Early-treated Phenylketonuria Research Articles

Cortical thickness and its relationship to cognitive performance and metabolic control in adults with phenylketonuria.

Despite good control of phenylalanine (Phe) levels during childhood and adolescence, adults with phenylketonuria (PKU) often show abnormalities in the white matter of the brain, which have been associated with poorer cognitive performance. However, whether such a relationship exists with cortical gray matter is still unknown. Therefore, we investigated cortical thickness and surface area in adults with early-treated PKU and their relationship to cognitive functions and metabolic control. We included 30 adult patients with early-treated and metabolically well-controlled PKU (median age: 35.5 years) and 54 healthy controls (median age: 29.3 years). Surface-based morphometry was derived from T1-weighted magnetic resonance images using FreeSurfer, and general intelligence, executive functions, and attention were assessed. Concurrent plasma Phe, tyrosine, and tryptophan levels were measured in patients. In addition, Phe levels were collected retrospectively to calculate the index of dietary control. Patients showed a thinner cortex than controls in regions of the bilateral temporal, parietal, and occipital lobes (effect size r= -0.34 to -0.42, p< 0.05). No group differences in surface area were found. In patients, accuracy in the working memory task was positively correlated with thickness in the left insula (r= 0.45, p= 0.013), left fusiform gyrus (r= 0.39, p= 0.032), and right superior temporal gyrus (r= 0.41, p= 0.024), but did not survive false discovery rate correction. Neither concurrent nor historical metabolic parameters were related to cortical thickness. Taken together, adults with PKU showed widespread reductions in cortical thickness despite good metabolic control in childhood and adolescence. However, alterations in cortical thickness were unrelated to metabolic parameters and cognitive performance.

A comprehensive assessment of neurocognitive and psychological functioning in adults with early-treated phenylketonuria.

Relative to youth with early-treated phenylketonuria (ETPKU), much less is known regarding the cognitive profile of adults with ETPKU. The present study aimed to address this gap by providing a comprehensive assessment of neuropsychological functioning among adults with ETPKU. A sample of 40 adults with ETPKU (ages 18 - 36) and a demographically matched group of 32 healthy individuals without PKU participated. Participants completed a comprehensive neuropsychological battery including the NIH Toolbox, Wechsler Abbreviated Scale of Intelligence - Second Edition (WASI-II), Conners' Continuous Performance Test (CPT-3), select subtests from the Weschler Adult Intelligence Scale - Fourth Edition (WAIS-IV) as well as several self-report measures of cognitive and psychoemotional functioning. Scores from these tests were combined to create cognitive composites reflecting overall task performance in the areas of verbal ability, visuospatial skills, executive functioning, motor skills, and processing speed. No group differences were observed for full scale IQ or verbal ability. However, individuals with ETPKU demonstrated poorer performance on measures of executive functioning, processing speed, motor skills, and visuospatial skills as compared to the non-PKU group. Within the ETPKU group, recent blood phenylalanine levels (an indicator of metabolic control) were significantly correlated with performance across most cognitive domains and aspects of psychological functioning. Present findings suggest that the neuropsychological profile of adult ETPKU is characterized by circumscribed impairments in select cognitive domains. In addition, the results underscore the importance of maintaining metabolic control across the lifespan in individuals with ETPKU.

Modeling the cognitive effects of diet discontinuation in adults with phenylketonuria (PKU) using pegvaliase therapy in PAH-deficient mice.

