Management of early treated adolescents and young adults with phenylketonuria: Development of international consensus recommendations using a modified Delphi approach.

BACKGROUND: Early treated patients with phenylketonuria (PKU) often become lost to follow-up from adolescence onwards due to the historical focus of PKU care on the pediatric population and lack of programs facilitating the transition to adulthood. As a result, evidence on the management of adolescents and young adults with PKU is limited. METHODS: Two meetings were held with a multidisciplinary international panel of 25 experts in PKU and comorbidities frequently experienced by patients with PKU. Based on the outcomes of the first meeting, a set of statements were developed. During the second meeting, these statements were voted on for consensus generation (≥70% agreement), using a modified Delphi approach. RESULTS: A total of 37 consensus recommendations were developed across five areas that were deemed important in the management of adolescents and young adults with PKU: (1) general physical health, (2) mental health and neurocognitive functioning, (3) blood Phe target range, (4) PKU-specific challenges, and (5) transition to adult care. The consensus recommendations reflect the personal opinions and experiences from the participating experts supported with evidence when available. Overall, clinicians managing adolescents and young adults with PKU should be aware of the wide variety of PKU-associated comorbidities, initiating screening at an early age. In addition, management of adolescents/young adults should be a joint effort between the patient, clinical center, and parents/caregivers supporting adolescents with gradually gaining independent control of their disease during the transition to adulthood. CONCLUSIONS: A multidisciplinary international group of experts used a modified Delphi approach to develop a set of consensus recommendations with the aim of providing guidance and offering tools to clinics to aid with supporting adolescents and young adults with PKU.

Metabolic control during the neonatal period in phenylketonuria: associations with childhood IQ.

BACKGROUND: In phenylketonuria, treatment and subsequent lowering of phenylalanine levels usually occur within the first month of life. This study investigated whether different indicators of metabolic control during the neonatal period were associated with IQ during late childhood/early adolescence. METHODS: Overall phenylalanine concentration during the first month of life (total "area under the curve"), proportion of phenylalanine concentrations above upper target level (360 µmol/L) and proportion below lower target level (120 µmol/L) during this period, diagnostic phenylalanine levels, number of days until phenylalanine levels were <360 µmol/L, and lifetime and concurrent phenylalanine levels were correlated with IQ scores of 64 PKU patients (mean age 10.8 years, SD 2.9). RESULTS: Overall phenylalanine concentration and proportion of phenylalanine concentrations >360 µmol/L during the first month of life negatively correlated with IQ in late childhood/early adolescence. Separately, phenylalanine concentrations during different periods within the first month of life (0-10 days, 11-20 days, 21-30 days) were negatively correlated with later IQ as well, but correlation strengths did not differ significantly. No further significant associations were found. CONCLUSIONS: In phenylketonuria, achievement of target-range phenylalanine levels during the neonatal period is important for cognition later in life, also when compared to other indicators of metabolic control. IMPACT: In phenylketonuria, it remains unclear during which age periods or developmental stages metabolic control is most important for later cognitive outcomes. Phenylalanine levels during the neonatal period were clearly and negatively related to later IQ, whereas no significant associations were observed for other indices of metabolic control. This emphasizes the relative importance of this period for cognitive development in phenylketonuria. No further distinctions were observed in strength of associations with later IQ between different indicators of metabolic control during the neonatal period. Thus, achievement of good metabolic control within 1 month after birth appears "safe" with respect to later cognitive outcomes.

Neurocognitive outcome and mental health in children with tyrosinemia type 1 and phenylketonuria: A comparison between two genetic disorders affecting the same metabolic pathway.

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism.

Correlations of blood and brain biochemistry in phenylketonuria: Results from the Pah-enu2 PKU mouse.

