electronic computer", you can remain mark in to WebMD.com on this data processor for up to 2 weeks or until you sign out. This indicate that a cookie will stay on your computer even when you exit or close your browser which may conquer your just of privacy and ease. You should never select this choice if you're using a publicly accessible computer, or if you're division a electronic computer with others. Even if you select this wishing there are some features of our situation that still require you to rock in for privacy argument. Forget your password? Having trouble signing in? Why should Isign up for WebMD? With a WebMD Account you can: Track your interval to weight detriment success Manage your class's vaccinations Join the conversation See more benefits Sign Up.

My WebMD Sign In Please insert email betake Enter your password Keep me token in on this computer Show more Information If you chooser "Keep me signed in on this computer", you can stay token in to WebMD.com on this computer for up to 2 weeks or until you sign out. This indicate that a cookie will stay on your data processor even when you outgang or close your browser which may abate your direct of privateness and defense. You should never select this option if you're using a openly accessible computer, or if you're sharing a data processor with others. Even if you choice this option there are some features of our place that still require you to log in for privacy reasons. Forget your password? Having trouble signing in? Why should Isign up for WebMD? With a WebMD Account you can: Track your way to weight detriment success Manage your house's vaccinations Join the colloquy See more use Sign Up.

My WebMD Sign In Please enter email woo Enter your password Keep me omen in on this computer Show more Information If you selected "Keep me signed in on this computer", you can stay emblem in to WebMD.com on this computer for up to 2 weeks or until you omen out. This means that a cookie will remain on your information processing system even when you departure or close your browser which may reduce your straightforward of privacy and security. You should never select this alternative if you're second-hand a publicly available computer, or if you're sharing a electronic computer with others. Even if you choose this option there are some shape of our place that still require you to log in for privacy reasons. Forget your pw? Having trouble signing in?.

Keep me signed in on this computer Show more Information If you select "Keep me signed in on this computer", you can stay type in to WebMD.com on this computer for up to 2 weeks or until you sign out. This abject that a cookie will stay on your data processor even when you death or conclude your browser which may lower your clear of intimity and security. You should never select this wishing if you're using a openly accessible computer, or if you're sharing a computer with others. Even if you select this option there are some form of our site that still require you to log in for secret reasons.

Show more Information If you opt "Keep me presage in on this computer", you can support presage in to WebMD.com on this computer for up to 2 weeks or until you token out. This means that a cookie will stay on your information processing system even when you exit or confine your browser which may reduce your levels of privacy and safety. You should never choice this privilege if you're using a publicly accessible information processing system, or if you're sharing a computer with others. Even if you select this alternative there are some shape of our place that still prescribe you to rock in for solitude consideration.

For a Complete Report: This is an abstract of a report from the National Organization for Rare Disorders (NORD). A transcript of the entire report can be copy liberated from the NORD website for registered users. The complete report contains additional notice contain symptoms, causes, affected population, related disarrangement, average and investigational therapies (if available), and references from medicinal science. For a full-text ver. of this topic, go to www.rarediseases.org and click on Rare Disease Database under "Rare Disease Information".

Sign Up! 6-Week Challenges Want to know more? Eat Better Challenge - No diets here. One fresh sound custom, one step at a delay. Get Up and Go Challenge - Get inhaled and hold motivated. Mood Boost Challenge - Fight the blahs, diminish significance, and be happy. I have read and comport to WebMD's Privacy Policy. Enter locule phone number - - Entering your ameba phone numerousness and importunate submit indicates you agree to receive SMS messages from WebMD narrated to this challenge. WebMD is utilizing a 3rd interest seller, CellTrust, to provide the messages. You can opt out at any age. Standard text rates devote Each object lasts for 6 weeks. You will receive 2 text messages per week for a sum of 12 topic messages. If you emblem up for more than one object, you’ll receive more than 12 text messages in a hebdomad. You can opt out at any time by following the instructions in each text express. You will retain a text messenger directly from WebMD’s cell service provider confirming your opt out suit. Each censure lasts for 6 weeks. You will receive 2 text messages per sennight for a total of 12 text messages. If you sign up for more than one challenge, you’ll receive more than 12 message messages in a hebdomad. You can opt out at any time by following the instructions in each text telegram. You will admit a text message directly from WebMD’s cell service caterer confirming your opt out request.

- - Entering your cell phone number and pressing submit discover you harmonize to receive text messages from WebMD told to this defiance. WebMD is utilizing a 3rd partial vendor, CellTrust, to supply the messages. You can opt out at any time. Standard text rates incline.