Existing phenylalanine hydroxylase (PAH)-deficient mice strains are useful models of untreated or late-treated human phenylketonuria (PKU), as most contemporary therapies can only be initiated after weaning and the pups have already suffered irreversible consequences of chronic hyperphenylalaninemia (HPA) during early brain development. Therefore, we sought to evaluate whether enzyme substitution therapy with pegvaliase initiated near birth and administered repetitively to C57Bl/6-Pahenu2/enu2 mice would prevent HPA-related behavioral and cognitive deficits and form a model for early-treated PKU. The main results of three reported experiments are: 1) lifelong weekly pegvaliase treatment prevented the cognitive deficits associated with HPA in contrast to persisting deficits in mice treated with pegvaliase only as adults. 2) Cognitive deficits reappear in mice treated with weekly pegvaliase from birth but in which pegvaliase is discontinued at 3 months age. 3) Twice weekly pegvaliase injection also prevented cognitive deficits but again cognitive deficits emerged in early-treated animals following discontinuation of pegvaliase treatment during adulthood, particularly in females. In all studies, pegvaliase treatment was associated with complete correction of brain monoamine neurotransmitter content and with improved overall growth of the mice as measured by body weight. Mean total brain weight however remained low in all PAH deficient mice regardless of treatment. Application of enzyme substitution therapy with pegvaliase, initiated near birth and continued into adulthood, to PAH-deficient Pahenu2/enu2 mice models contemporary early-treated human PKU. This model will be useful for exploring the differential pathophysiologic effects of HPA at different developmental stages of the murine brain.

Optical Coherence Tomography to Assess Neurodegeneration in Phenylalanine Hydroxylase Deficiency.

In phenylalanine hydroxylase (PAH) deficiency, an easily feasible method to access the progression of neurodegeneration is warranted to contribute to current discussions on treatment indications and targets. The objective of the present study was to investigate whether optical coherence tomography (OCT) measures as markers of neurodegeneration differ between patients with PAH deficiency and healthy controls (HCs) according to phenotype and metabolic control. In this single-center cross-sectional study, 92 patients with different phenotypes of PAH deficiency [PAH deficiency not requiring treatment, early treated phenylketonuria (ETPKU), and late-diagnosed phenylketonuria (PKU)] compared with 76 HCs were examined using spectral-domain OCT. Indices of phenylalanine elevation and variability were correlated with OCT parameters. Late-diagnosed PKU patients showed reduced peripapillary retinal nerve fiber layer (pRNFL) thickness and combined ganglion cell and inner plexiform layer (GCIPL) volume. Adult ETPKU patients were found to have lower GCIPL volume (p = 0.016), which correlated with the indices of phenylalanine control. In pediatric ETPKU patients with poor metabolic control, pRNFL was significantly reduced (p = 0.004). Patients with PAH deficiency not requiring treatment did not exhibit retinal degeneration. Inner nuclear layer (INL) was significantly increased in the pediatric ETPKU patients, driven by those with current poor metabolic control (p = 0.006). Our data provide evidence of retinal neuroaxonal degeneration and INL swelling, depending on the phenotype, current age, and metabolic control. These findings suggest that OCT is suitable to investigate neurodegeneration in PKU and we propose OCT as a sensitive, reliable, safe, low-burden, and low-cost examination for future multicenter studies.

The Impact of Phenylketonuria on Body Composition in Adults

Introduction: Patients with phenylketonuria (PKU) must follow a lifelong phenylalanine (Phe)-restricted diet with additional amino acid supplementations, and this may put them at risk for nutritional disturbances. However, the body composition and nutritional status of adult patients with PKU has only been partially explored. The current study aims to assess the body composition of adult patients with PKU using multifrequency bioimpedance analysis (MF-BIA) and to reveal potential correlations between therapy adherence and body composition. Additionally, we compared body composition of patients with healthy controls. Methods: Fifty adult patients with early-treated PKU (27 female and 23 male) and 40 healthy, age- and gender-matched controls were included in this single-center, cross-sectional study. MF-BIA was performed on all subjects. Additionally, we determined serum nutritional markers for all patients. In the PKU patient group, correlation analyses were performed between body composition parameters and therapy adherence. We compared body composition of patients with PKU and controls using BIA. Results: The proportion of overweight was 56% among all patients with PKU. Female patients with PKU had significantly higher body fat percentage compared with controls. In parallel with higher fat content, we observed lower muscle mass, protein, and mineral content among female patients with PKU compared to controls. Such findings were not observed in male patients. Female patients with PKU had decreased therapy adherence and had significantly lower prealbumin levels compared with males. There was no significant correlation observed between body composition parameters and therapy adherence over the last 10 years in the PKU patient group. Conclusion: Although female patients had less optimal therapy adherence over the last 10 years compared with male patients, our results suggest that this does not influence body composition fundamentally. Our results suggest that obesity is an important comorbidity in young adult patients with PKU, especially in females. We advocate that nutritional assessments and weight management should be additional objectives of PKU management to provide optimal care.