BACKGROUND: In phenylketonuria (PKU), treatment monitoring is based on frequent blood phenylalanine (Phe) measurements, as this is the predictor of neurocognitive and behavioural outcome by reflecting brain Phe concentrations and brain biochemical changes. Despite clinical studies describing the relevance of blood Phe to outcome in PKU patients, blood Phe does not explain the variance in neurocognitive and behavioural outcome completely. METHODS: In a PKU mouse model we investigated 1) the relationship between plasma Phe and brain biochemistry (Brain Phe and monoaminergic neurotransmitter concentrations), and 2) whether blood non-Phe Large Neutral Amino Acids (LNAA) would be of additional value to blood Phe concentrations to explain brain biochemistry. To this purpose, we assessed blood amino acid concentrations and brain Phe as well as monoaminergic neurotransmitter levels in in 114 Pah-Enu2 mice on both B6 and BTBR backgrounds using (multiple) linear regression analyses. RESULTS: Plasma Phe concentrations were strongly correlated to brain Phe concentrations, significantly negatively correlated to brain serotonin and norepinephrine concentrations and only weakly correlated to brain dopamine concentrations. From all blood markers, Phe showed the strongest correlation to brain biochemistry in PKU mice. Including non-Phe LNAA concentrations to the multiple regression model, in addition to plasma Phe, did not help explain brain biochemistry. CONCLUSION: This study showed that blood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters. TAKE-HOME MESSAGE: Blood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters.

Infant emotional responses to challenge predict empathic behavior in toddlerhood.

Although emotional responses are theorized to be important in the development of empathy, findings regarding the prediction of early empathic behavior by infant behavioral and physiological responses are mixed. This study examined whether behavioral and physiological responses to mild emotional challenge (still face paradigm and car seat task) in 118 infants at age 6 months predicted empathic distress and empathic concern in response to an empathy-evoking task (i.e, experimenter's distress simulation) at age 20 months. Correlation analyses, corrected for sex and baseline levels of physiological arousal, showed that stronger physiological and behavioral responses to emotional challenge at age 6 months were positively related to observed empathic distress, but not empathic concern, at age 20 months. Linear regression analyses indicated that physiological and behavioral responses to challenge at 6 months independently predicted empathic distress at 20 months, which suggests an important role for both physiological and behavioral emotional responses in empathy development. In addition, curvilinear regression analyses showed quadratic associations between behavioral responses at 6 months, and empathic distress and empathic concern at 20 months, which indicates that moderate levels of behavioral responsivity predict the highest levels of empathic distress and empathic concern.

Associations between empathy, inhibitory control, and physical aggression in toddlerhood.

Impaired empathy has been associated with aggression in children, adolescents and adults, but results have been contradictory for the preschool period. Impaired inhibitory control also increases the risk of aggression, and possibly moderates empathy-aggression associations. The current study investigated whether empathy and inhibitory control are associated with aggression in toddlerhood. Furthermore, we aimed to clarify the role of inhibitory control in empathy and aggression, specifically, whether inhibitory control moderates the association between empathy and aggression. During a laboratory visit at age 30 months (N = 103), maternal reports of physical aggression were obtained and child inhibitory control was examined using a gift delay task. Empathy was examined by obtaining behavioral observations and recording physiological responses (heart rate response and respiratory sinus arrhythmia response) to an empathy-eliciting event (i.e., simulated distress). Reduced inhibitory control was associated with more aggression. Behavioral and physiological indicators of empathy were not associated with aggression. Hierarchical regression analyses revealed an interaction effect of heart rate response to distress simulation with inhibitory control in the prediction of aggression. Post hoc analyses indicated a negative association between heart rate response and aggression when inhibitory control was high, but a positive association was found in toddlers who demonstrated low inhibitory control. These results suggest that children are less aggressive when they have both high levels of empathy and inhibitory control. Therefore, both empathy and inhibition are important targets for interventions aiming to reduce or prevent aggression at a young age.

Prenatal risk and physical aggression during the first years of life: The gender-specific role of inhibitory control.

