In the Netherlands, abnormal New-Born Screening (NBS) results are communicated to parents by the general practitioner (GP). Good communication and consequential trust in professionals is of the utmost importance in the treatment of phenylketonuria (PKU). The aim of this study was to assess parental satisfaction regarding the communication of an abnormal NBS result for PKU in the Netherlands. An email containing the link to a web-based questionnaire was sent by the Dutch PKU Association to their members. Responses to open questions were categorized, data of both open and closed questions were analysed with descriptive statistics and the Chi-Square test using SPSS. Out of 113 parents of a child with PKU (born between 1979 and 2020), 68 stated they were overall unsatisfied with the first communication of the NBS result. Seventy-five parents indicated that wrong or no information about PKU was given. A significant decrease was found in the number of parents being contact by their own GP over the course of 40 years (p < 0.05). More than half of all parents were overall unsatisfied with the first communication of the abnormal NBS result for PKU. Further research on how to optimize communication of an abnormal NBS results is necessary.

While the dietary treatment in phenylketonuria (PKU) is known to cause eating problems and social restrictions in children, knowledge of the prevalence and magnitude of these problems in adults is scarce. This study aimed to evaluate the impact of PKU and its dietary treatment on daily life of adults with PKU. A web-based questionnaire consisting of a PKU-specific questionnaire, the Patient-Reported Outcomes Measurement Information System (PROMIS) short forms, and the 36-Item Short Form Health Survey (SF36) was completed by 40 adults with PKU and 15 age-matched controls without PKU. PROMIS scores were compared to the US-norm (T-score of 50, SD 10), and SF36 scores were compared to age-matched healthy individuals participating in a large Dutch population-based cohort (N > 40.000). Participants with PKU tended to experience more stress during dinner outside the home and more often canceled dinner with friends in comparison to Dutch controls (median 2 versus 1, P < 0.001; median 4 versus 5, P = 0.041). Adults with PKU experienced more fatigue and limitations in daily life due to emotional problems in comparison to the large Dutch cohort (M = 55 versus 67, P < 0.001; M = 68 versus 90, P < 0.001), and they also reported reduced perceived mental and general health (M = 70 versus 79, P < 0.005; M = 63 versus 75, P < 0.001). PKU and its dietary treatment may affect adults with PKU, particularly in mental health related domains.

Since the 1960s, phenylalanine hydroxylase (PAH) deficiency can be detected via newborn screening, allowing early start of treatment to prevent severe intellectual disability. Precise determination of PAH deficiency severity continues to be hampered by several factors. Nevertheless, as therapeutic options broaden, precise determination of PAH deficiency severity becomes critical to inform individualized treatment selection. Although various methods (hepatic PAH activity, pretreatment phenylalanine (Phe) levels, Phe loading test, Phe tolerance, in vitro expression analysis, tracer studies, prediction models) have been used to assess and/or classify PAH deficiency, all of them still report inconsistencies in the correlation between genotype and biochemical phenotype. Establishing the genotype–phenotype correlation for different genotypes is complicated by the enormous genetic heterogeneity within the PAH gene. Furthermore, variability in the terminology applied to different phenotype strata further complicates interpretation. Here, we aim to summarize the methods that have been described in the literature to assess the classification of PAH deficiency and propose terminology to describe phenotype levels as a crucial step to overcome these issues.

Newborn screening (NBS) for inherited metabolic diseases (IMD) aims to find children in which immediate action can prevent severe symptoms. We previously studied parental satisfaction with the communication of the NBS result for phenylketonuria, which in the Netherlands is done by the general practitioners (GPs). More than half of all parents were unsatisfied with the communication of the abnormal NBS result. The aim of this qualitative exploratory study was to portray a number of GPs’ opinions and experiences in communicating an abnormal metabolic NBS result. We performed semi-structured interviews with ten GPs to evaluate the process of communicating the abnormal NBS result. An additional two GPs provided their answers via email. The data revealed four key themes: (1) dealing with the urgency of the metabolic NBS result, (2) the role of the GP in the NBS process, (3) the current organization of NBS in the Netherlands and (4) evaluating roles and responsibilities in communicating abnormal metabolic NBS results. Despite the willingness of GPs to inform parents about NBS results, it is questionable whether they have the necessary tools to effectively conduct these conversations given their limited experience with IMDs. In light of the increasing number of diseases in the NBS program, it would be interesting to explore alternative tools for communicating the NBS result to parents.

With the expanding treatment landscape for phenylketonuria (PKU), there is a growing need for a reliable, non-invasive method to quantify residual phenylalanine hydroxylase (PAH) activity and to determine disease severity to guide individualized treatment strategies. The 13C-Phenylananine (Phe) breath test (13C-PBT) has the potential to measure in vivo oxidation of Phe by quantifying conversion of 13C-Phe to 13CO2. Although the 13C-PBT has previously been used in PKU, its test-retest reliability in PAH deficient individuals has not been studied. The aim of this study was to assess the test-retest reliability of the 13C-PBT in individuals with PAH deficiency and to evaluate the association between 13C-Phe oxidation parameters and disease severity. To establish reference values and to optimize protocol, 10 healthy adults underwent the 13C-PBT once. Subsequently, 10 individuals with varying severities of PAH deficiency completed the test twice. After an overnight fast, all participants received an oral dose of 6 mg/kg 13C-Phe. Both area under the curve (AUC) and the maximum 13C-Phe oxidation showed a good-to-excellent test-retest reliability, expressed as an ICC of 0.93 (95% CI 0.71-0.98) and 0.91 (95% CI 0.68-0.98) respectively. When stratifying for the genotypic phenotype value (GPV), it was shown that a lower GPV was associated with lower oxidation parameters in comparison to higher GPV levels. These findings support the 13C-PBT as a reliable, easy to perform, non-invasive measure of in vivo PAH function that could potentially aid in the interpretation of PAH variants and the assessment of treatment response.

Background: Despite early and continued treatment, neurocognitive deficits have been reported in individuals with phenylketonuria (PKU). As treatment targets in PKU differ internationally, direct cross-national comparison of neurocognitive outcomes remains scarce, yet potentially valuable. This pilot study compared neurocognitive performance between Australian and Dutch individuals with PKU and examined associations between metabolic control and cognitive outcomes. Methods: Thirteen individuals with PKU from the Queensland Lifespan Metabolic Service (4M;9F, mean age 14 years) were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Data from 13 age-matched Dutch participants (4M;9F, mean age 15 years) were obtained from the Frist Dutch PKU Database (FDPD+) databank. Six cognitive domains were assessed: sustained attention, multitasking, emotion recognition, reaction time, visuospatial memory, and decision-making. Concurrent and prior-year Phe, Tyr, and Phe:Tyr ratios were collected for all participants. Results: The two cohorts performed comparably across most CANTAB domains. No significant between-group differences survived correction for multiple comparisons. Concurrent Phe was significantly associated with poorer sustained attention on both the RVP 1T (ρ = −0.57, p = 0.015) and RVP 3T (ρ = −0.78, p = 0.001). The concurrent Phe:Tyr ratio was similarly associated with RVP 3T performance (ρ = −0.76, p = 0.001). Participants with concurrent Phe ≥360 µmol/L showed significantly worse sustained attention compared to those with Phe <360 µmol/L (p = 0.048). Conclusion: The neurocognitive profile of Australian and Dutch individuals with PKU appeared broadly comparable in this pilot study. The association between concurrent Phe and sustained attention underscores the importance of maintaining metabolic control beyond childhood.