Tyrosinemia

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What is tyrosinemia?

Tyrosinemia is a genetic disorder characterized by elevated blood levels of the amino acid tyrosine, a building block of most proteins. Tyrosinemia is caused by the shortage (deficiency) of one of the enzymes required for the multistep process that breaks down tyrosine. If untreated, tyrosine and its byproducts build up in tissues and organs, which leads to serious medical problems.

There are three types of tyrosinemia, each with distinctive symptoms and caused by the deficiency of a different enzyme. Type I tyrosinemia is the most severe form of this disorder and is caused by a shortage of the enzyme fumarylacetoacetate hydrolase. Symptoms usually appear in the first few months of life and include failure to gain weight and grow at the expected rate (failure to thrive), diarrhea, vomiting, yellowing of the skin and whites of the eyes (jaundice), cabbagelike odor, and increased tendency to bleed (particularly nosebleeds). Type I tyrosinemia can lead to liver and kidney failure, problems affecting the nervous system, and an increased risk of liver cancer.

Type II tyrosinemia is caused by a deficiency of the enzyme tyrosine aminotransferase. This form of the disorder can affect the eyes, skin, and mental development. Symptoms often begin in early childhood and include excessive tearing, abnormal sensitivity to light (photophobia), eye pain and redness, and painful skin lesions on the palms and soles. About half of individuals with type II tyrosinemia are also mentally retarded.

Type III tyrosinemia is a rare disorder caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase. Characteristic features include mild mental retardation, seizures, and periodic loss of balance and coordination (intermittent ataxia).

About 10 percent of newborns have temporarily elevated levels of tyrosine. In these cases, the cause is not genetic. The most likely causes are vitamin C deficiency or immature liver enzymes due to premature birth.

How common is tyrosinemia?

Worldwide, type I tyrosinemia affects about 1 person in 100,000. This type of tyrosinemia is much more common in Quebec, Canada. The overall incidence in Quebec is about 1 in 16,000 individuals. In the Saguenay-Lac St. Jean region of Quebec, type 1 tyrosinemia affects 1 person in 1,846.

Type 2 tyrosinemia occurs in fewer than 1 in 250,000 individuals. Type 3 tyrosinemia is very rare; only a few cases have been reported.

What genes are related to tyrosinemia?

Mutations in the FAH, HPD, and TAT genes cause tyrosinemia.

In the liver, tyrosine is broken down in a five-step process to harmless molecules that are either excreted by the kidneys or used in reactions that produce energy. Mutations in the FAH, HPD, or TAT gene cause a shortage of one of the enzymes in this multistep process. The resulting enzyme deficiency leads to a toxic accumulation of tyrosine and its byproducts, which can damage the liver, kidneys, nervous system, or other tissues.

How do people inherit tyrosinemia?

This condition is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder each carry one copy of the altered gene but do not show signs and symptoms of the disorder.

Source: National Institutes of Health

Studies from Kumamoto University, Department of Pediatrics in the area of carcinoma cell biology described

"Disturbances in tyrosine metabolism lead to increased levels of succinylacetone and succinylacetoacetate. However, the mechanisms causing liver failure, cirrhosis, renal tubular dysfunction, and hepatocarcinoma are still unknown. Lethal albino deletion c14CoS mice and mice with target-disrupted Fah are models for HT I. They die in the perinatal period, although with a different phenotype from that seen in HT I in humans. In addition, 2 mouse strains that carry N-ethyl-N-nitrosourea-induced mutations in the Fah gene have been described. Mice with a splice mutation exhibit the milder features of the clinical phenotype. In mice that carry both Fah and 4-hydroxyphenylpyruvate dioxygenase gene mutations, administration of homogentisate results in rapid apoptosis of hepatocytes. Simultaneously, renal tubular epithelial cells are injured, resulting in Fanconi syndrome. These are central features of visceral injury in patients with HT I. Apoptosis of hepatocyte and renal tubular cells is prevented by the caspase inhibitors acetyl-Tyr-Val-Ala-Asp-CHO or acetyl-Asp-Glu-Val-Asp-CHO. Apoptosis of hepatocytes and renal tubular epithelial cells are central features of this disease. Alterations in gene expression found in the liver of patients with HT I are responsible for the pathogenesis of this disease, for example, acute liver failure. Therefore, gene expression analysis allows a better understanding of the specific pathogenesis. Cell fusion of hematopoietic stem cells with hepatocytes leads to liver regeneration after liver injury. This finding was possible after using the liver injury model of HT I in Fah null mice," wrote K. Nakamura and colleagues, Kumamoto University, Department of Pediatrics.

The researchers concluded: "Thus, animal models of tyrosinemia are unique and useful tools to reveal mechanisms of interest to both clinical and basic science."

Nakamura and colleagues published their study in the Journal of Nutrition (Animal models of tyrosinemia. Journal of Nutrition, 2007;137(6 Suppl 1):1556S-1560S; discussion 1).

For additional information, contact K. Nakamura, Kumamoto University Graduate School of Medical Science, Dept. of Pediatrics, Kumamoto 860-8556, Japan.

Publisher contact information for the Journal of Nutrition is: American Institute Nutrition, 9650 Rockville Pike, Bethesda, MD 20814, USA.

Keywords: Japan, Kumamoto, Carcinoma Cell Biology, Alternative Medicine, Carcinoma, Cell Biology, Oncology, Therapy, Treatment, Tyrosinemia.

This article was prepared by Biotech Business Week editors from staff and other reports. Copyright 2007, Biotech Business Week via NewsRx.com.