User:ShwethaJay/sandbox

Tyrosinemia Type I
Tyrosinemia type 1 is a rare genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed to break down the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system This condition is inherited in an autosomal recessive manner. It affects both boys and girls equally.

Genetics


Tyrosinemia type I is inherited as an autosomal recessive genetic condition.

Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder

Pathophysiology


Tyrosinemia type 1 is caused by mutations in the FAH gene. This gene is responsible for the production of the enzyme fumarylacetoacetate hydrolase. In the liver, enzymes break down tyrosine(an amino acid) in a five step process, resulting in molecules that are either excreted by the kidneys or used to produce energy or make other substances in the body. The FAH gene provides instructions for the fumarylacetoacetate hydrolase enzyme, which is responsible for the final step of tyrosine breakdown. Mutations in the FAH gene cause a decrease in the activity of one of the enzymes in the breakdown of tyrosine. As a result Fumarylacetoacetate accumulates in hepatocytes and proximal renal tubal cells and causes oxidative damage and DNA damage leading to cell death and dysfunctional gene expression which alters metabolic processes like protein synthesis and gluconeogenesis. The increase in fumarylacetoacetate inhibits previous steps in tyrosine degradation leading to an accumulation of tyrosine in the body.

Symptoms
Symptoms onset at infancy. Infants with tyrosinemia type I typically present with either the acute or chronic form of the disorder.

The acute form of tyrosinemia type I is present at birth or during the first months of life. This form of the disorder is more common and severe than the chronic form. Infants with the acute form exhibit rapid onset of symptoms usually beginning with failure to gain weight and grow at the expected rate (failure to thrive). Additional early symptoms include fever, diarrhea, bloody stools (melena), and vomiting. Affected infants may also exhibit an abnormally enlarged liver (hepatomegaly), a tendency to bruise easily, jaundice, lethargy, and/or irritability. In some cases, affected infants may develop a distinctive, cabbage-like odor.

Eventually infants with the acute form of tyrosinemia type I experience developmental delays, an abnormally enlarged spleen (splenomegaly), and accumulation of fluid (edema) in the abdomen (ascites). In many cases, the disorder rapidly progresses to acute life-threatening liver failure and blood clotting abnormalities (coagulopathy).

The chronic form of tyrosinemia type I occurs less frequently than the acute form and is characterized by a more gradual onset and less severe expression of the symptoms. Symptoms of tyrosinemia type I may not become apparent in infants with the chronic form of the disorder until after six months of age. Failure to thrive is often the first symptom. Additional symptoms include developmental delays and progressive scarring and impaired function (cirrhosis) of the liver resulting in chronic liver failure.

Many infants with tyrosinemia type I develop kidney (renal) abnormalities such as renal Fanconi syndrome, a rare disorder characterized by kidney dysfunction that often leads to progressive softening and weakening of the bone structure (rickets). Fanconi syndrome is also associated with episodes of vomiting, dehydration, weakness, and fever.

Diagnosis
Today, tyrosinemia type 1 is often diagnosed as a result of newborn screening. Most states now screen all newborns for tyrosinemia. Newborn screening for TT1 is performed by tandem mass spectrometry. Tandem mass spectrometry is an accurate way to measure newborn blood spot specimens for the presence of disease markers. If not detected by newborn screening, tyrosinemia type 1 may be suspected in infants who display failure to thrive and an enlarged liver during the first three months of life. Diagnosis may be confirmed through the detection of succinylacetone in the urine or decreased activity of the FAH enzyme in liver tissue or cultured fibroblasts.

Prenatal diagnosis of tyrosinemia type 1 is possible through detection of succinylacetone in the amniotic fluid or measurement of fumarylacetoacetase in amniotic fluid cells.

Treatements
MEDICAL TREATMENT: Nitisinone (Orfadin®), 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC), which blocks parahydroxyphenylpyruvic acid dioxygenase (p-HPPD), the second step in the tyrosine degradation pathway, prevents the accumulation of fumarylacetoacetate and its conversion to succinylacetone. Nitisinone treatment should begin as soon as the diagnosis of tyrosinemia type I is confirmed. Because nitisinone increases the blood concentration of tyrosine, dietary management with controlled intake of phenylalanine and tyrosine should be started immediately after diagnosis to prevent tyrosine crystals from forming in the cornea. If the blood concentration of phenylalanine becomes too low (<20 μmol/L), additional natural protein should be added to the diet. Prior to the availability of nitisinone, the only definitive therapy for tyrosinemia type I was liver transplantation, which now should be reserved for those children who have severe liver failure at presentation and fail to respond to nitisinone therapy or have documented evidence of malignant changes in hepatic tissue.

DIET: The diet is made up of foods that are very low in tyrosine and phenylalanine. This means your child will need to limit foods such as cow’s milk and regular formula. He or she will need to avoid meat, eggs and cheese. Regular flour, dried beans, nuts and peanut butter contain these amino acids and must also be limited.

Many vegetables and fruits have only small amounts of phenylalanine and tyrosine and can be eaten regularly in carefully measured amounts.

There are other medical foods such as special flours, pastas, and rice that are made especially for people with tyrosinemia 1. Some states offer help with payment, or require private insurance coverage for formula and other special medical foods.

BLOOD, URINE AND OTHER TESTS: Your child will have regular blood and urine tests to check:

Some experts suggest that children with tyrosinemia 1 have a CT scan or MRI scan of their liver once a year to check for scarring or cancer.
 * amino acid levels
 * the amount of succinylacetone
 * nitisinone level
 * liver and kidney function

LIVER TRANSPLANTATION: Before nitisinone was available, liver transplantation was one of the main treatments for tyrosinemia 1. Now, nitisinone can prevent or reverse many of the liver problems and decreases the risk of developing liver cancer. For most children, nitisinone will delay, and hopefully prevent, the need for liver transplant.

Liver transplantation is still an option for those children that show signs of liver cancer or liver failure. If you have questions, talk to your metabolic doctor or doctor about the benefits and risks of transplantation.