Entering your cell phone number and pressing submit particularize you agree to receive text messages from WebMD related to this challenge. WebMD is utilizing a 3rd party vendor, CellTrust, to condition the messages. You can opt out at any repetition.

Reference

Tyrosinemia, Hereditary. Retrieved on September 30, 2013, from http://children.webmd.com/tyrosinemia-hereditary.

Tyrosinemia, Type II | Hereditary Ocular Diseases. (2013). Retrieved on September 30, 2013, from http://disorders.eyes.arizona.edu/disorders/tyrosinemia-type-ii.

Tyrosinemia. (2013). Retrieved on September 30, 2013, from http://en.wikipedia.org/wiki/Tyrosinemia.

Hereditary Tyrosinaemia Type I

First, what is hereditary tyrosinemia type ITyrosine is a non- essential amino acids the human body , the main sources include dietary intake and phenylalanine (phenylalanine) metabolism of the intermediate product. When elevated plasma tyrosine , can be called high tyrosinemia (hypertyrosinaemia; tyrosinaemia), it causes may be due to an error from the primary metabolism , or by some other reasons caused by the liver caused by . However, due to the high Tyrosinemia cause liver damage , but many of the renewal of liver disease may also cause high Tyrosinemia , not easy to distinguish between the two . Based on past studies indicate that high Tyrosinemia associated with at least three enzymes : tyrosine transaminase ? (Tyrosine aminotrasferase; TAT), ρ- hydroxy - phenyl - Coke grape acid oxidation ? (Ρ- hydroxyphenylpyruvate dioxygenase; 4HPPD) and fumaric acid amide hydrolysis of acetylcholine ? (fumarylacetoacetate hydrolase; FAH), which , TAT lack can cause eye and skin high Tyrosinemia called tyrosinemia type II (Tyrosinaemia type II), also known as Richner-Hanhart syndrome (Richner-Hanhart syndrome), the main features of palms soles horny albinism (palmoplantar keratosis). The lack 4HPPD generates many abnormal metabolites, including the ρ- hydroxy - phenyl - Coke gluconic acid , ρ- hydroxy - phenyl - naphthalene acid and ρ- hydroxy - phenyl - naphthalene acetic acid , this is also known as casein acid aciduria . The lack of FAH will result in liver and kidney disease, known as tyrosinemia type I (Tyrosinaemia type I), also called tyrosine disease (tyrosinosis), can be divided into acute and chronic are two, the present the focus of discussion posts .
Premature newborns often temporary Tyrosinemia (Trainsient neonatal tyrosinaemia), full-term newborns may occasionally be seen . This may be a premature newborn 4HPPD or temporarily lacking , the high amount of phenylalanine and tyrosine intake, or caused by vitamin C deficiency . Such defects as the baby grows , 4HPPD matured and improved , but also by taking vitamin C and quickly corrected.
Biochemical mechanisms :Hereditary tyrosinemia type I is mainly caused because of lack of FAH . Throughout the tyrosine metabolized fumarate (fumarate) and acetoacetic acid (acetoacetate) by a total of five ? Catalyzed reaction steps :

