Diagnosis of tetrahydrobiopterin (BH4) responsive mild phenylketonuria in Japan over the past 10 years.

BACKGROUND A novel therapeutic strategy for phenylketonuria (PKU) has been initiated in Japan. Hyperphenylalaninemia (HPA) results from a phenylalanine hydroxylase (PAH) enzyme deficiency or a deficiency of its cofactor, tetrahydrobiopterin (BH4). BH4 can normalize blood phenylalanine levels in BH4 deficiency, but typically not in PKU. However, since 1999 it has been reported that many HPA patients (serum phenylalanine <20 mg/dL) showed a gradual decrease of serum phenylalanine levels after 24 hours from BH4 loading. The BH4 responsiveness seems to be regulated in mild PKU by PAH mutations, and affected by the BH4 dose and administration period. METHODS AND RESULTS In 2002 we formulated a provisional diagnostic criteria for patients with BH4-responsive PAH deficiency, and newly diagnosed 19 patients in 100 HPA cases between 2002 and 2006. The incidence in the recent 5 years for BH4-responsive mild PKU among patients with PAH deficiency was 25 %. CONCLUSION A total of 31 patients was detected in the past 10 years, and the incidence detected using the provisional diagnostic criteria had increased to 25% among PAH deficient patients. BH4 treatment for BH4-responsive mild PKU is a new and effective pharmacotherapy, which replaces or liberalises the phenylalanine-restricted diets for a considerable number of mild PKU patients.