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Abstract 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

Abstract Background Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism that, if untreated, causes Phe accumulation in the brain leading to neurophysiologic alterations and poor outcomes. Lifelong management centers on dietary Phe restriction, yet long-term complete metabolic control is unachievable for many adults. High blood Phe levels or chronic Phe and intact protein restriction in the diet may lead to somatic comorbidities. A systematic literature review was conducted to evaluate somatic comorbidities experienced by adults with PKU. Methods Clinical and observational studies reporting somatic comorbidities experienced by individuals with PKU aged ≥ 16 years (or classified as adults) evaluating a Phe-restricted diet with or without pharmacologic therapy versus no therapeutic intervention (including healthy controls), or pharmacologic therapy versus a Phe-restricted diet alone, were identified. PubMed® was searched (February 1, 2022 and updated November 1, 2023), using a pre-defined search strategy, followed by two-stage screening and data extraction. Included studies were grouped by PKU population comparison. Results 1185 records were screened; 51 studies across 12,602 individuals were extracted. Bone-related abnormalities were the most reported outcome (n = 21); several outcome measures were used. Original study groupings included: Phe-restricted diet versus healthy controls or reference values (n = 40); treatment-adherent versus those non-adherent (n = 12). Additional groups added as part of a protocol amendment included: different Phe-restricted diets (n = 4); severe versus less severe disease (n = 5). Vote counting indicated a higher burden of ≥ 1 comorbidity (or outcome measure) for the Phe-restricted diet group by 37 of 38 studies included in the analysis of Phe-restricted diet versus healthy controls; higher burden in healthy controls was reported in 12 studies. Vote counting was similar between those treatment adherent (n = 7) versus non-adherent (n = 10). Conclusions Adults with PKU have a higher comorbidity burden than a non-PKU population. More robust studies are needed to better understand the relationship between effective metabolic control and comorbidity burden, using consistent outcome measures. This SLR was supported by BioMarin Pharmaceutical Inc., Novato, CA, and is registered with the Research Registry (reviewregistry1476).

In Portugal, tetrahydrobiopterin (BH4)-responsive patients with phenylketonuria (PKU) are identified using a loading test (LT). Phenylalanine/natural protein (Phe/NP) intake is increased to elevate blood Phe prior to the LT. In a longitudinal retrospective study, the impact of Phe/NP titration post-LT in 58 patients (19.6 ± 8.2 years) with PKU during 4 study periods (SPs) was examined. In SP1 (2010-2013), patients were diet treated only; in SP2 (2014), the Phe/NP titration was followed by the LT in SP3 (2015). In SP4 (2016), patients received diet treatment only (n = 49) or BH4 + diet (n = 9). The median percentage blood Phe within the target range was higher in SP1 versus SP4 (64 [28-85] vs 45 [0-66]; P < .001). Our results suggest that transient Phe/NP titration, associated with a deliberate increase in NP, may adversely affect metabolic control. Controlled studies are necessary to examine the longer term impact of temporary increased NP with BH4 LT in non-BH4-responsive patients.

Lifelong low-phenylalanine (Phe) dietary management is the foundation of care in phenylketonuria (PKU). However, strict monitoring of food intake places a burden on patients and their caregivers, and adherence to the required diet frequently decreases in later childhood and adolescence. Rarely, parents of children with PKU refuse to recognise the importance of treatment and follow-up for this chronic condition. Here, two case studies are presented that document consideration of placement of children into foster care or kinship homes as a last resort to improve persistently high Phe concentrations. In the first case, social service referral led to a 3-year-old girl being placed in a kinship home with her grandparents, resulting in excellent Phe control thereafter. In the second case, discussion with the parents of possible placement of a 12-year-old child into foster care was sufficient to have a positive effect on Phe control. A staged approach for managing intractable non-adherence in PKU is proposed.