Improved attention linked to sustained phenylalanine reduction in adults with early-treated phenylketonuria.

Pegvaliase is approved to reduce phenylalanine (Phe) levels for people with phenylketonuria (PKU). PRISM‐1 (NCT01819727) and PRISM‐2 (NCT01889862) data were analyzed to evaluate the relationship between Phe and inattention in adult participants with PKU. In the modified‐intent‐to‐treat population (N = 156), baseline mean (SE) plasma Phe was 1263 (29) μmol/L and the Attention Deficit Hyperactivity Disorder Rating Scale‐IV Inattentive (IA) symptoms score was 9.8 (0.5). Mean (SE) IA scores fell 9.0 (1.1) in Quartile 1 (Phe reduction between 1166 and 2229 μmol/L) versus 4.3 (0.7) in Quartile 4 (Phe reduction of 139 μmol/L to increase of 934 μmol/L), p = 0.004. Least squares mean (SE) change from baseline IA score was −7.9 (0.7) for participants with final Phe ≤ 360 μmol/L and −4.5 (0.7) for final Phe > 360 μmol/L, p < 0.001. In the inattention subgroup, IA scores fell 13.3 (1.5) in Quartile 1 (Phe reduction between 1288 and 2229 μmol/L) versus 6.2 (1.3) in Quartile 4 (Phe reduction of 247 to increase of 934 μmol/L), p = 0.009. Inattention symptoms improved among those whose Phe levels decreased, particularly those with high baseline IA scores. IA improvements were larger among participants with the greatest plasma Phe reductions, supporting this value as a therapeutic goal.

Motor control and learning in individuals with early-treated phenylketonuria.

Although past studies have documented motor control impairments in individuals with early-treated phenylketonuria (ETPKU), much less is known regarding motor learning in ETPKU. The goal of the present study was to advance our understanding on this front. We isolated and examined motor kinematics associated with the learning of a rapid aimed limb movement in a sample of 40 individuals (13-34 years of age) with ETPKU and a matched comparison group of 40 individuals without phenylketonuria (PKU). Indices of motor learning included overall movement duration as well as the relative proportion of movement time devoted to ballistic and corrective submovements. (Note that practice of motor movements in nonclinical populations is associated with, not only improvements in overall speed, but also reduction in the proportion of movement time devoted to corrective submovements relative to an initial ballistic submovement.) Results: A group-by-time interaction was found. With practice, the non-PKU group showed a significant reduction in the proportion of movement time devoted to the corrected (as compared to the ballistic) submovement. A similar change was not observed for the ETPKU group. In addition, within the ETPKU group, the rate of improvement in total movement duration was correlated with recent blood phenylalanine levels (an indicator of treatment adherence). Motor learning is adversely affected in individuals with ETPKU. Further investigation into the behavioral and neural mechanisms of motor learning in ETPKU will advance our understanding of the etiologic basis for this disruption as well as how it relates to the broader neurocognitive profile of ETPKU. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Reduced macular thickness and macular vessel density in early-treated adult patients with PKU

