Expert Consensus on the Long-Term Effectiveness of Medical Nutrition Therapy and Its Impact on the Outcomes of Adults with Phenylketonuria.

Many adults with phenylketonuria (PKU) rely on medical nutrition therapy (MNT; low phenylalanine (Phe) diet with protein substitutes/medical foods) to maintain blood Phe concentrations within recommended ranges and prevent PKU-associated comorbidities. Despite disease detection through newborn screening and introduction of MNT as early as birth, adherence to MNT often deteriorates from childhood onwards, complicating the assessment of its effectiveness in the long term. Via a modified Delphi process, consensus (≥70% agreement) was sought on 19 statements among an international, multidisciplinary 13-member expert panel. After three iterative voting rounds, the panel achieved consensus on 17 statements related to the limitations of the long-term effectiveness of MNT (7), the burden of long-term reliance on MNT (4), and its potential long-term detrimental health effects (6). According to the expert panel, the effectiveness of MNT is limited in the long term, is associated with a high treatment burden, and demonstrates that adults with PKU are often unable to achieve metabolic control through dietary management alone, creating an unmet need in the adult PKU population.

Nutrition management of PKU with pegvaliase therapy: update of the web-based PKU nutrition management guideline recommendations.

BACKGROUND: The web-based GMDI/SERN PKU Nutrition Management Guideline, published before approval of pegvaliase pharmacotherapy, offers guidance for nutrition management of individuals with phenylketonuria (PKU) treated with dietary therapy and/or sapropterin. An update of this guideline aims to provide recommendations that improve clinical outcomes and promote consistency and best practice in the nutrition management of individuals with PKU receiving pegvaliase therapy. Methodology includes: formulation of a research question; review, critical appraisal, and abstraction of peer-reviewed studies and unpublished practice literature; expert input through Delphi surveys and a Nominal Group process; and external review by metabolic experts. RESULTS: Recommendations, summary statements, and strength of evidence are included for each of the following topics: (1) initiating a pegvaliase response trial, (2) monitoring therapy response and nutritional status, (3) managing pegvaliase treatment after response to therapy, (4) education and support for optimal nutrition with pegvaliase therapy, and (5) pegvaliase therapy during pregnancy, lactation, and adolescence. Findings, supported by evidence and consensus, provide guidance for nutrition management of individuals receiving pegvaliase therapy for PKU. Recommendations focus on nutrition management by clinicians, as well as the challenges for individuals with PKU as a result of therapy changes. CONCLUSIONS: Successful pegvaliase therapy allows the possibility for individuals with PKU to consume an unrestricted diet while still maintaining the benefits of blood phenylalanine control. This necessitates a perspective change in education and support provided to individuals in order to achieve healthy nutrient intake that supports optimal nutritional status. The updated guideline, and companion Toolkit for practical implementation of recommendations, is web-based, allowing for utilization by health care providers, researchers, and collaborators who advocate and care for individuals with PKU. These guidelines are meant to be followed always taking into account the provider's clinical judgement and considering the individual's specific circumstances. Open access is available at the Genetic Metabolic Dietitians International ( https://GMDI.org ) and Southeast Regional Genetics Network ( https://managementguidelines.net ) websites.

Nutrition status of adults with phenylketonuria treated with pegvaliase.

BACKGROUND: Pegvaliase is an enzyme substitution therapy that reduces blood phenylalanine (Phe) in adults with phenylketonuria (PKU), and often allows normalization of protein intake (≥0.8 g protein/kg). Here we examine the nutrition status of adults with PKU consuming a normal protein intake without medical food after being treated with pegvaliase for ≥1 year. METHODS: A cross-sectional study evaluating nutritional intake (3-day food record and food frequency questionnaire), anthropometrics, laboratory indices of protein, micronutrient, and essential fatty acid (EFA) status, and questionnaires evaluating food neophobia and Epicurean eating pleasure. RESULTS: Participants (n = 18, 61% female) started pegvaliase 4.9 ± 2.1 years prior to enrollment and were aged 38.2 ± 8.8 years with a mean BMI of 29.2 ± 4.1 kg/m2. Participants consumed a mean of 73.2 ± 17.6 g protein/d (1.0 ± 0.3 g/kg/d). Eleven participants had low blood Phe (<30 µmol/L) with adequate protein intake and normal indices of protein status. Micronutrient and EFA concentrations were normal except for mildly low vitamin D (<30 ng/mL, n = 12). Intakes of sodium, saturated fat, and added sugars exceeded recommendations for healthy adults, though mean diet quality was comparable to a US adult reference population. Lower food neophobia scores correlated with an increased aesthetic appreciation of food. However, 53% of participants self-reported having moderate (n = 6) to high (n = 3) food neophobia. DISCUSSION: Participants treated with pegvaliase consumed an unrestricted diet with adequate dietary protein and, overall, had normal protein, micronutrient, and fatty acid status. Despite low blood Phe, protein nutriture was not compromised. While nutritional deficiencies were not identified, diet quality was suboptimal and some participants reported food neophobia. Nutrition education remains an important component of care as patients adapt to a normal diet.

