Hyperphenylalaninemia, a common inherited metabolic disease, is due to phenylalanine hydroxylase deficiency. Patients with both classic and mild phenylketonuria require lifelong dietary protein restriction to prevent neurologic sequelae and to ensure normal cognitive development, whereas patients with mild Hyperphenylalaninemia may not require treatment. The highly restricted diet that is required is associated with a risk of nutritional deficiencies and is difficult to follow. Therefore, a search for non-dietary treatment alternatives has been encouraged.
In approximately 50 genetic diseases of humans involving enzyme deficiencies, treatment with high doses of a cofactor can increase enzyme activity. Tetrahydrobiopterin is a natural cofactor of aromatic amino acid hydroxylases and nitric oxide synthase. Supplementation with this compound is an established treatment for the rare patients with hyperphenylalaninemia that is due to defects in the biosynthesis of tetrahydrobiopterin. A recent study in the New England Journal of Medicine prospectively studied children with phenylalanine hydroxylase deficiency in an effort to determine the frequency of sensitivity to tetrahydrobiopterin in these patients, whether tetrahydrobiopterin restores their oxidative capacity for phenylalanine and whether responsiveness to tetrahydrobiopterin is related to specific genotypes.
Thirty-eight children with various classes of hyperphenylalaninemia were included in this study. Phenylalanine loading was accomplished by having patients consume a meal containing 100 mg of phenylalanine per kilogram of body weight. One hour after the end of the meal the patients ingested 20 mg of tetrahydrobiopterin per kilogram and then blood phenylalanine levels were determined. The rate of phenylalanine oxidation was determined twice in each child, once without treatment and once during treatment with tetrahydrobiopterin.
In 27 of 31 patients with mild hyperphenylalaninemia (10 patients) or mild phenylketonuria (21 patients), tetrahydrobiopterin significantly lowered blood phenylalanine levels. Phenylalanine oxidation was significantly enhanced in 23 of these 31 patients. Conversely, none of the seven patients with classic phenylketonuria had a response to tetrahydrobiopterin as defined in this study. Long-term treatment with tetrahydrobiopterin in five children increased daily phenylalanine tolerance, allowing them to discontinue their restricted diets. Seven mutations were classified as probably associated with responsiveness to tetrahydrobiopterin and six mutations were classified as potentially associated.
Muntau presented two lines of evidence that the metabolic phenotype of phenylalanine hydroxylase deficiency can be modified by pharmacologic doses of tetrahydrobiopterin. First, tetrahydrobiopterin loading led to normal or nearly normal blood phenylalanine concentrations in most patients with residual phenylalanine hydroxylase activity, suggesting that responsiveness to tetrahydrobiopterin is a common feature of mild hyperphenylalaninemia phenotypes. Second, tetrahydrobiopterin enhanced residual phenylalanine oxidative capacity in these patient groups. Therefore, the findings suggest that the in vivo phenylalanine oxidation test can discriminate among classes of hyperphenylalaninemia of different severity.
Ania C. Muntau, Wulf Roschinger, Matthias Habich, et al., Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria, N Engl J Med 347(26): 2122-2132 (December 26, 2002) [Address reprint requests to Dr. Roscher at Dr. von Hauner Children's Hospital Research Center, Ludwig Maximilians University, Lindwurmstrasse 2a, D-80337 Munich, Germany, or at adelbert.roscher@kkimed.uni-muenchen.de]
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