1 by transglutaminase to form ρ- hydroxyphenyl pyruvate (ρ-hydroxyphenylpyruvate).(2) containing three carbon atoms and branched chain transfer the simultaneous oxidation and decarboxylation to form a black acid (homogentisate).3 Connect the black oxidized to maleic acid amide acetylsalicylic acid alone (maleylacetoacetate).4 would maleic acid amide acetoacetate single row into the role of heterogeneous acetoacetic acid amide fumarate (fumarylacetoacetate).5 of fumaric acid amide hydrolysis of acetylcholine fumaric acid and acetylsalicylic acid.FAH in a fifth reaction. When FAH deficiency, the entire tyrosine metabolism will be hindered , making fumaric acid amide will be a substantial accumulation of acetylcholine , maleic acid mono amide acetylsalicylic acid may also be affected and accumulate in the body , causing liver and kidney damage . These metabolites will be restored (reduce) and go carboxyl (decarboxylate) into succinyl acetone (succinylacetone; SA), and gathered in the patient's plasma and urine. Therefore, the concentration of SA in vivo testing patients , the diagnosis can be used as an important basis for high Tyrosinemia . Further, since the metabolic suspension , may also cause ? - Hydroxyphenyl pyruvic acid and its derivatives in vivo accumulation .
FAH gene is located on the human body are known to 15th on the long arm of chromosome (15q23-q25), is autosomal recessive . Liver cells for patients for sequencing DNA sequence analysis showed that 34 point mutations related to lack of FAH .
Second, the clinical featuresI. Acute TyrosinemiaThis baby will have a rapid and fulminant course of the disease , if untreated , the patient will die quickly . Seizures usually 1-6 months old, patients often have loss of appetite , vomiting , diarrhea, bloating , and other symptoms of low blood sugar , will cause growth retardation , anxiety , fever, and hepatomegaly phenomena , while there will be black stools, vomiting blood, urine , and congestion and other hemolytic performance, then cause renal dysfunction (renal tubular dysfunction). Because the liver lesions occur , making the patient began to emerge rickets (rickets), hepatosplenomegaly and other symptoms. Some patients have neurological diseases and low tension phenomenon. These neurological disease may be accompanied by more serious complications , such as acute intermittent sometimes like ? Slightly deposition disease porphyria (acute intermittent porphyria) of symptoms , nerve endings in muscle weakness caused by disease and hypertension . As the disease intensifies, jaundice , edema , abdominal effusion, drowsiness , coma , liver failure , and even death phenomenon will occur .
II. Chronic TyrosinemiaMost of the children with chronic tyrosinemia in a developed symptoms after age . Growth retardation, gastrointestinal symptoms , progressive liver cirrhosis, kidney impairment and multiple clinical manifestations are rickets . Early in the disease may be elevated tyrosine , and later will exhibit methionine (methionine) is increased. Usually die before the age of 10 , autopsies often visible liver tumors.
Third, the clinical diagnosisI. prenatal1 if the parents known to cause high Tyrosinemia point mutations , amniotic fluid cells can be pumped pregnant women , the analysis of gene mutations .(2) can be detected in amniotic fluid concentrations of SA to see if too high.3 Take amniotic fluid cells or chorionic pregnant women , to be multiplication culture . Subject to collect a certain number of cells , the measurement of the activity of intracellular FAH , FAH see if there is a lack of the phenomenon.
II. Blood testHigh Tyrosinemia current test method is the most credible quantitative blood and urine SA and its precursor concentrations. This approach, while sharp, but there is still a small number of patients with low concentration of SA , at this time , it is necessary to detect the FAH activity in cultured cells as a diagnostic aid . Subject variability of genes , cultured cells of a healthy individual may also occur a phenomenon FAH low activity . Similarly , the patient's liver specimen cell culture may also be due to a genetic response (reversed) in the case , so that to obtain a high activity of the illusion of FAH . Therefore , FAH enzyme activity assay is used as a diagnostic reference only , and not as the sole diagnostic credentials.
In addition to the concentration of SA can be used as a diagnostic tool high Tyrosinemia , some biochemical aspects of testing may also apply to general patients . For example: serum tyrosine concentration will increase, but the concentration of methionine were not significantly improved. Urine ρ- hydroxy - phenyl - Coke gluconate , ρ- hydroxy - phenyl - Coke lactic acid and ρ- hydroxy - phenyl - Coke acetic acid concentration will increase . When the renal tubular damage occurs , it will show Fanconi 's syndrome (Fanconi syndrome), which means in the urine with high amounts of amino acids, glucose and phosphate. When the liver cells are destroyed, and affects protein synthesis also occurs when a number of diverse biochemical manifestations, can be used as a basis for diagnosis . For example: vitamin K dependent coagulation factors in patients with acute concentration is quite high , and chronic disease in vivo concentration is not normal . Relative to other liver enzyme activity , the patients in vivo activity of γ-Glutamyltransferase will increase . α-fetoprotein concentration in vivo acute patients has increased significantly , but in chronic patients are showing normal concentrations.
Fourth, clinical treatmentI. NTBC treatment (NTBC treament)NTBC (2 - (2-nitro-4-trifluoro-methylbenzoyl) -1,3-cyclo-hexanedione) is a good 4HPPD inhibitors can prevent ρ- hydroxyphenyl pyruvic acid into black , to reduce the generation of SA , the Last used to treat high Tyrosinemia approach. According to the research report: patient daily oral 0.6 mg / kg of NTBC , in addition to ρ- hydroxyphenyl pyruvic acid and tyrosine concentrations will increase , other biochemical abnormalities will become normal, and the clinical symptoms will play improvement of access . NTBC also be used to treat the neurological aspects of this and similar ? Slightly porphyria deposition disease symptoms. As the concentration of tyrosine as the use NTBC increase, therefore, the control diet are necessary .
Prolonged use of NTBC related research has been discussed , in particular the incidence of liver cancer among NTBC relevance, currently inconclusive. The earlier use of NTBC, is less prone to the more severe abnormalities . So far , NTBC no reports of any side effects .
II. Liver transplant (Liver Transplantation)Stolen goods to the liver transplant to treat first type high Tyrosinemia about 10 years of development schedule , as this type of patients will have the serious liver damage , so when the recipient if the liver has Contributors the normal performance when patients lack an enzyme phenomena can be improved , blood and urine is not normal metabolites will disappear. Get the disease after liver transplant can be a normal diet, does not require special control of tyrosine and phenylalanine intake. Even so , the patient is still in the urine will increase the concentration of SA , presumably due to the kidney caused the problem . Liver transplant kidneys after prolonged prognosis remains unclear.
III. Diet (Dietary treament)Diet control is used to treat high Tyrosinemia first method , which is to limit the concept of tyrosine and phenylalanine intake so low that only needed to provide normal growth . Such foods must come from a special recipe , mainly using protein hydrolyzate or without amino acids tyrosine and phenylalanine mixture , and then add a small amount of natural protein to supplement tyrosine and phenylalanine appropriate . When a patient of tyrosine and phenylalanine , respectively, the daily intake maintained at 15-20 mg / kg , the concentration of SA in vivo is difficult to be detected. With the control diet , because the resulting tubular dysfunction symptoms almost completely back to normal . However, liver disease and malignant tumors can not take this to generate access to treatment and prevention , so when the liver is severely damaged or tumors , such as liver transplants still need to be contacted by other methods such as improved condition .
IV. Supportive treatment (Supportive treament)For acute onset patients, supportive treatment is necessary. Patients often lack potassium and phosphate , therefore, need timely and appropriate supplement. In addition , coagulation factors, calcium , albumin , phosphate , electrolyte and acid-base balance of all need to be carefully monitored and corrected. When the patient is in acute cases, tyrosine and phenylalanine intake must be reduced to a minimum as much as possible . Increase vitamin D used to treat rickets ; patients if infection, infection control and needs to be addressed immediately .

