Hereditary tyrosinemia is a genetic inborn error of metabolism associated with severe liver disease in infancy. The disease is inherited in an autosomal recessive fashion which means that both parents must be carriers of the gene for the disease. In such families, there is a one out of four risk that pregnancies will produce an affected infant.
The clinical features of the disease tend to fall into two categories. In the so-called acute form of the disease, abnormalities appear in the first month of life. Babies may show poor weight gain, enlarged liver and spleen, distended abdomen, swelling of the legs and increased tendency to bleeding, particularly nose bleeds. Jaundice may or may not be prominent. Despite vigorous therapy, death from hepatic failure frequently occurs between three and nine months of age. Children with this form of disease are excellent candidates for liver transplantation.
Some children have a more chronic form of tyrosinemia with a gradual onset and less severe clinical features. In these, enlargement of the liver and spleen are prominent, the abdomen is distended with fluid, weight gain may be poor, and vomiting and diarrhea occur frequently. Affected patients usually develop cirrhosis and its complications. In older patients, there is an increased risk of liver cancer. These children also require liver transplantation.
The liver tests are often abnormal. Low serum albumin and clotting factors are frequently found. The transaminases may be mildly to moderately elevated, but the bilirubin is increased to a variable extent. Because of the biochemical defect, abnormal products may be measured in the urine which confirm diagnosis. These are parahydroxy phenylactic acid and parahydroxy phenylpyruvic acid. In addition, succinylacetone and succinylacetoacetate are found in the urine. There may be hypoglycemia (low blood sugar) and evidence of loss of certain substances in the urine including sugar, protein, and amino acids.
The basic biochemical defect is an abnormality in a key enzyme in the metabolism of an essential amino acid, phenylalanine. The enzyme is fumarylacetoacetate hydrolase (FAH) which is markedly reduced in affected patients. As a consequence, toxic metabolic products in the pathway by which phenylalanine is utilized build up and damage a variety of tissues, although the major findings occur in the liver and kidneys.
Prenatal diagnosis is possible and can be performed by measuring succinylacetone in the amniotic fluid or fumarylacetoacetate hydrolase (FAH) in amniotic fluid cells. This allows for genetic counseling and consideration of termination of pregnancy in affected infants.
Although treatment has not been shown to be of benefit, it is customary to place affected infants on diets low in phenylalanine, methionine and tyrosine. This will lead to normal blood amino acid levels which may be of some value. Strict attention to excellent nutrition, adequate vitamin and mineral intake, prevents nutritional deterioration and helps keep the patient as well as possible for transplantation. The most effective form of therapy at the present time is liver transplantation.
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