Phenylketonuria (PKU) is an autosomal recessive inherited disorder of phenylalanine metabolism caused by deficiency of the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. Untreated, PKU results in elevated phenylalanine levels in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. For this first revision of the European PKU Guidelines previous recommendations were re-evaluated and updated according to new research findings. Twenty-one professionals were divided across four working groups and supported by a coordinator and chair. In addition to an update of the previous 70 recommendations, 20 new topics were included, resulting in a total of 87 statements in this first revision of the guidelines. Research publications were reviewed up until September 2022. Evidence was graded as high, moderate, low, very low or expert opinion and the recommendations were graded conditional or strong according to GRADE methodology. All recommendations were discussed during 14 plenary online or in person meetings. Recommendations were accepted if more than 75 % of the professionals were in agreement. When recommendations were not amended, the text reported in the European guidelines of 2017 remains valid.

Phenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients. To this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations ≥1200 μmol/l; and 3) IQ ≥80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers. In total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms. Based on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients.

Although there is a general assumption that a phenylalanine (Phe)-restricted diet promotes overweight in patients with phenylketonuria (PKU), it is unclear if this presumption is supported by scientific evidence. This systematic review aimed to determine if patients with PKU are at a higher risk of overweight compared to healthy individuals. A literature search was carried out on PubMed, Cochrane Library, and Embase databases. Risk of bias of individual studies was assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, and the quality of the evidence for each outcome was assessed using the NutriGrade scoring system. From 829 articles identified, 15 were included in the systematic review and 12 in the meta-analysis. Body mass index (BMI) was similar between patients with PKU and healthy controls, providing no evidence to support the idea that a Phe-restricted diet is a risk factor for the development of overweight. However, a subgroup of patients with classical PKU had a significantly higher BMI than healthy controls. Given the increasing prevalence of overweight in the general population, patients with PKU require lifelong follow-up, receiving personalised nutritional counselling, with methodical nutritional status monitoring from a multidisciplinary team in inherited metabolic disorders.

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.

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.

In infants with phenylketonuria (PKU), dietary management is based on lowering and titrating phenylalanine (Phe) intake from breast milk or standard infant formula in combination with a Phe-free infant formula in order to maintain blood Phe levels within target range. Professionals use different methods to feed infants with PKU and our survey aimed to document practices across Europe. We sent a cross sectional, survey monkey® questionnaire to European health professionals working in IMD. It contained 31 open and multiple-choice questions. The results were analysed according to different geographical regions. Ninety-five centres from 21 countries responded. Over 60% of centres commenced diet in infants by age 10 days, with 58% of centres implementing newborn screening by day 3 post birth. At diagnosis, infant hospital admission occurred in 61% of metabolic centres, mainly in Eastern, Western and Southern Europe. Breastfeeding fell sharply following diagnosis with only 30% of women still breast feeding at 6 months.53% of centres gave pre-measured Phe-free infant formula before each breast feed and 23% alternated breast feeds with Phe-free infant formula. With standard infant formula feeds, measured amounts were followed by Phe-free infant formula to satiety in 37% of centres (n = 35/95), whereas 44% (n = 42/95) advised mixing both formulas together. Weaning commenced between 17 and 26 weeks in 85% centres, ≥26 weeks in 12% and < 17 weeks in 3%. This is the largest European survey completed on PKU infant feeding practices. It is evident that practices varied widely across Europe, and the practicalities of infant feeding in PKU received little focus in the PKU European Guidelines (2017). There are few reports comparing different feeding techniques with blood Phe control, Phe fluctuations and growth. Controlled prospective studies are necessary to assess how different infant feeding practices may influence longer term feeding development.