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Background Lifelong management of phenylketonuria (PKU) centers on medical nutrition therapy, including dietary phenylalanine (Phe) restriction in addition to Phe-free or low-Phe medical foods/protein substitutes. Studies have reported low bone mineral density (BMD) in mixed-age PKU populations, possibly related to long-term Phe restriction. Therefore, a meta-analysis investigating BMD specifically in adults with PKU was conducted. Methods Studies reporting BMD-related outcomes were identified from a systematic literature review evaluating somatic comorbidities experienced by adults with PKU on a Phe-restricted diet (searched February 1, 2022, updated November 1, 2023). Risk of study bias was assessed (Scottish Intercollegiate Guidelines Network checklists). The primary outcome of the meta-analysis was pooled mean BMD Z-scores of different bones. Secondary outcomes were the prevalence of low BMD Z-scores at pre-specified thresholds. Subgroup analyses of mean BMD Z-scores (decade of study publication, controlled versus uncontrolled blood Phe levels, gender) were conducted. Results BMD-related data from 4097 individuals across 10 studies rated as at least acceptable quality were included. Mean BMD Z-scores were statistically significantly lower compared with an age-matched control or reference (non-PKU) population, across bones, but still within the expected range for age (> -2.0): lumbar spine (seven studies, n  = 304), -0.63 (95% confidence interval (CI): -0.74, -0.52); femoral neck (four studies, n  = 170), -0.74 (95% CI: -1.25, -0.22); radius (three studies, n  = 114), -0.77 (95% CI: -1.21, -0.32); total body (four studies, n  = 157), -0.61 (95% CI: -0.77, -0.45). The small number of observations in the subgroup analyses resulted in a high degree of uncertainty, limiting interpretation. Estimated prevalence of BMD Z-scores ≤ -2.0 was 8% (95% CI: 5%, 13%; four studies, n  = 221) and < -1.0 was 42% (95% CI: 35%, 51%; five studies, n  = 144). Conclusions Adults with PKU had lower BMD Z-scores than the reference (non-PKU) population but < 1 in 10 were below the expected range for age. The low number of studies prevents identification of which population characteristics are most impacting BMD. This meta-analysis was supported by BioMarin Pharmaceutical Inc., Novato, CA and is registered with the Research Registry (reviewregistry1476).

Management of phenylketonuria (PKU) is mainly achieved through dietary control with limited intake of phenylalanine (Phe) from food, supplemented with low protein (LP) food and a mixture of free synthetic (FS) amino acids (AA) (FSAA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese making by the action of the enzyme chymosin. Because CGMP in its pure form does not contain Phe, it is nutritionally suitable as a supplement in the diet for PKU when enriched with specific AAs. Lacprodan® CGMP-20 (= CGMP) used in this study contained only trace amounts of Phe due to minor presence of other proteins/peptides. The aims were to address the following questions in a classical PKU mouse model: Study 1, off diet: Can pure CGMP or CGMP supplemented with Large Neutral Amino Acids (LNAA) as a supplement to normal diet significantly lower the content of Phe in the brain compared to a control group on normal diet, and does supplementation of selected LNAA results in significant lower brain Phe level?. Study 2, on diet: Does a combination of CGMP, essential (non-Phe) EAAs and LP diet, provide similar plasma and brain Phe levels, growth and behavioral skills as a formula which alone consist of FSAA, with a similar composition?. 45 female mice homozygous for the Pahenu2 mutation were treated for 12 weeks in five different groups; G1(N-CGMP), fed on Normal (N) casein diet (75%) in combination with CGMP (25%); G2 (N-CGMP-LNAA), fed on Normal (N) casein diet (75%) in combination with CGMP (19,7%) and selected LNAA (5,3% Leu, Tyr and Trp); G3 (N), fed on normal casein diet (100%); G4 (CGMP-EAA-LP), fed on CGMP (70,4%) in combination with essential AA (19,6%) and LP diet; G5 (FSAA-LP), fed on FSAA (100%) and LP diet. The following parameters were measured during the treatment period: Plasma AA profiles including Phe and Tyr, growth, food and water intake and number of teeth cut. At the end of the treatment period, a body scan (fat and lean body mass) and a behavioral test (Barnes Maze) were performed. Finally, the brains were examined for content of Phe, Tyr, Trp, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindole-acetic acid (5-HIAA), and the bone density and bone mineral content were determined by dual-energy x-ray absorptiometry. Study 1: Mice off diet supplemented with CGMP (G1 (N-CGMP)) or supplemented with CGMP in combination with LNAA (G2 (N-CGMP-LNAA)) had significantly lower Phe in plasma and in the brain compared to mice fed only casein (G3 (N)). Extra LNAA (Tyr, Trp and Leu) to CGMP did not have any significant impact on Phe levels in the plasma and brain, but an increase in serotonin was measured in the brain of G2 mice compared to G1. Study 2: PKU mice fed with mixture of CGMP and EAA as supplement to LP diet (G4 (CGMP-EAA-LP)) demonstrated lower plasma-Phe levels but similar brain- Phe levels and growth as mice fed on an almost identical combination of FSAA (G5 (FSAA-LP)). CGMP can be a relevant supplement for the treatment of PKU.

