Objective: Hyperphenylalaninaemia, caused by phenylalanine hydroxylase (PAH) deficiency, can be classified as classic phenylketonuria (cPKU), mild PKU (mPKU) and mild hyperphenylalaninaemia (mHPA) on the basis of tolerance and pretreatment phenylalanine levels. Recent reports show the effectiveness of tetrahydrobiopterin (BH4) in PAH deficiency.
Methods: BH4-responsiveness was tested in 16 HPA patients (six cPKU, five mPKU and five mHPA) by BH4 loading test. Two weeks before and during the testing period phenylalanine intake was distributed throughout the day. The BH4 loading test was performed with BH4 tablets (Schircks Laboratories, Switzerland) in two doses of 20 mg/kg at T0 and T24 h. Plasma phenylalanine was analysed at 0, 4, 8, 12, 24, 32 and 48 h.
Results: Nine patients (two cPKU, two mPKU and five mHPA) were BH4-responsive with a decrease greater than 30% in plasma phenylalanine from T0. All BH4-responsive patients were compound heterozygous for well-known mutations with at least one partly active allele (pR261Q, pL48S, pP281L, pR158Q, pD338Y). BH4-responsive patients started long-term BH4 treatment (10 mg/kg per day) and increased the dietary phenylalanine amount of 200 mg phenylalanine/day weekly. The follow-up period ranged from 2 to 11 months. Phenylalanine tolerance was increased from two to 9.7-fold; one patient achieved a liberalised diet. One patient reported headache, two reported epigastric abdominal pain, one developed appendicitis.
Conclusion: The most important predictor of BH4 responsiveness is the genotype. Long-term BH4 treatment is an effective therapy in selected patients and can partly or completely replace a restricted-phenylalanine diet.
Funding: The study is supported by Agenzia Italiana del Farmaco (Italy)