PurposeMacular structure is poorly evaluated in early-treated phenylketonuria (ETPKU). To evaluate potential changes, we aimed to examine retinas of PKU patients using optical coherence tomography (OCT) with additional OCT angiography (OCTA) and compare the results to healthy controls. MethodsA total of 100 adults were recruited in this monocentric, case-control study: 50 patients with ETPKU (mean age: 30.66 ± 8.00 years) and 50 healthy controls (mean age: 30.45 ± 7.18 years). Macular thickness, vessel density and flow area of the right eye was assessed with spectral domain OCT angiography SD-OCT(A). Macular microstructural data between the ETPKU and control group was compared. In the ETPKU group, the relationship between visual functional parameters (best corrected visual acuity [VA], spherical equivalent [SE], contrast sensitivity [CS] and near stereoacuity) and microstructural alterations was examined. The dependency of OCT(A) values on serum phenylalanine (Phe) level was analysed. ResultsThere was significant average parafoveal and perifoveal total retinal layer thinning in ETPKU patients compared to healthy controls (p < 0.016 and p < 0.001, respectively), while the foveal region remained unchanged in the ETPKU group. Whole macular and parafoveal superficial capillary plexus density was significantly decreased in ETPKU compared to controls (p < 0.001). There were no significant differences in the foveal avascular zone, nonflow area, macular superficial and deep capillary plexus between the groups. The temporal parafoveal inner retinal layer thickness was found to negatively correlate with individual Phe levels (r = −0.35, p = 0.042). There was no difference in vascular density and retinal thickness in the subgroup analysis of patients with good therapy adherence compared to patients on a relaxed diet. ConclusionsDurable elevation in Phe levels are only partially associated with macular retinal structural changes. However, therapy adherence might not influence these ophthalmological complications.

The effect of improved dietary control on cognitive and psychiatric functioning in adults with phenylketonuria: the ReDAPT study

BackgroundPhenylketonuria (PKU) is an autosomal recessive inherited disorder characterised by a deficiency in phenylalanine hydroxylase. Untreated, PKU is associated with a wide range of cognitive and psychiatric sequelae. Contemporary management guidelines recommend lifetime dietary control of phenylalanine (Phe) levels, however many individuals who discontinue dietary control subsequently suffer symptoms of anxiety, depression and disturbances to cognition. We undertook a prospective cohort study of patients with early-treated phenylketonuria who had ceased dietary control to test the hypothesis that resumption of dietary control of PKU is associated with improvements in measures of psychiatric morbidity and cognitive functioning.MethodsWe re-initiated dietary control for early-treated patients with PKU and monitored cognitive and psychiatric outcomes over a twelve-month period. Assessments included objective cognitive function (measured by cognitive proficiency index (CPI)), anxiety and depression scales. General linear mixed model (GLMM) analyses were performed to assess change in psychometric variables from baseline over twelve months after resumption of dietary control.ResultsA total of nine patients were recruited. Mean age was 33 years (SD = 8.75), five were female. Mean time off dietary control was 19.1 years (SD = 11.3), and mean baseline phenylalanine (Phe) levels were 1108 µmol/L (SD = 293). GLMM analysis demonstrated a positive relationship between CPI and time on diet (b = 0.56 [95% CI = 0.17, 0.95]). Age, time off diet, Phe levels and depression scores were not associated with cognitive function. There was a negative relationship between time on diet and anxiety (b = − 0.88 95% CI = [− 1.26, − 0.50]) and depression ratings (b = − 0.61, 95% CI = [− 0.95, − 0.26]).ConclusionsThis study demonstrated improvements in cognitive function, anxiety, and depression ratings associated with resumption of dietary control of PKU. Raw Phe levels were not strongly associated with psychiatric or cognitive scores in this cohort. These findings support the importance of lifelong treatment for PKU in improving the cognitive and psychiatric sequelae of the disease.

Supplemental Material for Motor Control and Learning in Individuals With Early-Treated Phenylketonuria

Supplemental Material for Motor Control and Learning in Individuals With Early-Treated Phenylketonuria

Inter- and intra-tract analysis of white matter abnormalities in individuals with early-treated phenylketonuria (PKU)