Neurologic crises in hereditary tyrosinemia

Abstract

Hereditary tyrosinemia results from an inborn error in the final step of tyrosine metabolism. The disease is known to cause acute and chronic liver failure, renal Fanconi's syndrome, and hepatocellular carcinoma. Neurologic manifestations have been reported but not emphasized as a common problem. In this paper, we describe neurologic crises that occurred among children identified as having tyrosinemia on neonatal screening since 1970. Of the 48 children with tyrosinemia, 20 (42 percent) had neurologic crises that began at a mean age of one year and led to 104 hospital admissions. These abrupt episodes of peripheral neuropathy were characterized by severe pain with extensor hypertonia (in 75 percent), vomiting or paralytic ileus (69 percent), muscle weakness (29 percent), and self-mutilation (8 percent). Eight children required mechanical ventilation because of paralysis, and 14 of the 20 children have died. Between crises, most survivors regained normal function. We found no reliable biochemical marker for the crises (those we evaluated included blood levels of tyrosine, succinylacetone, and hepatic aminotransferases). Urinary excretion of delta-aminolevulinic acid, a neurotoxic intermediate of porphyrin biosynthesis, was elevated during crises but also during the asymptomatic periods. Electrophysiologic studies in seven patients and neuromuscular biopsies in three patients showed axonal degeneration and secondary demyelination. We conclude that episodes of acute, severe peripheral neuropathy are common in hereditary tyrosinemia and resemble the crises of the neuropathic porphyrias.


Source Information

Department of Genetics, Hopital Sainte Justine, Montreal, PQ, Canada.




This article has been cited by other articles:


