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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.

Phenylketonuria is an inherited condition characterised by neurotoxic accumulation of phenylalanine (Phe). APHENITY assessed the efficacy and safety of orally administered synthetic sepiapterin in children and adults with phenylketonuria. APHENITY was a phase 3, randomised, double-blind, placebo-controlled study performed at 34 clinics, hospitals, and university sites in 13 countries. Individuals of all ages with a clinical diagnosis of phenylketonuria were eligible for inclusion if they had a blood Phe concentration of 360 μmol/L or higher at study entry, whereas individuals with hyperphenylalaninaemia due to pathogenic variants in GCH1, PTS, QDPR, SPR, and PCBD1, consistent with a diagnosis of primary BH4 deficiency, were excluded. Part 1 was a 14-day open-label assessment of blood Phe concentration response to sepiapterin. In part 2, sepiapterin-responsive participants were randomly assigned (1:1) by a web-response system based on a block randomisation schedule (permuted block size of 2 and 4) to 6 weeks of sepiapterin (forced-dose escalation: 20, 40, and 60 mg/kg per day per consecutive 2-week period) or placebo. The investigational drug and placebo were identical in their appearance and delivery. Dried blood samples were collected for analysis of Phe concentration on days –1, 1 (before dose was administered), 5, 10, 14, 19, 24, 28, 33, 38, and 42 in part 2, either in-clinic or at home. The primary endpoint for part 2, mean change from baseline in blood Phe after 6 weeks, was assessed in the primary analysis set of participants with at least a 30% reduction in blood Phe concentration in part 1, who took at least one dose in part 2. Safety was evaluated in all participants receiving at least one dose of treatment. The completed study is registered at EudraCT (2021-000474-29) and ClinicalTrials.gov (NCT05099640). APHENITY was conducted between Sept 30, 2021, and April 3, 2023. 187 people were assessed for eligibility, of whom 157 were enrolled. In part 1, 156 participants were assessed or evaluated, of whom 114 (73%) were sepiapterin-responsive (ie, ≥15% reduction in blood Phe from baseline). In part 2, 98 participants (49 in the placebo group and 49 in the sepiapterin group) were in the primary analysis set. There was a significant reduction of blood Phe concentration after 6 weeks of sepiapterin (–63%, SD 20) compared with placebo (1%, 29; least squares mean change –395·9 μmol/L, SE 33·8; p<0·0001). Treatment-emergent adverse events were reported in 33 (59%) of 56 participants who received sepiapterin and 18 (33%) of 54 participants who received placebo. Most treatment-emergent adverse events were mild gastrointestinal events (11 [20%] of 56 participants who received sepiapterin and ten [19%] of 54 participants who received placebo) that resolved quickly. There were no deaths and no serious or severe adverse events. Sepiapterin is a promising oral therapy for individuals with phenylketonuria, was well tolerated, and resulted in significant and clinically meaningful reductions in blood Phe concentration in participants with varying disease severity. PTC Therapeutics.

The usual treatment for phenylketonuria (PKU) is a phenylalanine-restricted diet. Following this diet is challenging, and long-term adherence (and hence metabolic control) is commonly poor. Patients with PKU (usually, but not exclusively, with a relatively mild form of the disorder) who are responsive to treatment with pharmacological doses of tetrahydrobiopterin (BH4) have either lower concentrations of blood phenylalanine or improved dietary phenylalanine tolerance. The availability of a registered formulation of BH4 (sapropterin dihydrochloride, Kuvan®) has raised many practical issues and new questions in the dietary management of these patients. Initially, patients and carers must understand clearly the likely benefits (and limitations) of sapropterin therapy. A minority of patients who respond to sapropterin are able to discontinue the phenylalanine-restricted diet completely, while others are able to relax the diet to some extent. Care is required when altering the phenylalanine-restricted diet, as this may have unintended nutritional consequences and must be undertaken with caution. New clinical protocols are required for managing any dietary change while maintaining control of blood phenylalanine, ensuring adequate nutrition and preventing nutritional deficiencies, overweight or obesity. An accurate initial evaluation of pre-sapropterin phenylalanine tolerance is essential, and the desired outcome from treatment with sapropterin (e.g. reduction in blood phenylalanine or relaxation in diet) must also be understood by the patient and carers from the outset. Continuing education and support will be required thereafter, with further adjustment of diet and sapropterin dosage as a young patient grows.

