Long-term follow-up of tetrahydrobiopterin therapy in patients with tetrahydrobiopterin deficiency in Japan.

Tetrahydrobiopterin (BH(4)) deficiency is a rare, congenital and lethal condition resulting in phenylalanine build-up that can lead to mental retardation and developmental defects, unless properly treated. About 1 million newborn infants in Japan undergo neonatal PKU screening every year, of which about 1 in 2 million are diagnosed with the condition. In this post-marketing surveillance study, 19 patients with BH(4) deficiency in whom BH(4) supplementation with sapropterin dihydrochloride (Biopten®) (hereafter referred to as 'BH(4) therapy') was initiated before the age of 4 years, were followed up for ≤28 years. Patients who screened positive for BH(4) deficiency were treated with supplemental BH(4) plus L-dopa and 5-hydroxytryptophan. Data on the patients' clinical courses were collected once yearly at 10 medical centers in Japan. Seventeen patients were diagnosed with 6-pyruvoyl tetrahydropterin synthase deficiency and two with dihydropteridine reductase deficiency at an average age of 3.6 months; the mean age at end of follow-up was 14.6 years. Average duration of BH(4) therapy (mean dose, 5 mg/kg per day) was 13.2 years. Serum phenylalanine was reduced from more than 10 mg/dL at the start of drug administration to less than 2 mg/dL at end of follow-up. No abnormalities in height or weight were observed in any patients, except for one female patient with familial obesity. No unwarranted side effects were reported throughout the long-term course of treatment, even during pregnancy. BH(4) therapy can effectively maintain serum phenylalanine levels within the normal range in patients with BH(4) deficiency, and demonstrated excellent long-term safety, with no side effects.

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.

Long-term treatment and diagnosis of tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene.

A novel therapeutic strategy for phenylketonuria (PKU) has been initiated in Japan. A total of 12 patients who met the criteria for tetrahydrobiopterin (BH(4))-responsive hyperphenylalaninemia (HPA) with a mutant phenylalanine hydroxylase (PAH) (EC 1.14.16.1) gene were recruited at 12 medical centers in Japan between June 1995 and July 2001. Therapeutic efficacy of BH(4) was evaluated in single-dose, four-dose, and 1-wk BH(4) loading tests followed by long-term BH(4) treatment, and also examined in relation to the PAH gene mutations. The endpoints were determined as the percentage decline in serum phenylalanine from initial values after single-dose (>20%), four-dose (>30%), and 1-wk BH(4) (>50%) loading tests. Patients with mild PKU exhibiting decreases in blood phenylalanine concentrations of >20% in the single-dose test also demonstrated decreases of >30% in the four-dose test. The 1-wk test elicited BH(4) responsiveness even in patients with poor responses in the shorter tests. Patients with mild HPA, many of whom carry the R241C allele, responded to BH(4) administration. No clear correlation was noted between the degree of decrease in serum phenylalanine concentrations in the single- or four-dose tests and specific PAH mutations. The 1-wk test (20 mg/kg of BH(4) per day) is the most sensitive test for the diagnosis of BH(4)-responsive PAH deficiency. Responsiveness apparently depends on mutations in the PAH gene causing mild PKU, such as R241C. BH(4) proved to be an effective therapy that may be able to replace or liberalize the phenylalanine-restricted diets for a considerable number of patients with mild PKU.