Prenatal risk and a lack of inhibitory control have consistently been related to the development of physical aggression in older children. This study examined whether inhibitory control mediated the relation between prenatal risk and aggression in infants and toddlers. The role of gender in this mediation model was also examined. The sample consisted of 161 mother-child dyads (83 boys). A prenatal cumulative risk score was created from a number of well-established risk factors including maternal psychopathology, substance use, and social and socioeconomic disadvantages. At 12 months, children performed an inhibitory control task. Physical aggression was assessed through maternal reports at 12 and 20 months of age. Results showed that higher prenatal risk was associated with more physical aggression. Inhibitory control mediated this association at both 12 and 20 months: higher prenatal risk was related to lower inhibitory control, which in turn led to higher aggression. At 20 months, gender moderated the mediation effect: the mediating role of inhibitory control was only found for girls. These results suggest that even before 2 years of age, inhibitory control is an important construct involved in the relation between prenatal risk and physical aggression.

The impact of metabolic control and tetrahydrobiopterin treatment on health related quality of life of patients with early-treated phenylketonuria: A PKU-COBESO study.

The aim of this study was to examine Health-Related Quality of Life (HRQoL) of patients with Phenylketonuria (PKU) in three different age groups and to investigate the impact of metabolic control and tetrahydrobiopterin (BH4) treatment on HRQoL of these patients. Participants were 90 early-treated patients aged 7 to 40 years (M = 21.0, SD = 10.1) and 109 controls aged 7 to 40.8 years (M = 19.4, SD = 8.6). HRQoL was assessed with the (generic) TNO-AZL questionnaires. Overall, good HRQoL was reported for children below 12 years of age, although they were judged to be less autonomic than their healthy counterparts. Adolescents aged 12-15 years showed poorer HRQoL in the domain "cognitive functioning" compared to controls. For adults ≥16 years, poorer age-controlled HRQoL was found for the domains cognition, depressive moods, and anger, with a further trend for the domain "pain". With respect to metabolic control, only for adult PKU-patients robust associations were observed, indicating poorer functioning, most notably in the domains cognition, sleep, pain, sexuality and anger, with higher historical and concurrent Phe-levels. With respect to BH4-use, effects on HRQoL were again only observed for adult PKU-patients. After controlling for age and historical Phe-levels, small but significant differences in favor of adult BH4-users compared to non-users were observed for HRQoL-categories happiness, anger, and social functioning. Together, these results show that, particularly for adult PKU-patients, HRQoL-problems are evident and that many of these problems are related to (history of) metabolic control. Beneficial effects of BH4-use appear to be limited to those associated with relief from the practical burdens related to the strict dietary treatment regimen, i.e. general mood and sociability, whereas metabolic control is more strongly related to basic physical and cognitive functioning.

Long-Term Follow-Up of Cognition and Mental Health in Adult Phenylketonuria: A PKU-COBESO Study.

Cognitive and mental health problems in individuals with the inherited metabolic disorder phenylketonuria (PKU) have often been associated with metabolic control and its history. For the present study executive functioning (EF) was assessed in 21 PKU patients during childhood (T1, mean age 10.4 years, SD = 2.0) and again in adulthood (T2, mean age 25.8 years, SD = 2.3). At T2 additional assessments of EF in daily life and mental health were performed. Childhood (i.e. 0-12 years) blood phenylalanine was significantly related to cognitive flexibility, executive motor control, EF in daily life and mental health in adulthood (i.e. at T2). Patients with a greater increase in phenylalanine levels after the age of 12 performed more poorly on EF-tasks at T2. Group-based analyses showed that patients with phenylalanine <360 µmol/L in childhood and phenylalanine ≥360 µmol/L from age 13 onwards (n = 11) had better cognitive flexibility and executive motor control than those who had phenylalanine ≥360 µmol/L throughout life (n = 7), supporting the notion that phenylalanine should be below the recommended upper treatment target of 360 µmol/L during childhood for better outcome in adulthood. Despite some results indicating additional influence of phenylalanine levels between 13 and 17 years of age, evidence for a continued influence of phenylalanine levels after childhood on adult outcomes was largely lacking. This may be explained by the fact that the patients in the present study had relatively low phenylalanine levels during childhood (mean: 330 µmol/L, range: 219-581 µmol/L) and thereafter (mean Index of Dietary Control at T2: 464 µmol/L, range: 276-743 µmol/L), which may have buffered against transitory periods of poor metabolic control during adolescence and early adulthood.

