Outcome of treatment in classic PKU is excellent. Most infants with classic PKU who are treated within the first
Figure 53-1 Metabolism of aromatic amino acids. (1) Phenylalanine hydroxylase, (2) transaminase, (3) p-hydroxyphenylpyruvate oxidase, (4) homogentisate oxidase, (5) maleylacetoacetate isomerase, (6) fumarylacetoacetate hydrolase, (7) dihydrobiopterin reductase, (8) tyrosine hydroxylase, (9) tryptophan hydroxylase. SA, Succinylacetone.
10 days of life achieve normal intelligence. However, learning problems and problems with executive function aremore frequent than in unaffected peers. The safe concentration of phenylalanine in older children and adults withPKU has not been clearly established. Reversible cognitivedysfunction is associated with acute elevations of plasmaphenylalanine in adults and children with PKU. If the elevated level has been sustained, the dysfunction may not bereversible. Treatment with modified preparation of tetrahydrobiopterin has shown good responses in some individualswith PKU.
Females with PKU and their families must be educated on the risks and prevention of “maternal PKU syndrome.” Maternal hyperphenylalaninemia requires rigorous management before conception and throughout pregnancy to prevent fetal brain damage, congenital heart disease, and microcephaly.
Tyrosinemia is identified in neonatal screening programs using tandem mass spectrometry methods to detect elevated tyrosine and/or succinylacetone. Elevated tyrosine levels also occur as a nonspecific consequence of severe liver disease or transient tyrosinemia of the newborn, which responds to ascorbic acid treatment. The inherited disorders of tyrosine metabolism are the target of neonatal screening. Tyrosinemia Type I, which is due to fumarylacetoacetate hydrolase deficiency (see Fig. 53-1), is a rare disease in which accumulated metabolites produce severe liver disease associated with bleeding disorder, hypoglycemia, hypoalbuminemia, elevated transaminases, and defects in renal tubular function. Hepatocellular carcinoma may eventually occur. Quantitative measurement of plasma tyrosine and blood or urine succinylacetone is performed after a positive neonatal screen. The diagnosis of tyrosinemia I is confirmed by an increased concentration of succinylacetone; DNA testing is available for some mutations. Treatment with nitisinone (NTBC) (an inhibitor of the oxidation of parahydroxyphenylpyruvic acid) effectively eliminates the production of the toxic succinylacetone. A low-phenylalanine, low-tyrosine diet may also play a role. These treatments have obviated the immediate need for liver transplantation in children identified by neonatal screening. Whether they completely eliminate the occurrence of hepatocellular carcinoma is unknown.
Tyrosinemias II and III are more benign forms of hereditary tyrosinemia. Blocked metabolism of tyrosine at earlier steps in the pathway is responsible, and succinylacetone is not produced. The clinical features include hyperkeratosis of palms and soles and keratitis, which can cause severe visual disturbance. Poor dietary compliance with type II tyrosinemia is associated with mild cognitive impairment. Treatment with a phenylalanineand tyrosine-restricted diet is effective.