Phenylketonuria (PKU) is a rare metabolic disorder caused by mutations in the phenylalanine hydroxylase gene. Depending on the severity of the genetic mutation, medical treatment, and patient dietary management, elevated phenylalanine (Phe) may occur in blood and brain tissues. Research has recently shown that high Phe not only impacts the central nervous system, but also other organ systems (e.g., heart and microbiome). This study used ex vivo proton nuclear magnetic resonance (1H-NMR) analysis of urine samples from PKU patients (mean 14.9 ± 9.2 years, n = 51) to identify the impact of elevated blood Phe and PKU treatment on metabolic profiles. Our results found that 24 out of 98 urinary metabolites showed a significant difference (p < 0.05) for PKU patients compared to age-matched healthy controls (n = 51) based on an analysis of urinary metabolome. These altered urinary metabolites were related to Phe metabolism, dysbiosis, creatine synthesis or intake, the tricarboxylic acid (TCA) cycle, end products of nicotinamide-adenine dinucleotide degradation, and metabolites associated with a low Phe diet. There was an excellent correlation between the metabolome and genotype of PKU patients and healthy controls of 96.7% in a confusion matrix model. Metabolomic investigations may contribute to a better understanding of PKU pathophysiology.

Background Phenylketonuria (PKU) is an inherited metabolic disorder where the body cannot break down phenylalanine (Phe), leading to its harmful accumulation if left untreated. Concerns have been raised about growth and risk of overweight in PKU patients, with conflicting research findings. This retrospective study aims to assess growth patterns and the prevalence of overweight and obesity in Danish children and adults with PKU by comparing them with Danish growth charts and prevalence rates. Results Data were collected from medical records of 291 Danish patients from the National PKU Clinic at Rigshospitalet in Copenhagen, including data on age, sex, PKU phenotype, Phe levels, and anthropometric measurements from their last clinic visit. Weight status for children was classified according to Danish guidelines, while World Health Organization criteria were used for adults. All data analyses were carried out separately for children and adults. A total of 291 PKU patients were included, 116 children and 175 adults. Children had normal growth patterns compared to Danish growth charts. The rates of overweight and obesity among children were 15% and 1%, respectively, while 32% of adults were overweight, and 28% were obese. Adults with classic PKU were significantly more obese and had higher BMI levels compared to other phenotypes. Additionally, a slight positive correlation was noted between high Phe levels and the risk of being overweight. Conclusions Children with phenylketonuria following a restricted diet achieve normal growth. However, overweight and obesity rates rise with age, particularly in adults with the most severe phenotype, suggesting disease severity may influence weight gain. The potential link between high phenylalanine levels and overweight requires further investigation. These findings highlight the need for ongoing weight and metabolic monitoring, as well as strategies to support weight management in adults with phenylketonuria.

