Tyrosinemia Type-1 (TYR I)

Background

Elevated blood tyrosine levels are seen in three inherited disorders of tyrosine metabolism. Tyrosinemia Type I was described in 1957 and is caused by deficiency of fumarylaceto-acetate hydrolase (FAH). While a predominance of patients are of French Canadian or Scandinavian decent, people from other ethnic groups have also been diagnosed. Overall, TYR I is estimated to occur in less than 1 in 100,000 live births but is as common as 1 in 12,500 in French Canadians.

Clinical

TYR I usually presents in the first few months of life with progressive hepatorenal symptoms. Infants exhibit failure-to-thrive, hepatomegaly, liver dysfunction, together with metabolic acidosis and electrolyte disturbances due to renal tubular dysfunction (renal Fanconi syndrome). Diminished biosynthetic function of liver, which results in decreased clotting factors and a bleeding diathesis, often precedes large elevations in serum transaminases. Liver disease progresses to cirrhosis, hepatic failure, and death in undiagnosed patients. At any time, patients may develop acute hepatic crises with ascites, jaundice, and gastrointestinal bleeding. Neurologic episodes of painful paresthesias, weakness, paralysis, and respiratory insufficiency occur. There is a high risk for development of hepatic nodules and hepatocellular carcinoma. Most untreated patients die in infancy or early childhood. Patients with Type I disease do not have intellectual disability.

Testing

Tyrosine and succinylacetone are readily measured in a newborn screening dried blood spot using tandem mass spectrometry. Also the Tyr/Cit ratio has been found informative for TYR I. Mild to moderate elevations of tyrosine that decrease and become normal with follow-up testing is consistent with transient tyrosinemia of the newborn. This transient elevation is a pattern associated with liver immaturity or dysfunction.

Tyrosine and succinylacetone are readily measured in a newborn screening dried blood spot using tandem mass spectrometry. Also the Tyr/Cit ratio has been found informative for TYR I. Mild to moderate elevations of tyrosine that decrease and become normal with follow-up testing is consistent with transient tyrosinemia of the newborn. This transient elevation is a pattern associated with liver immaturity or dysfunction.

Treatment

Normalization of the tyrosine level is hastened by dietary supplementation with vitamin C. Patients with Type I disease must be treated aggressively with dietary restriction of tyrosine and phenylalanine, and administration of 2(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). This drug inhibits 4HPPD and lowers tyrosine metabolites that are responsible for much of the Type I morbidity. Liver transplantation is a cure for patients with Type I disease, providing normal FAH activity.

Because the diagnosis and therapy of tyrosinemia is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

Inheritance

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.