Infant autonomic nervous system response and recovery: Associations with maternal risk status and infant emotion regulation.

This study examined whether risk status and cumulative risk were associated with autonomic nervous system reactivity and recovery, and emotion regulation in infants. The sample included 121 6-month-old infants. Classification of risk status was based on World Health Organization criteria (e.g., presence of maternal psychopathology, substance use, and social adversity). Heart rate, parasympathetic respiratory sinus arrhythmia, and sympathetic preejection period were examined at baseline and across the still face paradigm. Infant emotion regulation was coded during the still face paradigm. Infants in the high-risk group showed increased heart rate, parasympathetic withdrawal, and sympathetic activation during recovery from the still face episode. Higher levels of cumulative risk were associated with increased sympathetic nervous system activation. Moreover, increased heart rate during recovery in the high-risk group was mediated by both parasympathetic and sympathetic activity, indicating mobilization of sympathetic resources when confronted with socioemotional challenge. Distinct indirect pathways were observed from maternal risk to infant emotion regulation during the still face paradigm through parasympathetic and sympathetic regulation. These findings underline the importance of specific measures of parasympathetic and sympathetic response and recovery, and indicate that maternal risk is associated with maladaptive regulation of stress early in life reflecting increased risk for later psychopathology.

Neurological and Neuropsychological Problems in Tyrosinemia Type I Patients.

Clinically, Hereditary Tyrosinemia type I (HTI) is especially characterized by severe liver dysfunction in early life. However, recurrent neurological crises are another main finding in these patients when they are treated with a tyrosine and phenylalanine restricted diet only. This is caused by the accumulation of δ-aminolevulinic acid due to the inhibitory effect of succinylacetone on the enzyme that metabolizes δ-aminolevulinic acid. Due to the biochemical and clinical resemblance of these neurological crises and acute intermittent porphyria, this group of symptoms in HTI patients is mostly called porphyria-like-syndrome. The neurological crises in HTI patients disappeared after the introduction of treatment with 2-(2 nitro-4-3 trifluoro-methylbenzoyl)-1, 3-cyclohexanedione (NTBC). However, if NTBC treatment is stopped for a while, severe neurological dysfunction will reappear.If NTBC treatment is started early and given continuously, all clinical problems seem to be solved. However, recent research findings indicate that HTI patients have a non-optimal neurocognitive outcome, showing (among others) a lower IQ and impaired executive functioning and social cognition. Unfortunately the exact neuropsychological profile of these HTI patients is not known yet, neither are the exact pathophysiological mechanisms underlying these impairments. It may be hypothesized that the biochemical changes such as high blood tyrosine or low blood phenylalanine concentrations are important in this respect, but an direct toxic effect of NTBC or production of toxic metabolites (that previously characterized the disease before introduction of NTBC) cannot be excluded either. This chapter discusses the neurological and neuropsychological symptoms associated with HTI in detail. An extended section on possible underlying pathophysiological mechanisms of such symptoms is also included.

Social-cognitive functioning and social skills in patients with early treated phenylketonuria: a PKU-COBESO study.