Background/Objectives: Casein glycomacropeptide (cGMP) has been modified to enable its suitability as a low phenylalanine (Phe) protein substitute (PS) in phenylketonuria (PKU). No data is available about its global usage. Methods: A 60-item multiple choice and short answer/extended response questionnaire examining the use of modified cGMP in PKU was distributed globally to dietitians and physicians via web-based professional inherited metabolic disorder groups. Results: Respondents (n = 208) from 45 countries across 6 continents completed the questionnaire. Of these, 83.7% (n = 174) were dietitians/nutritionists, 14.9% (n = 31) medical doctors/physicians and 1.4% (n = 3) other health professionals, caring for both paediatric and adult patients (59.1%), paediatrics only (25.0%) or adults only (15.9%). cGMP PS were reported as not available in their centre/hospital by 19.7% (n = 41), mostly in Africa, South America, and southern and western Asia. The main reasons included lack of regulatory approval (65.8%), not promoted by manufacturers (41.5%), and cost (29.3%). An estimated 25% of represented patients globally were using cGMP PS; 78.4% (n = 163) following refusal/poor adherence with Phe-free amino acids and 54.8% (n = 114) for adult patients recommencing dietary treatment. There were concerns about the residual Phe in cGMP negatively impacting blood Phe levels in children <12y (66.3%), adolescents (48.0%), adults (34.6%), and the first trimester of pregnancy (53.1%). Sixty nine percent (n = 145) adjusted dietary Phe prescription according to the cGMP Phe content, particularly in regions with a higher percentage of severe PKU variants. Commonly perceived clinical advantages with cGMP were improved taste/palatability (93.2%, n = 194) and fewer gastrointestinal symptoms (55.8%, n = 116). Perceived clinical disadvantages were residual Phe (72.1%, n = 150), lack of data in children < 3 years (48.1%, n = 100), and the high energy content of some brands (45.2%, n = 94). There were concerns that cGMP PS were too high in sugar (34.1%, n = 71) and dissatisfaction or uncertainty about the adequacy of its Phe (66.3%) and amino acid (34.1%) content. Conclusions: There is global inconsistency in access to cGMP PS suitable for PKU, and in the interpretation of evidence-based research. Some professionals have significant concerns about its nutritional composition particularly residual Phe, limiting its estimated use to approximately 25% of PKU patients globally.

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.

Background/Objectives: In phenylketonuria (PKU), high blood phenylalanine (Phe) levels during pregnancy negatively influence foetal organogenesis and growth, leading to maternal PKU syndrome. Pregnancies must be carefully planned in order to maintain blood Phe levels ≤ 360 µmol/L pre-conception and throughout pregnancy. Our aim was to study metabolic control in PKU pregnancies across Europe. Methods: Eleven centres managing PKU participated. Data on blood Phe levels (µmol/L), natural protein intake (g/day), protein substitute intake (g/day) and maternal weight (kg) during pregnancy were collected retrospectively from dietetic records between 2012 and 2018. Results: In total, 84 female patients with PKU, accounting for 102 pregnancies (mean age: 30.4 ± 4.8 years), participated. Of these, 7 had hyperphenylalaninemia (HPA), 26 had mild PKU, 55 had classical PKU and 14 were unclassified. Sapropterin was prescribed in two pregnancies. Only 27% (28/102) of pregnancies successfully achieved consistent blood Phe levels ≤ 360 µmol/L for at least 2 weeks pre-conception. During pregnancy, 88% of blood Phe levels were ≤360 µmol/L, with a mean Phe of 229 ± 65 µmol/L. The mean number of blood Phe samples was 60 (1.5 per week) per pregnancy. In pre-pregnancy, over a mean of 2.9 years, only 35% of blood Phe levels were ≤360 µmol/L and 61% were <600 µmol/L. Post-pregnancy, over a mean of 2.8 years, 43% of Phe levels were <600 µmol/L with mean Phe 462 ± 226 µmol/L and 724 ± 230 µmol/L, respectively. 25% (25/102) had no levels performed post-pregnancy (mean of 2.8 ± 1.6 years) compared to 7% (7/102) pre-pregnancy (mean of 2.9 ± 1.5 years). Mean prescribed Phe intake pre-/during/post-pregnancy was 810 ± 721 vs. 787 ± 552 vs. 1110 ± 722 mg/day. Natural protein intake was 17 ± 15 vs. 17 ± 11 vs. 23 ± 15 g/day. Protein equivalent from protein substitute intake was 57 ± 21 vs. 66 ± 16 vs. 50 ± 23 g/day and total protein remained stable, 73 ± 14 vs. 83 ± 14 vs. 71 ± 19 g/day (1.1 ± 0.3 vs. 1.1 ± 0.4 vs. 1.0 ± 0.4 g/kg/day). Conclusions: Although a high level of metabolic control was maintained during pregnancy, fewer than 30% of pregnancies achieved constant Phe levels ≤ 360 µmol/L prior to conception, with minimal monitoring post-pregnancy. The long-term impact on the offspring remains unknown and requires further investigation.

