BH-04

Tetrahydrobiopterin (BH(4)) lowers blood phenylalanine (Phe) in individuals with PKU who are responders, but its effects on the brain and cognition have not been explored thoroughly. We examined blood Phe, microstructural white matter integrity, and executive abilities in 12 BH(4) responders before (i.e., baseline) and after (i.e., follow-up) six months of treatment with BH(4). Compared with baseline, Phe in these responders decreased by 51% during a 4 week screening period after initiation of treatment and remained lowered by 37% over the 6 month follow-up period. Significant improvements in white matter integrity, evaluated by mean diffusivity from diffusion tensor imaging, were also found following six months of treatment. Improvements in executive abilities were not identified, although six months may have been a period too brief for changes in cognition to follow changes in the brain. To our knowledge, our study is the first to explore relationships among Phe, white matter integrity, executive abilities, and BH(4) treatment within a single study.

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.