The effect of blood phenylalanine concentration on Kuvan™ response in phenylketonuria

Phenylketonuria (PKU) is caused by mutations in the phenylalanine hydroxylase gene (PAH) with consequent elevation of blood phenylalanine (Phe), reduction in tyrosine (Tyr) and elevation of Phe/Tyr ratio (P/T). Although newborn screening for PKU with early dietary treatment improved severe, irreversible brain damage, older patients suffer reversible losses in executive function when Phe concentrations are elevated. The maintenance of strict nutritional control in older children and adults remains difficult. An adjunct to dietary therapy, oral tetrahydrobiopterin (BH4) has recently been approved by the Food and Drug Administration as a stable, synthetic BH4 called Kuvan™. Published studies of Kuvan response in PKU varies and involved primarily children. In this prospective study we evaluated dose–response, response frequency and factors predicting response in 21 patients with PKU (aged 8–30 years), who required life-long dietary treatment. Response to Kuvan was defined at 24 h (acute) and over 4 weeks (chronic) as a ≥ 30% decline in the Phe or P/T ratio. A dose of 20 mg/kg Kuvan was chosen with 29% responding in 24 h and 33% of patients at 4 weeks. We then compared baseline Phe, Tyr, P/T, Phe intake, and frequency of “severe” versus “moderate” mutant PAH alleles among acute and chronic responders and non-responders to Kuvan. Predictors of response to Kuvan, both acute and chronic were baseline Phe and baseline P/T. Baseline Phe and P/T were higher among non-responders (P < 0.05). By contrast baseline Tyr was similar (P = 0.45). Phe intake tended to be higher (18 ± 20 mg/kg/24 h) among Kuvan responders than non-responders (15 ± 11 mg/kg/24 h), P < 0.07 NS. Similarly the frequency of “severe” mutant PAH alleles tended to be more frequent (67%) among non-responders than responders (40%) by Chi2 test, P = 0.08 NS. These results were reproducible in a “responder” to Kuvan. To assess directly the effect of elevated blood Phe, Phe was lowered in four, “non-responder” patients, but all failed to respond to Kuvan. We conclude that baseline blood Phe and P/T ratio can predict increased probability for response to Kuvan by patients with classic PKU, but the in vivo mechanisms of response to Kuvan remain enigmatic.