Nakamura, K., Tanaka, Y., Mitsubuchi, H., Endo, F. (2007). Animal Models of Tyrosinemia. J. Nutr. 137: 1556S-1560S [Abstract] [Full Text]
Burns, T. M., Ryan, M. M., Darras, B., Jones, H. R. Jr (2003). Current Therapeutic Strategies for Patients With Polyneuropathies Secondary to Inherited Metabolic Disorders. Mayo Clin Proc. 78: 858-868 [Abstract]
Evans, A. (2002). An Infant with Otitis Media and Abdominal Distension. CLIN PEDIATR 41: 537-541
Aponte, J. L., Sega, G. A., Hauser, L. J., Dhar, M. S., Withrow, C. M., Carpenter, D. A., Rinchik, E. M., Culiat, C. T., Johnson, D. K. (2001). Point mutations in the murine fumarylacetoacetate hydrolase gene: Animal models for the human genetic disorder hereditary tyrosinemia type 1. Proc. Natl. Acad. Sci. USA 98: 641-645 [Abstract] [Full Text]
Mitchell, G. (1996). Bad guy makes good: Inhibition of 4-Hydroxyphenylpyruvate Dioxygenase by 2-(2-Nitro-4-trifluoromethyl benzoyl)-cyclohexane-1,3-dione and 2-(2-Chloro-4- methanesulfonylbenzoyl)-cyclohexane-1,3-dione Ellis MK, Whitfield AC, Gowans LA, Auton TR, McLean Provan W, Lock EA and Smith LL Toxicology and Applied Pharmacology, 1995; 133: 12-19. Hum Exp Toxicol 15: 179-181
Grompe, M., St.-Louis, M., Demers, S. I., Al-Dhalimy, M., Leclerc, B., Tanguay, R. M. (1994). A Single Mutation of the Fumarylacetoacetate Hydrolase Gene in French Canadians with Hereditary Tyrosinemia Type I. NEJM 331: 353-357 [Abstract] [Full Text]
Grompe, M, al-Dhalimy, M, Finegold, M, Ou, C N, Burlingame, T, Kennaway, N G, Soriano, P (1993). Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice.. Genes Dev. 7: 2298-2307 [Abstract]
Bateman, R. L., Bhanumoorthy, P., Witte, J. F., McClard, R. W., Grompe, M., Timm, D. E. (2001). Mechanistic Inferences from the Crystal Structure of Fumarylacetoacetate Hydrolase with a Bound Phosphorus-based Inhibitor. J. Biol. Chem. 276: 15284-15291 [Abstract] [Full Text]

Hereditary tyrosinemia type I. Self-induced correction of the fumarylacetoacetase defect.

Abstract
Two Norwegian patients with chronic tyrosinemia type I showed > 50% residual fumarylacetoacetase activity in liver samples obtained during liver transplantation. The enzyme characteristics of both patients were comparable with those of a normal control. Immunohistochemistry on liver sections from these patients and from three other Norwegian tyrosinemia patients revealed a mosaicism of fumarylacetoacetase immunoreactivity corresponding completely or partly to some of the regenerating nodules. This appearance of enzyme protein is presumably induced by the disease process. The mechanism involved remains unclear and could be caused by a genetic alteration, regained translation of messenger RNA, or to enhanced stability of an abnormal enzyme.

Hereditary Tyrosinemia type I

Hereditary Tyrosinemia type I (HT1) is caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), which functions in the last step of the tyrosine breakdown cascade. Tyrosinemic patients suffer from progressive liver failure during infancy, kidney damage and early development of hepatocellular carcinoma. The substrate of FAH, fumarylacetoacetate (FAA) is thought to be hepatotoxic and mutagenic.
HT-1 patients are currently treated with NTBC, a drug blocking tyrosine catabolism upstream of FAH, thereby preventing accumulation of the toxic metabolite FAA. Unfortunately patients still develop hepatocellular carcinoma (HCC), despite the NTBC treatment.

In our lab we have mice that are FAH-deficient and have a neonatal lethal phenotype that can be rescued by treating the pregnant and nursing female with NTBC. Withdrawing adult FAH-deficient mice from NTBC elicits the HT1 phenotype. Without treatment these mice die within 4-8 weeks. FAH-deficient mice receiving life-long treatment with 1 mg/kg NTBC per day do develop HCC after 8-15 months.

When treating FAH-deficient mice on NTBC with homogentisic acid FAA, a toxic metabolite, can accumulate again. These mice become very ill within 4 hours and will die of acute liver damage. When treating FAH-deficient mice that were withdrawn from NTBC for 15 days, with the same dose of HGA these mice survive this lethal dose of HGA. FAH-deficient mice withdrawn from NTBC seem to have developed a resistancy to cell death caused by HGA.

Failure of cell-death programs, for example as a result of resistance to HGA, may lead to accumulation of damaged cells and enhance the risk for cancer. The goal of this project is to investigate the different pathways leading to cell death in our mouse models.