Even with early and continuous treatment, individuals with phenylketonuria (PKU) may exhibit abnormalities of cortical white matter (WM). The present study utilizes a new analysis approach called Automated Fiber-Tract Quantification (AFQ) to advance our understanding of the tract-specific patterns of change in WM abnormalities in individuals with early-treated PKU (ETPKU). Diffusion Tensor Imaging (DTI) data from a sample of 22 individuals with ETPKU and a demographically-matched sample of 21 healthy individuals without PKU was analyzed using AFQ. In addition, a subsample of 8 individuals with ETPKU was reevaluated six months later after demonstrating a significant reduction in blood phe levels following initiation of sapropterin treatment. Within-tract AFQ analyses revealed significant location-by-group interactions for several WM tracts throughout the brain. In most cases, ETPKU-related disruptions in mean diffusivity (MD) were more apparent in posterior (as compared to anterior) aspects of a given tract. Reduction in blood phe levels with the aforementioned ETPKU subsample was associated with a similar pattern of improvement (posterior-to-anterior) within most tracts. Taken together, these findings suggest that there is a systematic pattern of change in WM abnormalities in individuals with ETPKU in a posterior-to-anterior manner along individual WM tracts.

Everyday Life, Dietary Practices, and Health Conditions of Adult PKU Patients: A Multicenter, Cross-Sectional Study

Background: Only few data on dietary management of adult phenylketonuria (PKU) patients are published. Objectives: This study aimed to assess living situation, dietary practices, and health conditions of early-treated adult PKU patients. Methods: A total of 183 early-treated PKU patients ≥18 years from 8 German metabolic centers received access to an online survey, containing 91 questions on sociodemographic data, dietary habits, and health conditions. Results: 144/183 patients (66% females) completed the questionnaire. Compared with German population, the proportion of single-person households was higher (22 vs. 47%), the rate of childbirth was lower (1.34 vs. 0.4%), but educational and professional status did not differ. 82% of the patients adhered to a low-protein diet, 45% consumed modified low-protein food almost daily, and 84% took amino acid mixtures regularly. 48% of the patients never interrupted diet, and 14% stopped diet permanently. 69% of the patients reported to feel better with diet, and 91% considered their quality of life at least as good. The prevalence of depressive symptoms was high (29%) and correlated significantly to phenylalanine blood concentrations (p = 0.046). However, depressive symptoms were only mild in the majority of patients. Conclusion: This group of early-treated adult German PKU patients is socially well integrated, reveals a surprisingly high adherence to diet and amino acid intake, and considers the restrictions of diet to their daily life as low.

Altered visual functions, macular ganglion cell and papillary retinal nerve fiber layer thickness in early-treated adult PKU patients

PurposeRetinal changes are poorly described in early treated phenylketonuria (ETPKU). We aimed to investigate possible visual functional and ocular microstructural changes in adult patients with ETPKU. Optical coherence tomography (OCT) and its angiography (OCTA) data from patients with PKU were compared to healthy controls. MethodsIn this prospective, monocentric, cross-sectional, case-control study 50 patients with ETPKU and 50 healthy subjects were evaluated with OCT and OCTA. Measurements were performed on right eyes. The following visual function parameters were studied: best corrected visual acuity (BCVA), spherical equivalent (SE), contrast sensitivity and near stereoacuity; microstructural parameters: retinal nerve fiber layer thickness (RNFLT), ganglion cell layer (GCC) thickness, focal loss of volume (FLV), global loss of volume (GLV), peripapillary, papillary vessel density (VD), ocular axial length (AL) and intraocular pressure (IOP). ResultsAmong functional tests there were significant differences in contrast sensitivity at 1.5 (p < 0.001), 6 (p < 0.013), 12 (p < 0.001), 18 (p < 0.003) cycles per degree, in near stereoacuity (Titmus Wirt circles, p < 0.001) and in best corrected visual acuity (BCVA, p < 0.001). A statistically significant, moderate positive linear correlation was observed between BCVA and average Phe levels over the last ten years (β = 0.49, p < 0.001). The average (p < 0.001), superior (p < 0.001) inferior GCC (p < 0.001), the FLV (p < 0.003), GLV (p < 0.001) and the average RNFLT (p < 0.004) values of the PKU group were significantly lower than the controls. The serum phenylalanine level (Phe) in the PKU group negatively correlated with inferior (−0.32, p < 0.007), superior (r = −0.26, p < 0.028) and average (−0.29 p < 0.014) RNFL and with AL (−0.32, p < 0.026). In AL we detected a significant difference (p < 0.04) between the good and suboptimal dietary controlled group. There was no significant difference between the ETPKU and control group in the measured vessel density parameters and in IOP. ConclusionsOur results suggest that functional and ocular microstructural defects are present in patients with PKU, and some of them may depend on dietary control. The mechanism is unclear, but the correlation indicates the importance of strict dietary control in terms of preservation of retinal functions.

