Orphanet Journal of Rare Diseases | Study on Metabolic Control and Quality of Life in Adult Phenylketonuria Patients After Transition

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This study evaluates metabolic control, quality of life, and the impact of mental comorbidities in adult phenylketonuria (PKU) patients 4.5 years after a structured transition to adult care. It finds that structured transition helps maintain metabolic stability, but mental comorbidities significantly affect treatment adherence and quality of life.

 

Literature Overview

The article titled 'Navigating adulthood with PKU: metabolic outcomes, quality of life, and mental health 4.5 years post-transition', published in the Orphanet Journal of Rare Diseases, reviews and summarizes metabolic control, dietary adherence, quality of life, and comorbidity status in 45 adult phenylketonuria (PKU) patients over 4.5 years following transfer to an adult metabolic center. The study finds that while average phenylalanine (Phe) concentrations remain stable, mental comorbidities significantly affect Phe levels, dietary and supplement adherence, thereby impairing quality of life. It emphasizes the importance of structured transition and psychological support in adult PKU management.

Background Knowledge

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, leading to phenylalanine (Phe) accumulation and neurotoxicity. Untreated, it can result in severe neurological impairments such as intellectual disability and epilepsy. The global incidence is approximately 1:23,930, and 1:10,000 in Europe, making it one of the key conditions in newborn screening. Standard treatment involves a low-protein diet supplemented with amino acid mixtures devoid of phenylalanine (AAM), with some patients benefiting from pharmacological agents such as Sapropterin or Pegvaliase. Despite early diagnosis and treatment significantly improving outcomes, adult PKU management remains challenging, as most metabolic centers focus on pediatric care, leading to care discontinuity during the transition from adolescence to adulthood. This discontinuity may result in treatment interruptions, deteriorating metabolic control, and increased psychological burden. Additionally, prolonged high Phe levels are associated with declining neuropsychological function, and adult PKU patients face increased risks of comorbidities, including psychiatric disorders, reduced bone mineral density, obesity, and metabolic syndrome. Current European guidelines recommend maintaining adult Phe concentrations below 600 μmol/L, but actual achievement rates are low, and long-term intervention evidence is lacking. Quality of life (QoL) assessment is increasingly recognized as a crucial dimension in treatment evaluation, with disease-specific tools like PKU-QOL being more sensitive in capturing patients’ subjective burden. This study fills a gap in long-term follow-up data for adult PKU under structured transition models, revealing the central role of mental comorbidities in metabolic imbalance and providing empirical support for optimizing multidisciplinary management strategies.

 

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Research Methods and Experiments

This single-center, retrospective observational study included 45 PKU patients treated at the adult metabolic center of Jena University Hospital between December 2019 and April 2024. All patients underwent a structured transition program, including multidisciplinary consultations, medical record transfer, and personalized goal setting. Data were extracted from the electronic medical record system (EMIL®), including Phe concentrations (from venous blood and dried blood spots), dietary habits, AAM intake frequency, comorbidity diagnoses, and quality-of-life assessments (PKU-QOL and WHO-5). Phe levels were monitored quarterly, dietary and AAM adherence were recorded via interviews, and PKU-QOL was assessed annually. Statistical analyses employed mixed linear models and Mann-Whitney U tests to evaluate associations between Phe levels and various factors.

Key Findings and Insights

• Among 45 patients with a mean age of 32.8 years, the mean Phe concentration was 998.3 ± 290.4 μmol/L, remaining stable overall, though only 38% of measurements fell within individualized targets, and adherence declined over time
• Dietary adherence improved from a baseline of 77.8% to 100% at the third-year follow-up, and AAM intake increased from 62.5% to 85.8%, indicating that structured transition effectively improves treatment behaviors
• Regular AAM use (≥3 times/day) was associated with a 362.9 μmol/L reduction in Phe levels, and adherence to a low-protein diet was associated with a 304.1 μmol/L reduction, both statistically significant (p < 0.05)
• 89% of patients had comorbidities, with psychiatric disorders being most common (31.1%), including anxiety, depression, and post-traumatic stress disorder; patients with psychiatric comorbidities had significantly higher Phe levels (1169 vs 823 μmol/L, p < 0.05)
• Patients with psychiatric comorbidities showed significantly lower dietary adherence (33% vs 70%, p < 0.01), and PKU-QOL scores indicated worse quality of life in AAM adherence, practical impact of diet, and taste of low-protein foods
• No significant group differences were observed in WHO-5 scores, suggesting that subjective well-being does not fully reflect metabolic and psychological burdens, necessitating comprehensive assessment using disease-specific tools

Research Significance and Outlook

This study is the first to systematically evaluate the impact of a structured transition model on long-term metabolic control in adult PKU patients, confirming its value in maintaining Phe stability and improving treatment adherence. It underscores the importance of personalized goal setting and shared decision-making, avoiding rigid adherence to guideline-recommended values to enhance patient engagement and sustainability.

More importantly, the study highlights the central role of mental comorbidities in PKU management—not only as common comorbidities but also as drivers of metabolic imbalance and reduced quality of life. This suggests that psychological assessment and support should be integrated into routine care pathways rather than offered as ancillary services. Future research should explore the effectiveness of integrated psychological interventions (e.g., cognitive behavioral therapy) in PKU management and develop targeted support tools.

Despite a small sample size and single-center design, the low loss-to-follow-up rate (4.4%) and real-world data enhance the credibility of the findings. The study calls for the establishment of a national adult PKU registry to track long-term outcomes and optimize resource allocation. Ultimately, a multidisciplinary collaborative model—particularly the triad of psychological, nutritional, and metabolic management—should become the standard of care for adult PKU.

 

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Conclusion

This study demonstrates that a structured transition to adult care can effectively support phenylketonuria patients in maintaining metabolic stability and gradually improving treatment adherence. Although average phenylalanine concentrations remain high (approximately 998 μmol/L), above the European guideline recommendation of below 600 μmol/L, regular use of amino acid mixtures and adherence to a low-protein diet significantly reduce Phe levels. Notably, mental comorbidities are highly prevalent among patients (31.1%) and are significantly associated with higher Phe concentrations, lower dietary and supplement adherence, and poorer quality of life. This reveals the critical role of psychological factors in PKU management, suggesting that optimizing dietary regimens alone is insufficient for favorable outcomes. The study emphasizes integrating psychological support into routine adult PKU care through multidisciplinary collaboration to identify high-risk individuals and provide early interventions. Larger, multicenter studies are needed to validate these findings and explore the long-term impact of psychological interventions on metabolic control. This study provides crucial practical evidence for improving the management of adult rare metabolic disorders, promoting a shift from 'disease control' to a 'holistic health' model.

 

Antonia Albers, Nadine Kuniß, Christof Kloos, Sebastian Schmidt, and Nicolle Müller. Navigating adulthood with PKU: metabolic outcomes, quality of life, and mental health 4.5 years post-transition. Orphanet Journal of Rare Diseases.