Inconsistencies in the Nutrition Management of Glutaric Aciduria Type 1: An International Survey.

Glutaric aciduria type 1 (GA-1) is a cerebral organic aciduria characterized by striatal injury and progressive movement disorder. Nutrition management shifted from a general restriction of intact protein to targeted restriction of lysine and tryptophan. Recent guidelines advocate for a low-lysine diet using lysine-free, tryptophan-reduced medical foods. GA-1 guideline recommendations for dietary management of patients over the age of six are unclear, ranging from avoiding excessive intake of intact protein to counting milligrams of lysine intake. A 22-question survey on the nutrition management of GA-1 was developed with the goal of understanding approaches to diet management for patients identified by newborn screening under age six years compared to management after diet liberalization, as well as to gain insight into how clinicians define diet liberalization. Seventy-six responses (25% of possible responses) to the survey were received. Nutrition management with GA-1 is divergent among surveyed clinicians. There was congruency among survey responses to the guidelines, but there is still uncertainty about how to counsel patients on diet optimization and when diet liberalization should occur. Ongoing clinical research and better understanding of the natural history of this disease will help establish stronger recommendations from which clinicians can best counsel families.

Metabolomic Markers of Essential Fatty Acids, Carnitine, and Cholesterol Metabolism in Adults and Adolescents with Phenylketonuria.

Background: Individuals with phenylketonuria (PKU) have a risk of cognitive impairment and inflammation. Many follow a low-phenylalanine (low-Phe) diet devoid of animal protein in combination with medical foods (MFs). Objective: To assess lipid metabolism in participants with PKU consuming amino acid MFs (AA-MFs) or glycomacropeptide MFs (GMP-MFs), we conducted fatty acid and metabolomics analyses. Methods: We used subsets of fasting plasma and urine samples from our randomized crossover trial in which participants with early-treated classical and variant (milder) PKU consumed a low-Phe diet combined with AA-MFs or GMP-MFs for 3 wk each. Fatty acid profiles of red blood cell (RBC) membranes were determined for 25 adults (aged 18-49 y) with PKU and 143 control participants. Metabolomics analyses of plasma and urine samples were conducted by Metabolon for 9-10 adolescent and adult participants with PKU and for 15 control participants. Results: RBC fatty acid profiles were not significantly different with AA-MFs or GMP-MFs. PKU participants showed higher total n-6:n-3 (ω-6:ω-3) fatty acids (mean ± SD percentages of total fatty acids: AA-MF = 5.45% ± 1.07%; controls = 4.33%; P < 0.001) and lower docosahexaenoic acid (DHA; AA-MF = 3.21% ± 0.98%; controls = 3.70% ± 1.01%; P = 0.02) and eicosapentaenoic acid (AA-MF = 0.33% ± 0.12%; controls = 0.60% ± 0.43%; P < 0.001) in RBCs than did control participants. Despite higher carnitine intake from AA-MFs than GMP-MFs (mean ± SE intake: AA-MFs = 58.6 ± 5.3 mg/d; GMP-MFs = 0.3 ± 0.01 mg/d; P < 0.001), plasma concentrations of carnitine were similar and not different from those in the control group (AA-MF compared with GMP-MF, P = 0.73). AA-MFs resulted in higher urinary excretion of trimethylamine N-oxide (TMAO), which is synthesized by bacteria from carnitine, compared with GMP-MFs (mean ± SE scaled intensity-TMAO: AA-MFs = 1.2 ± 0.1, GMP-MFs = 0.9 ± 0.1; P = 0.005). Plasma deoxycarnitine was lower in PKU participants than in control participants, suggesting reduced carnitine biosynthesis in PKU (AA-MF = 0.9 ± 0.1; GMP-MF = 1.0 ± 0.1; controls = 1.3 ± 0.1; AA-MF compared with controls, P = 0.01; GMP-MF compared with controls, P = 0.04). Conclusions: Supplementation with DHA is needed in PKU. Carnitine supplementation of AA-MFs shows reduced bioavailability due, in part, to bacterial degradation to TMAO, whereas the bioavailability of carnitine is greater with prebiotic GMP-MFs. This trial was registered at www.clinicaltrials.gov as NCT01428258.