The clinical relevance of novel biomarkers as outcome parameter in adults with phenylketonuria.

Recent studies in PKU patients identified alternative biomarkers in blood using untargeted metabolomics. To test the added clinical value of these novel biomarkers, targeted metabolomics of 11 PKU biomarkers (phenylalanine, glutamyl-phenylalanine, glutamyl-glutamyl-phenylalanine, N-lactoyl-phenylalanine, N-acetyl-phenylalanine, the dipeptides phenylalanyl-phenylalanine and phenylalanyl-leucine, phenylalanine-hexose conjugate, phenyllactate, phenylpyruvate, and phenylacetate) was performed in stored serum samples of the well-defined PKU patient-COBESO cohort and a healthy control group. Serum samples of 35 PKU adults and 20 healthy age- and sex-matched controls were analyzed using ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry. Group differences were tested using the Mann-Whitney U test. Multiple linear regression analyses were performed with these biomarkers as predictors of (neuro-)cognitive functions working memory, sustained attention, inhibitory control, and mental health. Compared to healthy controls, phenylalanine, glutamyl-phenylalanine, N-lactoyl-phenylalanine, N-acetyl-phenylalanine, phenylalanine-hexose conjugate, phenyllactate, phenylpyruvate, and phenylacetate were significant elevated in PKU adults (p < 0.001). The remaining three were below limit of detection in PKU and controls. Both phenylalanine and N-lactoyl-phenylalanine were associated with DSM-VI Attention deficit/hyperactivity (R2 = 0.195, p = 0.039 and R2 = 0.335, p = 0.002, respectively) of the ASR questionnaire. In addition, N-lactoyl-phenylalanine showed significant associations with ASR DSM-VI avoidant personality (R2 = 0.265, p = 0.010), internalizing (R2 = 0.192, p = 0.046) and externalizing problems (R2 = 0.217, p = 0.029) of the ASR questionnaire and multiple aspects of the MS2D and FI tests, reflecting working memory with R2 between 0.178 (p = 0.048) and 0.204 (p = 0.033). Even though the strength of the models was not considered strong, N-lactoyl-phenylalanine outperformed phenylalanine in its association with working memory and mental health outcomes.

Defining tetrahydrobiopterin responsiveness in phenylketonuria: Survey results from 38 countries.

BACKGROUND: A subset of patients with phenylketonuria benefit from treatment with tetrahydrobiopterin (BH4), although there is no consensus on the definition of BH4 responsiveness. The aim of this study therefore was to gain insight into the definitions of long-term BH4 responsiveness being used around the world. METHODS: We performed a web-based survey targeting healthcare professionals involved in the treatment of PKU patients. Data were analysed according to geographical region (Europe, USA/Canada, other). RESULTS: We analysed 166 responses. Long-term BH4 responsiveness was commonly defined using natural protein tolerance (95.6%), improvement of metabolic control (73.5%) and increase in quality of life (48.2%). When a specific value for a reduction in phenylalanine concentrations was reported (n = 89), 30% and 20% were most frequently used as cut-off values (76% and 19% of respondents, respectively). When a specific relative increase in natural protein tolerance was used to define long-term BH4 responsiveness (n = 71), respondents most commonly reported cut-off values of 30% and 100% (28% of respondents in both cases). Respondents from USA/Canada (n = 50) generally used less strict cut-off values compared to Europe (n = 96). Furthermore, respondents working within the same center answered differently. CONCLUSION: The results of this study suggest a very heterogeneous situation on the topic of defining long-term BH4 responsiveness, not only at a worldwide level but also within centers. Developing a strong evidence- and consensus-based definition would improve the quality of BH4 treatment.

Indicators of affective empathy, cognitive empathy, and social attention during emotional clips in relation to aggression in 3-year-olds.

Research indicates that impaired empathy is a risk factor of aggression and that social attention is important for empathy. The role of social attention in associations between empathy and aggression has not yet been fully elucidated. Therefore, indicators of affective empathy, cognitive empathy, social attention, and aggression were simultaneously assessed in children aged 45 months. A total of 61 mother-child dyads participated in a lab visit, during which maternal reports of aggression were obtained. Children watched three clips showing a sad, scared, and happy child, respectively, and a neutral social clip while heart rate was recorded. Heart rate change from nonsocial baseline clips to emotional clips was calculated as an index of affective empathy. Questions about the emotions of the children in the clips were asked to assess cognitive empathy. Social attention was defined as time spent looking at faces during the clips. Correlation analyses revealed negative associations between affective empathy and aggression and between social attention and aggression. Furthermore, multivariate linear regression analyses indicated that the association between affective empathy and aggression was moderated by social attention; the negative association between affective empathy and aggression was stronger in children with relatively reduced social attention. No association was found between cognitive empathy and aggression. Therefore, both affective empathy and social attention are important targets for early interventions that aim to prevent or reduce aggression.

Cerebral dopamine deficiency, plasma monoamine alterations and neurocognitive deficits in adults with phenylketonuria.

