Glycomacropeptide for nutritional management of phenylketonuria: a randomized, controlled, crossover trial

Abstract

Background: To prevent cognitive impairment, phenylketonuria requires lifelong management of blood phenylalanine (Phe) concentration with a low-Phe diet. The diet restricts intake of Phe from natural proteins in combination with traditional amino acid medical foods (AA-MFs) or glycomacropeptide medical foods (GMP-MFs) that contain primarily intact protein and a small amount of Phe.

Objective: We investigated the efficacy and safety of a low-Phe diet combined with GMP-MFs or AA-MFs providing the same quantity of protein equivalents in free-living subjects with phenylketonuria.

Design: This 2-stage, randomized crossover trial included 30 early-treated phenylketonuria subjects (aged 15-49 y), 20 with classical and 10 with variant phenylketonuria. Subjects consumed, in random order for 3 wk each, their usual low-Phe diet combined with AA-MFs or GMP-MFs. The treatments were separated by a 3-wk washout with AA-MFs. Fasting plasma amino acid profiles, blood Phe concentrations, food records, and neuropsychological tests were obtained.

Results: The frequency of medical food intake was higher with GMP-MFs than with AA-MFs. Subjects rated GMP-MFs as more acceptable than AA-MFs and noted improved gastrointestinal symptoms and less hunger with GMP-MFs. ANCOVA indicated no significant mean ± SE increase in plasma Phe (62 ± 40 μmol/L, P = 0.136), despite a significant increase in Phe intake from GMP-MFs (88 ± 6 mg Phe/d, P = 0.026). AA-MFs decreased plasma Phe (-85 ± 40 μmol/L, P = 0.044) with stable Phe intake. Blood concentrations of Phe across time were not significantly different (AA-MFs = 444 ± 34 μmol/L, GMP-MFs = 497 ± 34 μmol/L), suggesting similar Phe control. Results of the Behavior Rating Inventory of Executive Function were not significantly different.

Conclusions: GMP-MFs provide a safe and acceptable option for the nutritional management of phenylketonuria. The greater acceptability and fewer side effects noted with GMP-MFs than with AA-MFs may enhance dietary adherence for individuals with phenylketonuria. This trial was registered at www.clinicaltrials.gov as NCT01428258.

Keywords: executive function; inborn errors of amino acid metabolism; medical food; phenylalanine; sapropterin dihydrochloride; threonine; tyrosine.

© 2016 American Society for Nutrition.

Figures

FIGURE 1

Study design and protocol. Thirty subjects with early-treated phenylketonuria completed a 2-stage randomized crossover trial in which they consumed, in random order for 3 wk each, a low-Phe diet combined with GMP-MFs or AA-MFs at home. Each medical food treatment was preceded by 1 wk of education regarding the protocol with a 3-wk washout period between treatments; subjects consumed AA-MFs during these times (A). The protocol for each dietary treatment included 2 study visits with venipuncture to obtain blood samples, one at baseline (day 1) and one at final (day 22), collection of 8 blood spot specimens on filter paper during each 3-wk treatment period, completion of daily medical food logs, 3-d food records, and diet acceptability questionnaires (day 7 and day 21), and neuropsychological testing at the final study visit for each diet (B). AA-MF, amino acid medical food; GMP-MF, glycomacropeptide medical food; Neuropsych, neuropsychological.

FIGURE 2

Flow diagram of the study selection process. GMP, glycomacropeptide; PEG-PAL, pegylated phenylalanine ammonia lyase.

FIGURE 3

The number of phenylketonuria subjects with T-scores for the Behavioral Rating Inventory of Executive Function Global Executive Composite in the normative, borderline significant, and clinically significant categories after following a low-phenylalanine diet in conjunction with AA medical foods and GMP medical foods for 3 wk at home, n = 30 subjects. A T-score of 1.5 SD (15 points) above the mean (50 points) is indicative of reduced executive function. AA, amino acid; GMP, glycomacropeptide.

FIGURE 4

Change in fasting plasma concentration of Phe (A) and dietary intake of Phe (B) in participants with phenylketonuria who followed a low-Phe diet in conjunction with AA medical foods and GMP medical foods for 3 wk at home. Plasma data were analyzed by ANCOVA to compare the change in plasma Phe concentrations with AA medical foods and the GMP medical foods with adjustment for covariates for baseline Phe concentration (P = 0.0001) and dietary Phe intake (P = 0.0212) based on the final 3-d food records. Results indicate a significant treatment effect (mean difference, −147 ± 39, P = 0.0008) without significant sequence or treatment–sequence effects. The GMP treatment showed no significant increase in plasma Phe concentration (62 ± 40, P = 0.136), and the AA treatment showed a modest but significant decrease in plasma Phe concentration (−85 ± 40, P = 0.044). The box and whisker figure illustrates the variation in Phe response with consumption of AA and GMP medical foods; dots indicate individual values outside the 10th–90th percentiles. The box represents the middle 50% of all 30 subjects (25th–75th percentile) with a line showing the median value; the whiskers indicate the 10th and 90th percentiles. Dietary Phe intake was compared for the AA treatment and the GMP treatment by paired t test. Dietary Phe intake did not increase significantly with the AA treatment, but it did increase significantly with the GMP treatment (P = 0.0259) because of an additional intake of 88 ± 6 mg Phe/d from the GMP medical foods. AA medical foods do not contain Phe. Intake of Phe from natural foods was not significantly different for the AA and GMP treatments. Values are least-squares means (plasma Phe) or means (Phe intake) ± SEs, n = 30. AA, amino acid; GMP, glycomacropeptide; NSD, not significantly different; ↑, increase in Phe intake.

FIGURE 5

Fasting plasma Tyr concentrations after treatment with the AA and GMP medical foods for 3 wk were NSD (P = 0.105), despite significantly greater Tyr intake with AA medical foods than with GMP medical foods (P = 0.0001). Statistical analysis for final plasma Tyr concentration used ANCOVA with a covariate for baseline Tyr concentration; values are least-squares means ± SEs, n = 30. Statistical analysis for Tyr intake from the final 3-d food records was ANOVA; values are means ± SEs, n = 30. AA, amino acid; GMP, glycomacropeptide; NSD, not significantly different.

FIGURE 6

Fasting concentrations of Phe (A) and Tyr (B) in blood were based on analysis of dried blood spots collected by subjects and analyzed with tandem mass spectrometry. (C) Daily intake of protein equivalents from medical food was based on daily medical food logs completed by subjects. Repeated-measures ANOVA indicated there was no significant treatment effect due to ingestion of AA and GMP medical foods on blood concentrations of Phe and Tyr and daily intake of protein equivalents from medical food over the 3-wk treatment period (P = 0.175–0.9522). Values are means ± SEs, n = 26–30 for each of the 8 time points for blood Phe and Tyr concentrations. The insert shows the average blood concentrations of Phe and Tyr and average daily intake of protein from medical foods across time (least-squares means ± SEs). AA, amino acid; GMP, glycomacropeptide.

FIGURE 7

Negative correlation of plasma Thr concentration and plasma Phe concentration as measured by Pearson’s correlation coefficient for the glycomacropeptide medical foods treatment, n = 29.