Spanish BH4-responsive phenylalanine hydroxylase-deficient patients: Evolution of seven patients on long-term treatment with tetrahydrobiopterin

A novel subtype of patients with mutations in the phenylalanine hydroxylase (PAH) gene that show a positive response during a tetrahydrobiopterin (BH4) loading test has recently been recognized. These studies suggest that a number of phenylketonuric (PKU) patients may benefit from BH4 substitution, eliminating the need of life-long dietary restrictions. In our unit, we performed BH4 overload tests in 50 PAH-deficient patients. Overall, 38% of the patients had a positive response, mostly MHP and mild PKU patients, all with at least one missense mutation with presumed residual activity. Seven of the patients that required dietary restrictions have received treatment with BH4 from 5 to 18 months. All the patients included in the long-term treatment protocol had a mild PKU phenotype. BH4 therapy began at 10 mg/kg/day and changes were made over time depending on Phe levels. All patients at least doubled their protein ingestion and some could follow a completely free diet. Patients with a smaller decrease in Phe levels during the BH4 overload required higher BH4 doses and/or dietary restrictions to maintain adequate Phe levels over time. The genotype and the potential mechanisms underlying BH4 responsiveness and interindividual differences in pharmacokinetics of the administered cofactor are probably the basis for the differences in prolonged treatment.