•Parents’ knowledge regarding phenylketonuria food selection was relatively high.•Certain foods posed a challenge for most respondents.•Restricted foods were better identified than \"free\" foods (phenylalanine <50 mg/100 g). Dietary treatment is the main therapy for most patients with phenylketonuria (PKU). Parental knowledge regarding food selection is crucial to ensure adequate metabolic control and brain development during childhood and to promote lifelong adherence and healthy dietary behavior in the offspring. The aims of this study were to assess whether parental or caregiver knowledge regarding nutritional selection for children with PKU is in accordance with medical recommendations and to evaluate factors that influence their level of knowledge. This was a cross-sectional observational study. An online or paper survey (N = 178) was distributed throughout the United States. The survey included a validated food selection questionnaire to assess whether the respondent adequately identified foods that require certain restrictions versus foods that can be consumed freely by an individual with PKU. General knowledge of food selection among the caregivers was very high or high in nearly 60% (60–98th score percentile). Participants with the lowest scores in general knowledge of the PKU diet (quartile 1) were more likely to label allowed foods incorrectly. Respondents with the highest scores (quartile 4) were more likely to label limited foods correctly but incorrectly label allowed items. Knowledge of restricted foods is important to avoid poor metabolic control, but knowledge of allowed foods can be just as important to allow for a diet that is diverse, palatable, and nutritionally balanced.

Background: In 2011, a European phenylketonuria (PKU) survey reported that the blood phenylalanine (Phe) levels were well controlled in early life but deteriorated with age. Other studies have shown similar results across the globe. Different target blood Phe levels have been used throughout the years, and, in 2017, the European PKU guidelines defined new targets for blood Phe levels. This study aimed to evaluate blood Phe control in patients with PKU across Europe. Methods: nine centres managing PKU in Europe and Turkey participated. Data were collected retrospectively from medical and dietetic records between 2012 and 2018 on blood Phe levels, PKU severity, and medications. Results: A total of 1323 patients (age range:1–57, 51% male) participated. Patient numbers ranged from 59 to 320 in each centre. The most common phenotype was classical PKU (n = 625, 48%), followed by mild PKU (n = 357, 27%) and hyperphenylalaninemia (HPA) (n = 325, 25%). The mean percentage of blood Phe levels within the target range ranged from 65 ± 54% to 88 ± 49% for all centres. The percentage of Phe levels within the target range declined with increasing age (<2 years: 89%; 2–5 years: 84%; 6–12 years: 73%; 13–18 years: 85%; 19–30 years: 64%; 31–40 years: 59%; and ≥41 years: 40%). The mean blood Phe levels were significantly lower and the percentage within the target range was significantly higher (p < 0.001) in patients with HPA (290 ± 325 μmol/L; 96 ± 24%) and mild PKU (365 ± 224 μmol/L; 77 ± 36%) compared to classical PKU (458 ± 350 μmol/L, 54 ± 46%). There was no difference between males and females in the mean blood Phe levels (p = 0.939), but the percentage of Phe levels within the target range was higher in females among school-age children (6–12 years; 83% in females vs. 78% in males; p = 0.005), adolescents (13–18 years; 62% in females vs. 59% in males; p = 0.034) and adults (31–40 years; 65% in females vs. 41% in males; p < 0.001 and >41 years; 43% in females vs. 28% in males; p < 0.001). Patients treated with sapropterin (n = 222) had statistically significantly lower Phe levels compared to diet-only-treated patients (mean 391 ± 334 μmol/L; percentage within target 84 ± 39% vs. 406 ± 334 μmol/L; 73 ± 41%; p < 0.001), although a blood Phe mean difference of 15 µmol/L may not be clinically relevant. An increased frequency of blood Phe monitoring was associated with better metabolic control (p < 0.05). The mean blood Phe (% Phe levels within target) from blood Phe samples collected weekly was 271 ± 204 μmol/L, (81 ± 33%); for once every 2 weeks, it was 376 ± 262 μmol/L, (78 ± 42%); for once every 4 weeks, it was 426 ± 282 μmol/L, (71 ± 50%); and less than monthly samples, it was 534 ± 468 μmol/L, (70 ± 58%). Conclusions: Overall, blood Phe control deteriorated with age. A higher frequency of blood sampling was associated with better blood Phe control with less variability. The severity of PKU and the available treatments and resources may impact the blood Phe control achieved by each treatment centre.

Hyperammonaemia is a metabolic derangement that may cause severe neurological damage and even death due to cerebral oedema, further complicating the prognosis of its triggering disease. In small children it is a rare condition usually associated to inborn errors of the metabolism. As age rises, and especially in adults, it may be precipitated by heterogeneous causes such as liver disease, drugs, urinary infections, shock, or dehydration. In older patients, it is often overlooked, or its danger minimized. This protocol was drafted to provide an outline of the clinical measures required to normalise ammonia levels in patients of all ages, aiming to assist clinicians with no previous experience in its treatment. It is an updated protocol developed by a panel of experts after a review of recent publications. We point out the importance of frequent monitoring to assess the response to treatment, the nutritional measures that ensure not only protein restriction but adequate caloric intake and the need to avoid delays in the use of specific pharmacological therapies and, especially, extrarenal clearance measures. In this regard, we propose initiating haemodialysis when ammonia levels are >200–350 µmol/L in children up to 18 months of age and >150–200 µmol/L after that age.