There is an ongoing debate regarding the impact of phenylketonuria (PKU) and its treatment on growth. To date, evidence from studies is inconsistent, and data on the whole developmental period is limited. The primary aim of this systematic review was to investigate the effects of a phenylalanine (Phe)-restricted diet on long-term growth in patients with PKU. Four electronic databases were searched for articles published until September 2018. A total of 887 results were found, but only 13 articles met eligibility criteria. Only three studies had an adequate methodology for meta-analysis. Although the results indicate normal growth at birth and during infancy, children with PKU were significantly shorter and had lower weight for age than reference populations during the first four years of life. Impaired linear growth was observed until the end of adolescence in PKU. In contrast, growth impairment was not reported in patients with mild hyperphenylalaninemia, not requiring dietary restriction. Current evidence indicates that even with advances in dietary treatments, “optimal” growth outcomes are not attained in PKU. The majority of studies include children born before 1990s, so further research is needed to show the effects of recent dietary practices on growth in PKU.

Introduction. Management of phenylketonuria (PKU) is achieved through low-phenylalanine (Phe) diet, supplemented with low-protein food and mixture of free-synthetic (FS) amino acid (AA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese-making and does not contain Phe. Lacprodan® CGMP-20 used in this study contained a small amount of Phe due to minor presence of other proteins/peptides. Objective. The purpose of this study was to compare absorption of CGMP-20 to FSAA with the aim of evaluating short-term effects on plasma AAs as well as biomarkers related to food intake. Methods. This study included 8 patients, who had four visits and tested four drink mixtures (DM1–4), consisting of CGMP, FSAA, or a combination. Plasma blood samples were collected at baseline, 15, 30, 60, 120, and 240 minutes (min) after the meal. AA profiles and ghrelin were determined 6 times, while surrogate biomarkers were determined at baseline and 240 min. A visual analogue scale (VAS) was used for evaluation of taste and satiety. Results. The surrogate biomarker concentrations and VAS scores for satiety and taste were nonsignificant between the four DMs, and there were only few significant results for AA profiles (not Phe). Conclusion. CGMP and FSAA had the overall same nonsignificant short-term effect on biomarkers, including Phe. This combination of FSAA and CGMP is a suitable supplement for PKU patients.

At the Kennedy Centre for Phenylketonuria, Denmark, large neutral amino acids (LNAAs) are being used to treat adult and adolescent patients who are nonadherent to dietary treatment for phenylketonuria (PKU). At the start of treatment, a patient must undergo dietary analysis and regular blood sampling to measure plasma amino acid (AA) concentrations. The aim of this analysis and treatment is that the patient receives 25–30% of the daily protein requirement from LNAA supplementation and the remaining 70–75% from natural, low-phenylalanine proteins (although some patients have difficulties in maintaining this level of protein intake). Patients are therefore able to follow a more “normal” diet than those adhering to a PKU diet with AA supplementation (in which only 20% of the daily protein requirement is provided from the diet and 80% from AA supplementation). LNAAs have also been used to treat older patients with untreated/late-diagnosed PKU who show profound intellectual, psychological, and behavioral impairments. Treatment with LNAAs has been shown to improve measures of concentration and awareness of external stimuli in some of these patients and thus enhance their socialization, emotionality, frustration tolerance, and mood.