The effects of early-treated phenylketonuria on volumetric measures of the cerebellum

Past murine studies of phenylketonuria (PKU) have documented significant effects on cerebellum at both the gross and cellular levels. The profile of neurocognitive and motor difficulties associated with early-treated PKU (ETPKU) is also consistent with potential cerebellar involvement. Previous neuroanatomical studies of cerebellum in patients with PKU, however, have yielded mixed results. The objective of the present study was to further examine potential differences in cerebellar morphometry between individuals with and without ETPKU. To this end, we analyzed high resolution T1-weighted MR images from a sample of 20 individuals with ETPKU and an age-matched comparison group of 20 healthy individuals without PKU. Measurements of whole brain volume, whole cerebellum volume, cerebellar gray matter volume, and cerebellar white matter volume were collected by means of semiautomatic volumetric analysis. Data analysis revealed no significant group differences in whole brain volume, whole cerebellar volume, or cerebellar white matter volume. A significant reduction in cerebellar gray matter volume, however, was observed for the ETPKU group compared to the non-PKU comparison group. These findings expand on previous animal work suggesting that cerebellar gray matter is impacted by PKU. It is also consistent with the hypothesis that the cognitive difficulties experienced by individuals with ETPKU may be related to disruptions in gray matter. Additional studies are needed to fully elucidate the timing and extent of the impact of ETPKU on cerebellum and the associated neurocognitive consequences.

Executive function in phenylketonuria (PKU): Insights from the Behavior Rating Inventory of Executive Function (BRIEF) and a large sample of individuals with PKU.

Previous research has documented executive function (EF) impairments in individuals with early treated phenylketonuria (ETPKU). It remains unclear, however, whether some aspects of EF may be more affected than others. A number of factors, including small sample sizes and variability in EF tasks, have likely contributed to past mixed findings. The present objective was to elucidate further the EF profile associated with ETPKU, particularly as it relates to report-based assessment of EF. Data from 286 individuals (5-48 years of age) with ETPKU on the child and adult versions of the Behavior Rating Inventory of Executive Function (BRIEF), a well-established report-based assessment tool, were analyzed. The Working Memory scale showed the largest effect size in both young and older ETPKU samples, with 19% of children and 29% of adults scoring in the "abnormally elevated" range. In addition, EF impairment appeared more general (i.e., affecting more domains) in the adult sample as compared to the child sample. Exploratory analyses also suggested that the presence/absence of overall impairment on the BRIEF among our ETPKU participants could be predicted based on a small subset of items. A 10-item subset showed total classification accuracy values of 90% and above for both groups. Working memory represents an aspect of EF that appears to be particularly affected in individuals with ETPKU. Findings also provide preliminary support of the viability for the development and/or adoption of an abbreviated screening measure for EF difficulties in children and adults with ETPKU. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Health Related Quality of Life assessment among early-treated Hungarian adult PKU patients using the PKU-QOL adult questionnaire