Theses:

Marjanka Luijerink - Novel insights into the pathogenesis of Hereditary Tyrosinemia Type 1. 16 November 2004
Saskia Jacobs - Hereditary Tyrosinemia type 1 revisited. 1 November 2005

Involvement of Endoplasmic Reticulum Stress in Hereditary Tyrosinemia Type I*

Anne Bergeron, Rossana Jorquera, Diana Orejuela, and Robert M. Tanguay1
From the Laboratory of Cell and Developmental Genetics, Department of Medicine, Centre de Recherche sur la Fonction, la Structure, et l'Ingénierie des Protéines, Pavillon Marchand, Université Laval, Ste-Foy, Québec G1K 7P4, Canada

Hereditary tyrosinemia type I (HTI) is the most severe disease of the tyrosine degradation pathway. HTI is caused by a deficiency of fumarylacetoacetate hydrolase (FAH), the enzyme responsible for the hydrolysis of fumarylacetoacetate (FAA). As a result, there is an accumulation of metabolites such as maleylacetoacetate, succinylacetone, and FAA. The latter was shown to display mutagenic, cytostatic, and apoptogenic activities and to cause chromosomal instability. Herein, we demonstrate that FAA also causes a cellular insult leading to the endoplasmic reticulum (ER) stress signaling. Treatment of V79 Chinese hamster lung cells with an apoptogenic dose of FAA (100 µM) causes an early induction of the ER resident chaperone GRP78/BiP and a simultaneous phosphorylation of the eIF2. FAA treatment also causes a subsequent induction of the proapoptotic CHOP (CEBP homologous protein) transcription factor as well as a late activation of caspase-12. Data obtained from fah–/– mice taken off the therapeutic 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3 cyclohexanedione drug are similar. However, in this mouse model, there is also an increase in proteasome activity indicative of ER-associated degradation. This difference observed between the two models may be due to the fact that the murine model measures the effects of all metabolites accumulating in hereditary tyrosinemia type I as opposed to the cellular model that only measures the effects of exogenous FAA.

What are "Orphan Drugs"?

What are "Orphan Drugs"?

Orphan products are drugs, biologics, or other therapeutics that treat diseases that affect fewer than 200,000 people in the United States.

What is the Orphan Drug Act of 1983?

The U.S. Orphan Drug Act (1983) gives incentives to pharmaceutical companies to develop drugs, biologics, or other therapeutics that will treat diseases that affect fewer than 200,000 people in the United States. The orphan drug law offers tax breaks and a seven-year exclusivity on product sales to induce companies to undertake the development and manufacturing of such product, which otherwise might not be profitable because of the small potential market. (Of the 5,000 diseases covered under the act, 47% affect fewer than 25,000 people.) The law has led to the introduction of over 200 valuable new products for the treatment of rare diseases.



Hereditary Tyrosinemia Type I FAQ's

• What is it? • Hereditary Tyrosinemia Type I
• General Questions • Technical Questions
• Administration & Dosage • Side Effects



What is Hereditary Tyrosinemia Type I?

Hereditary Tyrosinemia Type I is a rare genetic metabolic disorder characterized by lack of a liver enzyme called fumarylacetoacetate hydrolase (FAH), which is needed to break down the amino acid tyrosine. Failure to properly break down a nutrient found in everyone's diet, tyrosine, leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system.
Symptoms and physical findings associated with Hereditary Tyrosinemia Type I include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Hereditary Tyrosinemia Type I may progress to more serious complications such as severe liver disease. Hereditary Tyrosinemia type one is inherited as an autosomal recessive trait. Unless the patient receives a liver transplant or the drug Orfadin TM, the patient could die within the first year of life.

GENERAL (questions 1-10)

1. What is the indication?

Orfadin® capsules (nitisinone) are indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1

2. Contraindications?

None Known

3. Any Drug Interactions?

No drug-drug interaction studies have been conducted with nitisinone

4. What is the chemical designation for Orfadin® (nitisinone)?

2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione

or

C 14 H 10 F 3 NO 5

5. How does Orfadin® work?
Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme upstream of FAH in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites Succinylacetone and Succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation of 5-Aminolevulinate, a neurotoxin responsible for the porphyric crisis characteristic of HT-1.


6. How were the clinical trials done?

An open-label study conducted by 96 investigators at 87 hospitals in 25 countries.

7. How quickly does Orfadin® work?

The median time to normalization was 0.3 months for the excretion of succinylacetone in urine and for porphobilinogen synthase (PBG) activity of erythrocytes. Plasma concentrations of succinylacetone normalized in a median time of 3.9 months


8. How does Orfadin® affect the overall survival of HT-1 patients?

Patients presenting with HT-1 under 2 months of age and treated with dietary restrictions alone had 2 and 4-year survival probabilities of 29% and 29%, respectively; HOWEVER- patients presenting with HT-1 under 2 months of age and treated with dietary restriction and nitisinone had 2 and 4-year survival probabilities of 88% and 88%, respectively in the study patients.

