Master's in Genetic Counseling (MGC)

Tyrosinemia

The tyrosinemias are a group of autosomal recessive disorders of tyrosine metabolism. Transient neonatal tyrosinemia (resulting from a physiologic immaturity of 4-hydroxyphenylpyruvate dioxygenase [4HPPD]), type I tyrosinemia (fumarylacetoacetase hydroxylase [FAH] deficiency), type II tyrosinemia (tyrosine aminotransferase [TAT] deficiency), and type III tyrosinemia (4-hydroxyphenylpyruvate dioxygenase [4HPPD] deficiency) can all be detected by newborn screening, as each demonstrates elevated levels of tyrosine.

Clinical Features

Each type of tyrosinemia differs in its clinical presentation. Infants with neonatal tyrosinemia may present with lethargy, difficulty swallowing, impaired motor activity, and jaundice. Mild developmental and language delays, along with mild mental retardation, have been noted in untreated children. Neonatal tyrosinemia is the most common of this group of disorders.

Type I tyrosinemia may present as either an acute form or a chronic form depending on the amount of residual FAH enzyme activity. The more severe acute form presents with failure to thrive, vomiting, diarrhea, hepatomegaly, fever, jaundice, edema, and progressive liver disease that may result in death within the first year of life. The chronic form is similar but with milder features including chronic liver disease and Fanconi syndrome. Other noted features are hypertrophic obstructive cardiomyopathy, abdominal crises, hypertension, polyneuropathy, and hepatoma. Death usually occurs during the first decade of life. (OMIM)

Type II tyrosinemia is an oculocutaneous syndrome with eye findings that may be limited to lacrimation, photophobia, and redness. Long term effects on the eye may include corneal clouding, nystagmus, and glaucoma. The skin findings, which usually begin the same time as or after the eye lesions develop, may present as painful blisters on the palms and soles. The skin lesions may be difficult to distinguish from the more common forms of keratosis. Mental retardation, along with self mutilating behavior, fine motor coordination disturbances, and language deficits, have been noted. (OMIM)

Type III tyrosinemia is characterized by normal liver function, acute intermittent ataxia, seizures, drowsiness, and mild mental retardation. (OMIM)

Laboratory Tests

Screening for tyrosinemia is performed by determining the level of tyrosine in the dried filter paper blood spot. Elevated levels of tyrosine may be suggestive of tyrosinemia. A genetic/metabolic consultation is recommended for diagnostic testing and management of this disorder. Confirmatory testing may consist of a quantitative amino acid profile of both urine and blood. Neonatal tyrosinemia is characterized by elevated levels of phenylalanine and tyrosine. Type I tyrosinemia shows elevated levels of urine succinylacetone and nonspecific aminoaciduria. For confirmation, type I tyrosinemia also requires tissue analysis (fibroblasts, erythrocytes, lymphocytes or liver) for FAH activity. Elevated tyrosine only in urine and blood is characteristic of type II tyrosinemia. If type III tyrosinemia is present, urine organic acids will reveal elevated 4-hydroxyphenyllactate, 4-hydroxyphenylacetate, and 4-hyroxyphenylpyruvate. Deficient activity of 4-HPPD may be shown in liver or kidney biopsy samples.

Treatment

Management of tyrosinemia consists mainly of a dietary restriction of tyrosine and phenylalanine. Some infants affected by neonatal tyrosinemia have responded to a lower protein intake and ascorbic acid supplementation.

If started early, therapy with NTBC has shown promise for decreasing succinylacetone production in type I tyrosinemia. Liver transplantation has also been beneficial in type I disease but is not effective in treating all of the metabolic abnormalities

Management for type II disease consists of a diet low in phenylalanine and tyrosine. Close management by a nutritionist experienced with metabolic conditions is necessary. For specific treatment guidelines, please consult with a genetic/metabolic specialist.

Screening Practice Considerations

Screening for tyrosinemia is dependent upon milk ingestion. Optimal results are obtained if the specimen is collected 24 to 72 hours after the initiation of milk feedings.

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• Maryland