Background: The implementation of neonatal screening and the early initiation of lifelong therapy have helped to prevent severe complications and enabled much more favorable outcomes for early-treated phenylketonuria (ETPKU) patients. However, PKU patients tend to develop subtle cognitive and psychosocial abnormalities and the strict dietary therapy can present financial and social burden. Thus, PKU is expected to affect the quality of life (QoL) of these patients. There is insufficient evidence regarding the relationship between metabolic control and Health-Related QoL (HRQoL). We aimed to assess the effect of short- and long-term therapy on QoL among Hungarian adult PKU patients using the standardized PKU-specific PKU-QoL questionnaire.Methods: We conducted a single-centre, cross-sectional, observational study in Hungary. We included adult PKU patients treated with diet and amino acid supplements only. Patients reported HRQoL using the standardized adult PKU-QoL questionnaire and mean blood Phe concentrations were assessed for three different time periods: the previous 10 years, the previous year and concentration at the time of completing the questionnaire. The correlation between patients’ QoL scores and their Phe levels was assessed. The classical PKU group was further divided into “good” and “suboptimal” adherence groups based on individual mean Phe levels in the examined time period. We evaluated differences in QoL among the two subgroups of classical PKU patients. QoL scores between classical and non-classical patients were also compared.Results: Data from 88 adult patients were analysed (66 had classical PKU). No median PKU-QoL score reached major or severe impact/frequent symptoms in any domain. The highest scores (meaning larger burden) were mostly related to emotional impact of PKU and disease management. When performing correlation analysis between Phe levels and QoL scores by all patients we found weak to fair positive correlation in several domains either short or long term. Patients with classical PKU reported greater financial impact of PKU than patients with less severe PKU. Classical PKU patients with good therapy adherence tended to report better HRQoL scores than patients with suboptimal adherence.Conclusion: We conclude that patients showed good HRQoL using the PKU-specific questionnaire. Our study demonstrates that suboptimal metabolic control is negatively associated with patients' HRQoL.

The PKU & ME study: A qualitative exploration, through co-creative sessions, of attitudes and experience of the disease among adults with phenylketonuria in Italy

BackgroundPhenylketonuria (PKU) is a hereditary metabolic disease that can be diagnosed and successfully treated from birth with a lifelong phenylalanine-restricted dietary regimen. However, optimal adherence to diet remains an issue and often progressively decreases after adolescence. The study aimed to explore the experience of adults living with PKU in order to gain insights related to their adherence to diet and engagement in managing their condition. MethodsThe study adopted a qualitative methodology in sessions that combined specifically designed co-creation exercises with focus group discussion. Adults with early-treated classic PKU were enrolled for 2 different sessions - one for adherent and one for non-adherent patients. The verbatim notes of both sessions and focus group were analyzed using content analysis. ResultsTwelve adherent and nine non-adherent adults with PKU participated. Besides the behavioral dictates of following a strict diet, adherent adults reported a positive mental approach and organizational rigor; they seemed aware of the consequences of high-phenylalanine levels, reporting that it can affect mood and consequently social interactions which they value highly. In the non-adherent group, the individuals seemed to not fully accept their disease: they were aware of the consequences of non-adherence in children but not in adults, they felt the management of PKU was an individual burden and they experienced a feeling of ‘diversity’ in the social context (related to eating) that caused emotional distress. PKU seemed a very influential element of the identity both for adherent and non-adherent adults, but with different consequences for the two groups. Finally, all participants reported the desire to be assisted in a healthcare setting dedicated to adults. ConclusionsThe findings expand the understanding of the psychological experience of adult patients with PKU in relation to their disease and its dietary requirements, highlighting specific factors that might drive tailored educational or psychological intervention to improve adherence and engagement in the care process.

Impact of phenylalanine on cognitive, cerebral, and neurometabolic parameters in adult patients with phenylketonuria (the PICO study): a randomized, placebo-controlled, crossover, noninferiority trial

