Using change in plasma phenylalanine concentrations and ability to liberalize diet to classify responsiveness to tetrahydrobiopterin therapy in patients with phenylketonuria

Tetrahydrobiopterin (BH₄) responsiveness is currently defined as a decrease in plasma phenylalanine concentrations in patients with phenylketonuria (PKU). This definition does not offer insight beyond the initial assessment of patients, which may lead to treatment ambiguity in patients who only experience an initial decrease in plasma phenylalanine concentrations. We present our experience with a novel classification approach using sequentially-applied criteria. Plasma phenylalanine concentrations were measured at baseline and after one month of BH₄ therapy (20mg/kg/day) in 58 PKU patients (34 M, 24 F; age 17.3±11.0years). Thirty-two patients (55.2%) were classified as “preliminary responders” at one month, experiencing at least a 15% decrease in plasma phenylalanine concentrations. Preliminary responders' ability to liberalize their dietary restrictions was then systematically assessed. “Definitive responders” were defined as preliminary responders who could increase their dietary phenylalanine tolerance by at least 300mg/day and lower prescribed medical food needs by at least 25% while maintaining metabolic control (plasma phenylalanine ≤360μmol/L) and consuming adequate dietary protein. Preliminary responders who could not liberalize their diets according to these criteria were classified as “provisional responders.” Nineteen patients (32.8% of patients initiating BH₄ therapy) met the definitive responder criteria, increasing dietary phenylalanine tolerance from 704±518mg/day to 1922±612mg/day and reducing medical food to 16.7±19.5% of their baseline prescription. Nine patients (15.5% of patients initiating BH₄ therapy) were classified as provisional responders, all remaining on 100% of their baseline medical food prescription. From this classification approach, a subgroup of provisionally responsive patients emerged who experienced an initial decrease in plasma phenylalanine concentrations but who could not substantially increase their dietary phenylalanine tolerance or decrease medical food needs. Diet liberalization is an essential component of BH₄-responsiveness classification.