Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria
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Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. / Muntau, Ania C; Röschinger, Wulf; Habich, Matthias; Demmelmair, Hans; Hoffmann, Björn; Sommerhoff, Christian P; Roscher, Adelbert A.
In: NEW ENGL J MED, Vol. 347, No. 26, 26.12.2002, p. 2122-32.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria
AU - Muntau, Ania C
AU - Röschinger, Wulf
AU - Habich, Matthias
AU - Demmelmair, Hans
AU - Hoffmann, Björn
AU - Sommerhoff, Christian P
AU - Roscher, Adelbert A
N1 - Copyright 2002 Massachusetts Medical Society
PY - 2002/12/26
Y1 - 2002/12/26
N2 - 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 IVS4-5C-->G) 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.
AB - 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 IVS4-5C-->G) 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.
KW - Adolescent
KW - Biopterins/analogs & derivatives
KW - Child
KW - Child, Preschool
KW - Humans
KW - Infant
KW - Infant, Newborn
KW - Molecular Conformation
KW - Mutation, Missense
KW - Oxidation-Reduction/drug effects
KW - Phenylalanine/blood
KW - Phenylalanine Hydroxylase/chemistry
KW - Phenylketonurias/classification
KW - Prospective Studies
U2 - 10.1056/NEJMoa021654
DO - 10.1056/NEJMoa021654
M3 - SCORING: Journal article
C2 - 12501224
VL - 347
SP - 2122
EP - 2132
JO - NEW ENGL J MED
JF - NEW ENGL J MED
SN - 0028-4793
IS - 26
ER -