OBJECTIVE: Early treatment of phenylketonuria (ET-PKU) prevents mental retardation, but many patients still show cognitive and mood problems. In this study, it was investigated whether ET-PKU-patients have specific phenylalanine (Phe-)related problems with respect to social-cognitive functioning and social skills. METHODS: Ninety five PKU-patients (mean age 21.6 ± 10.2 years) and 95 healthy controls (mean age 19.6 ± 8.7 years) were compared on performance of computerized and paper-and-pencil tasks measuring social-cognitive abilities and on parent- and self-reported social skills, using multivariate analyses of variance, and controlling for general cognitive ability (IQ-estimate). Further comparisons were made between patients using tetrahydrobiopterin (BH4, N = 30) and patients not using BH4. Associations with Phe-levels on the day of testing, during childhood, during adolescence and throughout life were examined. RESULTS: PKU-patients showed poorer social-cognitive functioning and reportedly had poorer social skills than controls (regardless of general cognitive abilities). Quality of social-cognitive functioning was negatively related to recent Phe-levels and Phe-levels between 8 and 12 years for adolescents with PKU. Quality of social skills was negatively related to lifetime phenylalanine levels in adult patients, and specifically to Phe-levels between 0 and 7, and between 8 and 12 years. There were no differences with respect to social outcome measures between the BH4 and non-BH4 groups. CONCLUSION: PKU-patients have Phe-related difficulties with social-cognitive functioning and social skills. Problems seem to be more evident among adolescents and adults with PKU. High Phe-levels during childhood and early adolescence seem to be of greater influence than current and recent Phe-levels for these patients.

Parental Perceptions of Aggressive Behavior in Preschoolers: Inhibitory Control Moderates the Association With Negative Emotionality.

Inhibitory control (IC) and negative emotionality (NE) are both linked to aggressive behavior, but their interplay has not yet been clarified. This study examines different NE × IC interaction models in relation to aggressive behavior in 855 preschoolers (aged 2-5 years) using parental questionnaires. Hierarchical regression analyses revealed that NE and IC predict aggression both directly and interactively. The highest aggression levels were reported in children with high NE and low IC. Interestingly, the protective effect of IC for aggressive behavior increases with rising levels of NE. Analyses focusing on physical aggression revealed a significant NE × IC interaction in boys aged 4-5 years only. These findings shed new light on potential compensatory mechanisms for aggressive behavior in developing children.

Is BRIEF a useful instrument in day to day care of patients with phenylketonuria?

OBJECTIVES: Despite early and continuous treatment many patients with phenylketonuria (PKU) still experience neurocognitive problems. Most problems have been observed in the domain of executive functioning (EF). For regular monitoring of EF, the use of the Behavior Rating Inventory of Executive Function (BRIEF) has been proposed. The aim of this study was to investigate whether the BRIEF is indeed a useful screening instrument in monitoring of adults with PKU. STUDY DESIGN: Adult PKU patients (n = 55; mean age 28.3 ± 6.2 years) filled out the BRIEF-A (higher scores=poorer EF) and performed computerized tasks measuring executive functions (inhibition, cognitive flexibility, and working memory). The outcome of the BRIEF-A questionnaire was compared with the neurocognitive outcome as measured by three tasks from the Amsterdam Neuropsychological Tasks (ANT). RESULTS: Forty-two percent of the PKU patients scored in the borderline/clinical range of the BRIEF-A. Six of the 55 patients (11%) scored >1 SD above the normative mean, mostly on the Metacognition Index. With respect to ANT measurements, patients mainly showed deficits in inhibitory control (34-36%) and cognitive flexibility (31-40%) as compared to the general Dutch population. No significant correlations between the two methods were found, which was confirmed with the Bland-Altman approach where no agreement between the two methods was observed. Only with respect to inhibitory control, patients scored significantly worse on both BRIEF-A and ANT classifications. No other associations between classification according to the BRIEF-A and classifications according to the ANT tasks were found. CONCLUSIONS: Patients reporting EF problems in daily life are not necessarily those that present with core EF deficits. The results of this study suggest that regular self-administration of the BRIEF-A is not a sufficient way to monitor EF in adult PKU patients.

Prenatal reflective functioning in primiparous women with a high-risk profile.

The concept of maternal reflective functioning (RF) has been gaining increasing interest as a possible intermediate mechanism in associations between a wide range of psychosocial risk factors and poor child outcomes. The purpose of the present study was to determine which psychosocial risk factors are linked to prenatal RF in a high-risk (HR) group of primiparous women. Differences in prenatal RF between the HR group and a low-risk (LR) control group also were examined. The sample consisted of 162 women (M = 22.22 years, SD = 2.39; 83 classified as HR). RF was coded from the Pregnancy Interview (A. Slade, 2007a). Risk status was assessed by means of the Mini-International Neuropsychiatric Interview-plus (M.I.N.I.-plus; D.V. Sheehan et al., 1997) and several questionnaires. HR women demonstrated significantly lower RF quality than did the LR group. Regression analyses indicated that maternal education, size of social support network, and substance use during pregnancy were the strongest predictors of prenatal RF for the HR group. The results suggest that maternal RF potentially could be an important target for those prevention and intervention programs that aim to reduce adverse psychosocial development in offspring of HR mothers.

