JIMD Reports - Case and Research Reports, 2012/5

Mary Lou Lindegren, Shanthi Krishnaswami, Tyler Reimschisel, Christopher Fonnesbeck, Nila A. Sathe, Melissa L. McPheeters

Context: Dietary management is the mainstay of effective treatment in PKU, but dietary restriction is difficult and additional treatment options are needed. Objective: To systematically review evidence regarding sapropterin (BH4) use as an adjunct to dietary restriction in individuals with PKU. Data Sources: Five databases including MEDLINE up to August 2011. Study Selection: Two reviewers independently assessed studies against predetermined inclusion/exclusion criteria. Data Extraction: Two reviewers independently extracted data regarding participant and intervention characteristics and outcomes and assigned overall quality and strength of evidence ratings based on predetermined criteria. Results: BH4 research includes two randomized controlled trials (RCTs) and three uncontrolled open-label trials. Phenylalanine (Phe) levels were reduced by at least 30 % in up to half of treated participants (32-50 %). In one RCT comparing placebo on likelihood of a 30 % reduction in Phe, 9 % of those on placebo achieved this effect, compared with 44 % of the treated group after 6 weeks. Phe tolerance and variability were improved in treated participants in studies assessing those outcomes. No comparative studies assessed long-term outcomes including cognitive effects, nutritional status, or quality of life. Conclusions: Adjuvant pharmacologic therapy has the potential to support individuals in achieving optimal Phe levels. BH4 has been shown to reduce Phe levels in some individuals, with significantly greater reductions seen in treated versus placebo groups. The strength of the evidence is moderate for short-term effects on reducing Phe in a subset of initially BH4-responsive individuals, moderate for a lack of significant harms, low for longer-term effects on cognition, and insufficient for all other outcomes.