PKU causes significant cognitive and psychiatric morbidity and worsening quality of life through a number of mediating factors. Though current guidelines reflect the established move towards lifelong dietary control rather than cessation after critical periods of neurodevelopment, individual patients may have received differing advice on when to cease or continue a Phe-restricted diet depending on their age and locale. As a result, many adults with PKU have ceased the PKU diet either through medical advice or personal preference. The motivation of patients to maintain adherence to the PKU diet is often suboptimal(26), and likely worsened by deficits in executive function and poor mood as direct sequelae of the disease. In this study, we evaluated the cognitive and psychiatric effects of resumption of dietary control of phenylketonuria in adult patients who had previously ceased dietary control to determine if these symptoms could be improved.
Across the twelve-month study duration, we found that resumption of the PKU diet was associated with improvements in symptoms of depression, anxiety, and measures of cognitive functioning. Multiple mechanisms may underlie such improvements. Firstly, the restoration of central levels of key monoamines, results in a relative normalisation of monoaminergic tone and thus a reduction in dimensional levels of depression and anxiety. Secondly, the attenuation of impaired myelination (itself intimately related to monoaminergic signaling), improves cognitive functions that are underpinned by more widely distributed cortico-cortical and cortico-subcortical networks, such as working memory and processing speed(27). Improvements to cognitive functioning were not explained by improvement in mood, with only time on diet being a significant covariate. Processing speed (in this study captured by CPI scores), which is well recognised as being reduced in adults with PKU(10,28), is centrally mediated and likely reflective of the underlying dysmyelination that has been observed in PKU(29). Assessing neurological structural changes in this cohort may further shed light on the underlying mechanisms of our findings.
Whilst the association between PKU and psychiatric and cognitive disturbance has been well established, the total time on diet following resumption, more so than serum Phe, appeared to be the most significant factor in determining improvements in cognition or mood and anxiety symptoms in our cohort. This apparent lack of correlation may also be explained by the cross-sectional nature of the Phe measurements. Phe may fluctuate significantly day-to-day in patients with even well controlled PKU(30), and it may be that the time-on-diet metric was acting as a proxy measure of Phe levels as an average over time. The lack of correlation between cognitive or mood symptoms with Phe has been observed previously(31), and may be more reflective of improvements to white matter integrity with dietary control rather than contemporaneous Phe levels. This would be in keeping with previous studies which have demonstrated improvements to hypomyelination in individuals who have resumed dietary control(32). Our findings are consistent with previous studies suggesting at least partial reversibility of cognitive and psychiatric deficits in adults with PKU when dietary control is resumed or improved, and are broadly consistent with the notion that clinical goals in PKU should include maintaining the lowest possible Phe lifelong as this will result in significantly improved cognitive and psychiatric outcomes.
Though the benefits to psychiatric symptoms and cognition are likely to improve the overall wellbeing of patients, the task of maintaining adherence to the PKU diet can be onerous and frustrating for those who miss the restricted foods, or find supplementation products unpleasant or distasteful(33). High rates of attritional loss to follow-up of patients in metabolic clinics has also been recognised(34,35), likely in part owing to the neuropsychiatric sequelae of the disease and further heightens the risk of ongoing morbidity from the disease. Further advances in pharmacological management of PKU offer hope to those who find dietary control unachievable whilst allowing for improved quality of life. Tetrahydrobiopterin (BH4), an essential co-factor for PAH in the metabolism of Phe to Tyr(36) has been utilised as a treatment option for PKU as sapropterin dihydrochloride. Administration of sapropterin has been found to be effective in reducing serum Phe by ≥ 30% from baseline in up to half of those treated(37), though patients with milder PKU were more likely to derive benefit(38). Novel emergent therapies such as the recently FDA approved PEGylated adducts of phenylalanine ammonia lyase have recently been shown to be efficacious in reducing Phe levels(39,40), and may offer alternatives or adjuncts to dietary control as the mainstay of management.
The rigours of maintaining the PKU diet may in themselves prove detrimental to a sense of wellbeing, and despite the well documented benefits to neuropsychiatric symptoms, may not improve overall subjective quality of life. In a study of quality of life in those restarting the PKU diet, though 60% found that adherence conferred overall benefits, 40% felt that their overall quality of life was unchanged despite restarting dietary control(33).
Our study was limited by a relatively small sample size and would benefit from replication on a larger scale. The longitudinal nature of the study, however, mitigates against this risk. The use of confidence intervals allowed us to understand the effect that the small sample size had on parameter uncertainty, which was relatively minimal. Whilst significant improvements in anxiety and depression were observed in the group, the majority of participants endorsed mild or moderate symptoms – inclusion in future studies of those with more severe psychopathology may potentially yield greater results. Of particular note, the low-frequency testing of Phe levels may result in measurements not representative of average Phe as individual variance in day-to-day Phe levels can be large. This may in part explain the lack of a clear association between Phe levels and the significant improvement in measures of anxiety and depression symptoms and cognitive outcomes. During the study one patient had their antidepressant changed by their primary care physician, and a second commenced an SSRI which may have had a small effect on overall results. Other, less readily measurable benefits were not necessarily captured in our study design. Within our own cohort, individual feedback in some cases was of subtle improvements to domains such as improved frustration tolerance, improved concentration and improvements in skin complexion. These benefits may not necessarily be captured in what can be blunt measurement tools.