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.

Background Special low protein foods (SLPF) are essential in the nutritional management of patients with phenylketonuria (PKU). The study objectives were to: 1) identify the number of SLPF available for use in eight European countries and Turkey and 2) analyse the nutritional composition of SLPF available in one of these countries. Methods European Nutritionist Expert Panel on PKU (ENEP) members (Portugal, Spain, Belgium, Italy, Germany, Netherlands, UK, Denmark and Turkey) provided data on SPLF available in each country. The nutritional composition of Portuguese SLPF was compared with regular food products. Results The number of different SLPF available in each country varied widely with a median of 107 [ranging from 73 (Portugal) and 256 (Italy)]. Food analysis of SLPF available from a single country (Portugal) indicated that the mean phenylalanine content was higher in low protein baby cereals (mean 48 mg/100 g) and chocolate/energy bars/jelly (mean 41 mg/100 g). The energy content of different foods from a sub-group of SLPF (cookies) varied widely between 23 and 96 kcal/cookie. Low protein bread had a high fat content [mean 5.8 g/100 g (range 3.7 to 10)] compared with 1.6 g/100 g in regular bread. Seven of the 12 SLPF sub-groups (58 %) did not declare any vitamin content, and only 4 (33 %) identified a limited number of minerals. Conclusions Whilst equal and free access to all SLPF is desirable, the widely variable nutritional composition requires careful nutritional knowledge of all products when prescribed for individual patients with PKU. There is a need for more specific nutritional standards for special low protein foods.

In phenylketonuria (PKU), natural protein intake is thought to increase with age, particularly during childhood and adolescence. Longitudinal dietary intake data are scarce and lifelong phenylalanine tolerance remains unknown. Nine centres managing PKU in Europe and Turkey participated in a retrospective study. Data were collected from dietetic records between 2012 and 2018 on phenylalanine (Phe), natural protein, and protein substitute intake. A total of 1323 patients (age range: 1–57 y; 51% male) participated. Dietary intake data were available on 1163 (88%) patients. Patient numbers ranged from 59 to 320 in each centre. A total of 625 (47%) had classical PKU (cPKU), n = 357 (27%) had mild PKU (mPKU), n = 325 (25%) had hyperphenylalaninemia (HPA), and n = 16 (1%) were unknown. The mean percentage of blood Phe levels within target ranged from 65 ± 54% to 88 ± 49%. When intake was expressed as g/day, the mean Phe/natural protein and protein equivalent from protein substitute gradually increased during childhood, reaching a peak in adolescence, and then remained consistent during adulthood. When intake was expressed per kg body weight (g/kg/day), there was a decline in Phe/natural protein, protein equivalent from protein substitute, and total protein with increasing age. Overall, the mean daily intake (kg/day) was as follows: Phe, 904 mg ± 761 (22 ± 23 mg/kg/day), natural protein 19 g ± 16 (0.5 g/kg/day ± 0.5), protein equivalent from protein substitute 39 g ± 22 (1.1 g/kg/day ± 0.6), and total protein 59 g ± 21 (1.7 g/kg/day ± 0.6). Natural protein tolerance was similar between males and females. Patients with mPKU tolerated around 50% less Phe/natural protein than HPA, but 50% more than cPKU. Higher intakes of natural protein were observed in Southern Europe, with a higher prevalence of HPA and mPKU compared with patients from Northern European centres. Natural protein intake doubled with sapropterin usage. In sapropterin-responsive patients, 31% no longer used protein substitutes. Close monitoring and optimisation of protein intake prescriptions are needed, along with future guidelines specifically for different age groups and severities.

Background: Severe intellectual disability and growth impairment have been overcome by the success of early and continuous treatment of patients with phenylketonuria (PKU). However, there are some reports of obesity, particularly in women, suggesting that this may be an important comorbidity in PKU. It is becoming evident that in addition to acceptable blood phenylalanine control, metabolic dieticians should regard weight management as part of routine clinical practice. Summary: It is important for practitioners to differentiate the 3 levels for overweight interpretation: anthropometry, body composition and frequency and severity of associated metabolic comorbidities. The main objectives of this review are to suggest proposals for the minimal standard and gold standard for the assessment of weight management in PKU. While the former aims to underline the importance of nutritional status evaluation in every specialized clinic, the second objective is important in establishing an understanding of the breadth of overweight and obesity in PKU in Europe. Key Messages: In PKU, the importance of adopting a European nutritional management strategy on weight management is highlighted in order to optimize long-term health outcomes in patients with PKU.