Additionally;
Patients historically presenting with HT-1 under 6 months of age and treated with dietary restriction alone had 2 and 4-year survival probabilities of 74% and 60%, respectively; HOWEVER- patients presenting with HT-1 under 6 months of age and treated with dietary restriction and ORFADIN® had 2 and 4 year survival probabilities of 94% and 94% respectively in the study patients.

9. What are the effects of Orfadin® treatment on the incidence of liver transplantation and death due to liver failure?

The long-term prognosis of patients treated with nitisinone wth regard to hepatic function is not yet known and long term studies are being conducted in Sweden.

The results of this clinical study suggest a market reduction (>75%) in the risk of early onset liver failure that characterizes the natural history of HT-1

10. How should Orfadin® be stored?

Store refrigerated, 2-8°C or 36-46°F


ADMINISTRATION AND DOSAGE (questions 11-18)

11. How is it dosed?

(Treatment should be initiated by a physician experienced in the treatment of hereditary tyrosinemia type 1) The dose of nitisinone should be adjusted in each patient. The recommended initial dose is 1mg/kg/day divided for morning and evening administration.

12. Can it be taken with food?

Since an effect of food is unknown, nitisinone should be taken at least one hour before a meal

13. How can it be given to infants and children too small to swallow a capsule?
For young children, capsules may be opened and the contents suspended in a small amount of water, formula, or apple sauce immediately before use

14. What kind of diet should I prescribe for the child?

A nutritionist skilled in managing children with inborn errors of metabolism should be employed to design a low-protein diet deficient in tyrosine and phenylalanine

15. How and when do you adjust (titrate) the dosage?

Treatment should lead to normalized porphyrin metabolism. Succinylacetone should not be detectable in urine or plasma.

If the biochemical parameters (except plasma succinylacetone) are not normalized within one month… the dose should be increased to 1.5 mg/kg/day. For plasma succinylacetone, it may take up to three months before the level is normalized after the start of nitisinone treatment.

16. What is the maximum recommended dose for all patients?

2 mg/kg/day

17. Are strict dietary restrictions enough?

Dietary restrictions of tyrosine and phenylalanine may improve liver and kidney function but does not prevent the progression of the disease.

18. Why is there a concern about patient taking Orfadin® needing to follow a strict dietary regimen?

Since nitisinone inhibits catabolism of tyrosine, use of this drug can result in elevated plasma levels of this amino acid. Treatment with nitisinone therefore, requires restriction of the dietary intake of tyrosine and phenylalanine to prevent the toxicity associated with elevated plasma levels of tyrosine


HEREDITARY TYROSINEMIA TYPE I (questions 19-23)


19. What are the clinical symptoms of hereditary tyrosinemia type 1?

• Progressive liver failure
• Increased risk of hepatocellular carcinoma
• Coagulopathy
• Painful neurologic crisis
• Renal tubule dysfunction resulting in rickets


20. What are the three types of hereditary tyrosinemia type 1?

Acute, subacute and chronic:

Most patients exhibit symptoms before 6 months of age with the acute form of the disease.

In the subacute form children present with symptoms between 6 and 12 months

Chronic form patients do not exhibit symptoms until after one year of age. These patients have a more gradual progression to liver failure but are at increased risk of developing hepatocellular carcinoma.

21. Who (or which form is) at risk for the painful porphyria-like neurologic crises?

Patients with all forms of the disease are at risk of painful porphyria-like neurologic crises, which occur in 5-20% of patients per year as apart of the natural history of the disorder

22. What is the upside of liver transplantation in HT-1 patient?

Liver transplant can correct most of the metabolic effects of the disorder except for the renal tubular dysfunction, which may be due to local production of toxic metabolites in the kidney

23. What is the downside of liver transplantation in HT-1 patient?

• availability
• cost
• a 5-25% retransplantation rate
• onerous drug regimen

TECHNICAL (questions 24-29)

24. Have pharmacokinetics/ drug metabolism studies been done in children?

No pharmacokinetics studies of nitisinone have been conducted in children or in HT-1 patients.

25. Are there concerns about using nitisinone in special populations?

The effects on the pharmacokinetics of nitisinone have not been studied in the following special populations:

• Geriatric: No studies/ no patients

• Gender: Not studied

• Race: Not studied

• Renal Insufficiency: Not studied

• Hepatic Dysfunction: Not studied


26. What is porphobilinogen synthase (PBG)?-

Porphobilinogen synthase (PBG) is one of the 8 requisite enzymes of heme biosynthesis. Abnormally elevated porphyrin levels and their precursors including PBG results in a group of disorders known as porphyrias. Deficiencies in PBG result in porphyria-like neurologic symptoms.