Neurocognitive evidence for revision of treatment targets and guidelines for phenylketonuria.

OBJECTIVES: To compare the neurocognitive outcomes of patients with phenylketonuria (PKU) to determine whether decreasing phenylalanine (Phe) levels to <240 is preferable to the use of 360 µmol/L as an upper-target Phe level. An additional aim was to establish the influence of biochemical indices other than Phe on neurocognitive outcomes. STUDY DESIGN: Patients with PKU (n = 63; mean age 10.8 ± 2.3 years) and healthy controls (n = 73; mean age 10.9 ± 2.2 years) performed computerized tasks measuring neurocognitive functions (inhibitory control, cognitive flexibility, and motor control). Lifetime and concurrent blood Phe levels, Phe-to-tyrosine ratio (Phe:Tyr), and Phe variations were examined in relation to neurocognitive outcomes using nonparametric tests and regression analyses. RESULTS: Patients with PKU with Phe levels ≤240 µmol/L and healthy controls performed equally well. Patients with Phe levels between 240 and 360 µmol/L and ≥360 µmol/L performed more poorly than did controls across tasks. Patients with Phe levels ≤240 µmol/L performed significantly better than patients with levels between 240 and 360 µmol/L on tasks measuring inhibitory control and cognitive flexibility. Absolute Phe levels and Phe variation were the best predictors of motor control, whereas Phe:Tyr were the best predictors of inhibitory control. CONCLUSIONS: The results of this study suggest that upper Phe targets should be lowered to optimize neurocognitive outcomes. Moreover, Phe variation and Phe:Tyr appear to be of additional value in treatment monitoring.

Executive functioning in context: Relevance for treatment and monitoring of phenylketonuria.

This paper presents findings from studies of EF in individuals with early-treated PKU within the context of recent advances in neuropsychological theory and research. It focuses on means of assessment, contexts of assessment, and the best way to define and investigate EF. Several conclusions can be drawn based on the findings presented here. The first conclusion is that there is clear evidence for phenylalanine-related EF-deficits in early-treated PKU, particularly with respect to prepotent response inhibition and the manipulation or monitoring component of working memory. An important note, however, is that measurement of EF in PKU has become too fragmented, as different researchers and clinicians use different definitions of EF, and subsequently, different instruments to measure EF. This appears to be one of the most important causes of mixed results. A second conclusion is that there appears to be a need to incorporate at least one specific, relatively new taxonomy of EF in PKU-research, i.e. the taxonomy that distinguishes hot and cool EFs, where hot EF is associated with regulation of affect/emotions and motivation, or regulatory functions when the context contains such elements, while cool EF concerns decontextualized regulatory abilities. PKU in adults is increasingly associated with different mental health problems, despite supposedly good treatment standards and adherence throughout childhood and adolescence. Since hot EF is strongly associated with such mental health problems, it is recommended that the hot-cool taxonomy will feature more prominently in future PKU-studies.

Mental health and social functioning in early treated Phenylketonuria: the PKU-COBESO study.

