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Previous Volume 347:2122-2132 December 26, 2002 Number 26 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Perspective by Seashore, M. R. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Hyperphenylalaninemia is a common inherited metabolic disease that is due to phenylalanine hydroxylase deficiency, and at least half the affected patients have mild clinical phenotypes. Treatment with a low-phenylalanine diet represents a substantial psychosocial burden, but alternative treatments have not been effective.

Methods To explore the therapeutic efficacy of tetrahydrobiopterin, we performed a combined phenylalanine–tetrahydrobiopterin loading test and analyzed the in vivo rates of [¹³C]phenylalanine oxidation in 38 children with phenylalanine hydroxylase deficiency (age range, 1 day to 17 years). We assessed whether responsiveness to tetrahydrobiopterin was associated with specific genotypes, and we mapped mutations using a structural model of the phenylalanine hydroxylase monomer.

Results In 27 (87 percent) 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 (74 percent). 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 (P314S, Y417H, V177M, V245A, A300S, E390G, and IVS4–5CG) were classified as probably associated with responsiveness to tetrahydrobiopterin, and six mutations (A403V, F39L, D415N, S310Y, R158Q, and I65T) were classified as potentially associated. Four mutations (Y414C, L48S, R261Q, and I65V) were inconsistently associated with this phenotype. Mutations connected to tetrahydrobiopterin responsiveness were predominantly in the catalytic domain of the protein and were not directly involved in cofactor binding.

Conclusions Tetrahydrobiopterin responsiveness is common in patients with mild hyperphenylalaninemia phenotypes. Responsiveness cannot consistently be predicted on the basis of genotype, particularly in compound heterozygotes.

Source Information

From the Research Center, Department of Biochemical Genetics and Molecular Biology (A.C.M., W.R., M.H., A.A.R.), and the Department of Metabolic Disorders and Nutrition (H.D., B.H.), Dr. von Hauner Children's Hospital; and the Department of Clinical Chemistry and Clinical Biochemistry, Surgical Clinic (C.P.S.) — all at Ludwig Maximilians University, Munich, Germany.

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{at}kk-i.med.uni-muenchen.de.

Full Text of this Article

Related Letters:

Tetrahydrobiopterin and Mild Phenylketonuria
Ponzone A., Peduto A., Spada M., Hanley W. B., D'agostino R. D., Roscher A. A., Muntau A. C., Röschinger W.
Extract | Full Text | PDF  
N Engl J Med 2003; 348:1722-1724, Apr 24, 2003. Correspondence

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