Hypertyrosinemia

ABSTRACT

• In humans, tyrosine is obtained from two sources, dietary intake and hydroxylation of phenylalanine. Tyrosine degradation occurs primarily in the cytoplasm of hepatocytes and is both glucogenic and ketogenic. Under most circumstances, the rate of tyrosine degradation is determined by the activity of tyrosine aminotransferase.

• Most inborn errors of tyrosine catabolism produce hypertyrosinemia. Hypertyrosinemia is also encountered in various acquired conditions, in particular severe hepatocellular dysfunction.

• Deficiency of cytoplasmic tyrosine aminotransferase (TAT) results in oculocutaneous tyrosinemia, characterized by palmoplantar keratosis and painful corneal erosions with photophobia (OMIM 276600). Half of reported patients have mental retardation. Ocular and cutaneous symptoms respond to dietary restriction of phenylalanine and tyrosine. Canine and mink models of TAT deficiency exist.

• Three different conditions have been associated with dysfunction of 4-hydroxyphenylpyruvate dioxygenase (4HPPD): hereditary 4-hydroxyphenylpyruvic acid dioxygenase (4HPPD) deficiency, hawkinsinuria, and transient tyrosinemia of the newborn.

• Primary 4HPPD deficiency (OMIM 276710) has been described in at least three patients, all of whom were neurologically abnormal. The biochemical phenotype showed hypertyrosinemia and elevated urinary excretion of 4-hydroxyphenyl derivatives. A mouse model of this condition has been described.

• Hawkinsinuria (OMIM 140350) is an autosomal dominant condition presumably caused by dysfunction of 4HPPD. It results in metabolic acidosis and failure to thrive in infancy. Hypertyrosinemia is minimal or absent. The presence in the urine of hawkinsin, an amino acid felt to be derived from an intermediate of the 4HPPD reaction, is diagnostic of this condition. Symptoms respond to dietary protein restriction and to the administration of ascorbate.

• Transient tyrosinemia (OMIM 276500) of the newborn results from a combination of 4HPPD immaturity, elevated dietary phenylalanine and tyrosine intake, and a relative ascorbate deficiency. Improvement is spontaneous but can be accelerated by the administration of ascorbate and by dietary protein restriction. Although most children with transient neonatal tyrosinemia are asymptomatic and have normal development, some adverse effect on development cannot be eliminated.

• A human maleylacetoacetate isomerase (MAI) cDNA has been cloned. No patients with clearly documented MAI deficiency have yet been identified.

• Hepatorenal tyrosinemia is an autosomal recessive disease caused by deficiency of fumarylacetoacetate hydrolase (FAH) (OMIM 276700). Symptoms are highly variable and include acute liver failure, cirrhosis, hepatocellular carcinoma, renal Fanconi syndrome, glomerulosclerosis, and crises of peripheral neuropathy. Hypertyrosinemia is present in most untreated patients. The presence of elevated levels of succinylacetone in plasma or urine is diagnostic for this condition. Most patients show a partial response to dietary restriction of phenylalanine and tyrosine. Hepatic transplantation cures the liver manifestations and prevents further neurologic crises. Patients treated with NTBC, an inhibitor of 4HPPD, have not developed acute hepatic or neurologic crises, but current data do not allow conclusions on the long-term risk of hepatocellular carcinoma in NTBC-treated patients. The human FAH gene has been cloned and mapped to chromosome 15 q23-q25. In hepatocytes of many patients, disease-causing mutations revert to the normal sequence. Such hepatocytes form nodules with normal FAH enzyme activity. Thirty-four different FAH mutations have been defined. Founder mutations ...