This article presents a new Dutch multicenter study ("PKU-COBESO") into cognitive and behavioral sequelae of early and continuously treated Phenylketonuria (PKU) patients. Part of the study sample will consist of young adult PKU patients who have participated in a large neuropsychological study approximately 10 years ago, when they were 7-to-15-year-olds (Huijbregts et al., 2002 [1]). Their neurocognitive development will be mapped in association with their earlier and continued metabolic history, taking into account possible changes in, for instance, medication. A second part of the sample will consist of PKU patients between the ages of 7 and approximately 40 years (i.e., born in or after 1974, when neonatal screening was introduced in The Netherlands), who have not participated in the earlier neuropsychological study. Again, their cognitive functioning will be related to their metabolic history. With respect to aspects of cognition, there will be an emphasis on executive functioning. The concept of executive functioning will however be extended with further emphasis on the impact of cognitive deficits on the daily lives of PKU patients, aspects of social cognition, social functioning, and behavior/mental health (i.e., COgnition, BEhavior, SOcial functioning: COBESO). In addition to a description of the PKU-COBESO study, some preliminary results with respect to mental health and social functioning will be presented in this article. Thirty adult PKU patients (mean age 27.8, SD 6.4) and 23 PKU patients under the age of 18 years (mean age 11.0, SD 3.3) were compared to 14 (mean age 26.9 years, SD 5.9) and 7 matched controls (mean age 10.5, SD 2.6) respectively, with respect to their scores on the Adult Self-Report or Child Behavior Checklist (measuring mental health problems) and the Social Skills Checklist or Social Skills Rating System (measuring social skills). Whereas there were very few significant group differences (except for mental health problems in the internalizing spectrum for adult PKU patients), possibly due to the small control groups, several significant associations between mental health problems and Phe levels were observed for the PKU patients. Childhood Phe levels and internalizing problems for adult PKU patients were related; concurrent Phe was associated with both internalizing and externalizing behavioral problems for those under the age of 18. These preliminary results underline the importance of early dietary adherence.

Dietary Liberalization in Tetrahydrobiopterin-Treated PKU Patients: Does It Improve Outcomes?

PURPOSE: this systematic review aimed to assess the effects of dietary liberalization following tetrahydrobiopterin (BH4) treatment on anthropometric measurements, nutritional biomarkers, quality of life, bone density, mental health and psychosocial functioning, and burden of care in PKU patients. METHODS: the PubMed, Cochrane, and Embase databases were searched on 7 April 2022. We included studies that reported on the aforementioned domains before and after dietary liberalization as a result of BH4 treatment in PKU patients. Exclusion criteria were: studies written in a language other than English; studies that only included data of a BH4 loading test; insufficient data for the parameters of interest; and wrong publication type. Both within-subject and between-subject analyses were assessed, and meta-analyses were performed if possible. RESULTS: twelve studies containing 14 cohorts and 228 patients were included. Single studies reported few significant differences. Two out of fifteen primary meta-analyses were significant; BMI was higher in BH4-treated patients versus controls (p = 0.02; standardized mean difference (SMD) (95% confidence interval (CI)) = -0.37 (-0.67, -0.06)), and blood cholesterol concentrations increased after starting BH4 treatment (p = 0.01; SMD (CI) = -0.70 (-1.26, -0.15)). CONCLUSION: there is no clear evidence that dietary liberalization after BH4 treatment has a positive effect on anthropometric measurements, nutritional biomarkers, or quality of life. No studies could be included for bone density, mental health and psychosocial functioning, and burden of care.

Does cognitive impairment explain behavioral and social problems of children with neurofibromatosis type 1?

Thirty NF1-patients (mean age 11.7 years, SD = 3.3) and 30 healthy controls (mean age 12.5 years, SD = 3.1) were assessed on social skills, autistic traits, hyperactivity-inattention, emotional problems, conduct problems, and peer problems. Cognitive control, information processing speed, and social information processing were measured using 5 computer tasks. GLM analyses of variance showed significant group differences, to the disadvantage of NF1-patients, on all measures of behavior, social functioning and cognition. General cognitive ability (a composite score of processing speed, social information processing, and cognitive control) accounted for group differences in emotional problems, whereas social information processing accounted for group differences in conduct problems. Although reductions were observed for group differences in other aspects of behavior and social functioning after control for (specific) cognitive abilities, group differences remained evident. Training of cognitive abilities may help reducing certain social and behavioral problems of children with NF1, but further refinement regarding associations between specific aspects of cognition and specific social and behavioral outcomes is required.