BackgroundThe population of adult patients with early-treated phenylketonuria (PKU) following newborn screening is growing substantially. The ideal target range of blood phenylalanine (Phe) levels in adults outside pregnancy is a matter of debate. Therefore, prospective intervention studies are needed to evaluate the effects of an elevated Phe concentration on cognition and structural, functional, and neurometabolic parameters of the brain.MethodsThe PICO (Phenylalanine and Its Impact on Cognition) Study evaluates the effect of a 4-week Phe load on cognition and cerebral parameters in adults with early-treated PKU in a double-blind, randomized, placebo-controlled, crossover, noninferiority trial.ParticipantsThirty adult patients with early-treated PKU and 30 healthy controls comparable to patients with regard to age, sex, and educational level will be recruited from the University Hospitals Bern and Zurich, Switzerland. Patients are eligible for the study if they are 18 years of age or older and had PKU diagnosed after a positive newborn screening and were treated with a Phe-restricted diet starting within the first 30 days of life.Intervention: The cross-over intervention consists of 4-week oral Phe or placebo administration in patients with PKU. The study design mimics a Phe-restricted and a Phe-unrestricted diet using a double-blinded, placebo-controlled approach.ObjectivesThe primary objective of the PICO Study is to prospectively assess whether a temporarily elevated Phe level influences cognitive performance (working memory assessed with a n-back task) in adults with early-treated PKU. As a secondary objective, the PICO Study will elucidate the cerebral (fMRI, neural activation during a n-back task; rsfMRI, functional connectivity at rest; DTI, white matter integrity; and ASL, cerebral blood flow) and neurometabolic mechanisms (cerebral Phe level) that accompany changes in Phe concentration. Cognition, and structural and functional parameters of the brain of adult patients with early-treated PKU will be cross-sectionally compared to healthy controls. All assessments will take place at the University Hospital Bern, Switzerland.RandomizationCentral randomization will be used to assign participants to the different treatment arms with age, sex, and center serving as the stratification factors. Randomization lists will be generated by an independent statistician.Blinding: All trial personnel other than the statistician generating the randomization list and the personnel at the facility preparing the interventional product are blinded to the assigned treatment.DiscussionUsing a combination of neuropsychological and neuroimaging data, the PICO Study will considerably contribute to improve the currently insufficient level of evidence on how adult patients with early-treated PKU should be managed.Trial registrationThe study is registered at clinicaltrials.gov (NCT03788343) on the 27th of December 2018, at kofam.ch (SNCTP000003117) on the 17th of December 2018, and on the International Clinical Trials Registry Platform of the WHO.

Bone mineral density is within normal range in most adult phenylketonuria patients.

Low bone mineral density (BMD) as a risk factor for fractures has been a long‐standing concern in phenylketonuria (PKU). It is hypothesised that the disease itself or the dietary treatment might lead to a low BMD. Previous studies show conflicting results of BMD in PKU due to differences in age, techniques to assess BMD and criteria used. To assess the prevalence of low BMD and define possible risk factors in a large number of adult, early treated PKU (ETPKU) patients. European centres were invited for a survey, collecting retrospective data including results of dual‐energy X‐ray absorptiometry (DXA) scans of adult ETPKU patients. BMD of 183 adult ETPKU patients aged 18‐46 (median age 28, all females premenopausal) years was lower than in the general population at most skeletal sites but the frequency of low BMD (Z‐score <−2) was at maximum 5.5%. No risk factors for low BMD in PKU patients could be identified. Low BMD occurs only in a small subset of PKU patients. DXA scans should be considered for well controlled patients from age 35‐40 years and up and on indication in those PKU patients considered to be at increased risk for fractures.

Attention Deficit Disorder with Hyperactivity Symptoms in Early-Treated Phenylketonuria Patients.

Objectives To assess the presence of symptoms consistent with Attention Deficit Disorder with Hyperactivity (ADHD) in all patients with early-treated phenylketonuria (PKU) in the State of Santa Catarina in southern Brazil. All of the patients diagnosed with PKU by newborn-screening tests, with ages varying from 6 to 18 years and who started treatment before 60 days of life and presented phenylalanine levels consistently below 6 mg/dL throughout treatment, were included. The subjects were invited to complete a questionnaire that collected sociodemographic, gestational and clinical data. ADHD symptoms were assessed using the revision of the Swanson, Nolan and Pelham Questionnaire. A total of 34 patients were evaluated, who were 53% male and 94% white and had an average age of 12 years, and 15% were born premature. According to the Swanson, Nolan and Pelham Questionnaire, 13 patients (38%) met the diagnostic criteria for ADHD, with 2 patients having the inattentive type, 6 patients having the hyperactive or impulsive type and 1 patient having the oppositional defiant disorder type. Although the patients with PKU were regularly treated from birth, there was a high prevalence of symptoms consistent with ADHD. A pathophysiological interface that involves the dopamine metabolic pathway may exist between the two conditions.