Porphobilinogen synthase is formed in the heme biosynthesis pathway by the conversion of aminolevulinic acid (ALA) into PBG. Succinylacetoacetone is a potent inhibitor of ALA thus a resulting in a deficiency of PBG.

27. How does Orfadin® affect porphyrin metabolism?

Porphyric crisis was observed in 0.3% cases per year. This compares to the incidence of 5-20% cases per year expected as part of the natural history of the disorder

28. What were the effects of Orfadin® on renal function?

At the one year visit, both urine excretion of amino acids and serum concentration of phosphate were within the reference range in studied patients

29. What is the significance of serum alpha-fetoprotein concentrations?

Increased alpha-fetoprotein may be a sign of inadequate treatment or may be indicative of hepatic malignancy.



SIDE EFFECTS (questions 30-35)

30. Are there Warnings for use of Orfadin®?

High Plasma Tyrosine Levels
Inadequate restriction of tyrosine and phenylalanine intake can result in elevations of plasma tyrosine. Plasma tyrosine levels should be kept below 500 μmol/L in order to avoid toxic effects. Toxic effects of elevate plasma tyrosine include:

Eyes
• corneal ulcers
• corneal opacities
• keratitis
• conjunctivitis
• eye pain
• photophobia

Skin
• painful hyperkeratotic plaques on the soles and palms

Nervous System
• various degrees of mental retardation
• developmental delay

Transient Thrombocytopenia and Leucopenia
3% of patients treated were observed to develop transient thrombocytopenia and leucopenia, while 1.5% developed both. Decreasing the dose, stopping treatment for observation were employed on various patients –all of whom normalized their platelet and white blood counts and continued on Orfadin®.

Platelet and white blood counts should be monitored regularly during treatment with Orfadin®


31. Are there Precautions for use of Orfadin®?

Ophthalmologic Care
• Slit-lamp examination of the eyes should be performed before initiation of nitisinone treatment
• Patients that become symptomatic need re-examination and measurement of plasma tyrosine concentration
• More restricted diet should be implemented if the plasma tyrosine level is above 500 μmol/L
• Nitisinone dosage should not be adjusted in order to lower the plasma tyrosine concentration, since HT-1 metaoblic defect may result in deterioration of the patient’s clinical condition

Risks of Porphyric Crises, Liver Failure and Hepatic Neoplasms
Patients were observed to suffer these afflictions during a median time of 22 months the clinical study as follows:

• Liver transplantation 13%
• Liver failure 7%
• Malignant hepatic neoplasms 5%
• Benign hepatic neoplasms 3%
• Porphyria 0.5%

Regular liver monitoring by imaging and laboratory tests including serum alpha-fetoprotein concentration is recommended

32. What about overdosage?

Accidental ingestion will result in elevated tyrosine levels, however, there is no information available on a specific treatment. Patients should be monitored for adverse events.

33. Are there any Drug/ Laboratory Test Interactions?

None Known

34. How about Carcinogenesis?

According to the Package Insert:
“Studies in animals have not been performed to evaluate the carcinogenic potential of nitisinone. Nitisinone was not mutagenic in the Ames test. In a single dose-group study in rats given 100 mg/kg/day (12 times the recommended clinical dose based on relative body surface area), reduced litter size, decreased pup weight at birth, and decreased survival of pups after birth was demonstrated.”

35. What were the adverse reactions observed during the study?

1% or Greater:

Liver and Biliary System-hepatic neoplasm 8%, liver failure 7%

Visual System- conjunctivitis 2%, corneal opacity 2%, keratitis 2%, photophobia 2%, blephraritis 1%, eye pain 1% and cataracts 1%

Hemic and Lymphatic- thrombocytopenia 3%, leucopenia 3%, porphyria 1%, epistaxis 1%

Skin and Appendages-pruritis 1%, exfoliative dermatitis 1%, dry skin 1%, maculopapular rash 1%, alopecia 1%

Less than 1%:

Death

Nervous System- seizures, brain tumor, encephalopathy, headache, hyperkinesia

Cardiovascular-cyanosis

Digestive System- abdominal pain, diarrhea, enanthema, gastritis, gastroenteritis, gastrointestinal hemorrhage, melena, tooth discoloration

Liver and Biliary System-elevated hepatic enzymes, hepatic function disorder, liver enlargement

Metabolic and Nutritional-dehydration, hypoglycemia, thirst

Resistance Mechanism Disorders- Infection, septicemia, otitis

Respiratory-bronchitis, respiratory insufficiency

Musculoskeletal-pathologic fracture

Female Reproductive- amenorrhea

Psychiatric- nervousness, somnolence