BACKGROUND: Phenylketonuria (PKU), a genetic metabolic disorder that is characterized by the inability to convert phenylalanine to tyrosine, leads to severe intellectual disability and other cerebral complications if left untreated. Dietary treatment, initiated soon after birth, prevents most brain-related complications. A leading hypothesis postulates that a shortage of brain monoamines may be associated with neurocognitive deficits that are observable even in early-treated PKU. However, there is a paucity of evidence as yet for this hypothesis. METHODS: We therefore assessed in vivo striatal dopamine D2/3 receptor (D2/3R) availability and plasma monoamine metabolite levels together with measures of impulsivity and executive functioning in 18 adults with PKU and average intellect (31.2 ± 7.4 years, nine females), most of whom were early and continuously treated. Comparison data from 12 healthy controls that did not differ in gender and age were available. RESULTS: Mean D2/3R availability was significantly higher (13%; p = 0.032) in the PKU group (n = 15) than in the controls, which may reflect reduced synaptic brain dopamine levels in PKU. The PKU group had lower plasma levels of homovanillic acid (p < 0.001) and 3-methoxy-4-hydroxy-phenylglycol (p < 0.0001), the predominant metabolites of dopamine and norepinephrine, respectively. Self-reported impulsivity levels were significantly higher in the PKU group compared with healthy controls (p = 0.033). Within the PKU group, D2/3R availability showed a positive correlation with both impulsivity (r = 0.72, p = 0.003) and the error rate during a cognitive flexibility task (r = 0.59, p = 0.020). CONCLUSIONS: These findings provide further support for the hypothesis that executive functioning deficits in treated adult PKU may be associated with cerebral dopamine deficiency.

Cognitive, neurophysiological, neurological and psychosocial outcomes in early-treated PKU-patients: a start toward standardized outcome measurement across development.

The aim of this paper is to provide a concise summary of findings from outcome studies in early-treated phenylketonuria (PKU). The paper should not be considered as an extensive review of the many different outcome measures that have been used in PKU-research, but as an attempt to integrate such findings so that they will be of additional value for day to day monitoring of PKU-patients and may direct future research to fill the present gaps of knowledge. Neurological, neuropsychological, neurophysiological, neuroimaging, quality of life, and psychosocial findings will be discussed in the context of their potential contributions to lifelong follow-up and treatment of PKU-patients being summarized in statements.

Correction to: PKU dietary handbook to accompany PKU guidelines.

An amendment to this paper has been published and can be accessed via the original article.

PKU dietary handbook to accompany PKU guidelines.

BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. MAIN BODY: In 2017 the first European PKU Guidelines were published. These guidelines contained evidence based and/or expert opinion recommendations regarding diagnosis, treatment and care for patients with PKU of all ages. This manuscript is a supplement containing the practical application of the dietary treatment. CONCLUSION: This handbook can support dietitians, nutritionists and physicians in starting, adjusting and maintaining dietary treatment.

Cognitive control in adolescents with neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a genetic disorder characterized by partial loss of growth control that affects the central nervous system. NF1 has been consistently associated with cognitive dysfunction, although there is no consensus on the cognitive profile in NF1 or on brain-cognition relationships. To clarify the pattern of cognitive dysfunction, performance of 16 NF1 patients and 16 age- and sex-matched controls (mean age = 14.5 years, SD = 1.3) was compared on computerized tasks measuring perception, executive functioning (inhibitory control, cognitive flexibility, and working memory), and motor control. A further aim of this study was to contrast performance on tasks or task parts requiring varying levels of cognitive control to find out whether this could explain potential difficulties experienced by this population in different cognitive domains or at different stages of information processing. Repeated measures analyses of variance showed that group differences, indicating poorer performance of NF1 patients, varied as a function of the level of cognitive control required. Evidence was also found for more basic motor skill problems in NF1 patients. Furthermore, NF1 patients were generally slower than controls. Results are discussed in the context of what is known about brain-cognition relationships in NF1.

Mindfulness-Based Stress Reduction in Prison: Experiences of Inmates, Instructors, and Prison Staff.

Mindfulness intervention aims to reduce stress and to improve physical and mental health. The present study investigated feasibility and effectiveness of mindfulness intervention in a prison context, in both a qualitative and quantitative fashion. Specifically, the mindfulness-based stress reduction (MBSR) intervention was investigated, in a retrospective pre-post design, in five Dutch prisons. Twenty-two inmates (out of 25 approached, mean age: 40.1 years (SD = 11.1), convicted of murder, manslaughter, sexual offenses, drug offenses, robbery with violence, and/or illegal restraint/kidnap, and sentenced to incarceration between 15 and 209 months (M = 5.5 years; SD = 3.8) took part in a semistructured interview after completion of the MBSR intervention. The interviews addressed level of satisfaction and challenges regarding the MBSR intervention as well as potential effects on stress responsivity, coping style, impulse control, aggression, and self-esteem. Ten staff members and four MBSR instructors were interviewed about their own practical issues experienced while providing or facilitating the MBSR intervention, and about the effects or changes they observed in the inmates who underwent the intervention. Both participants and instructors/prison staff reported improvements in all of the addressed domains and expressed satisfaction with the intervention. Challenges were mainly identified in practical issues regarding the organization of the intervention sessions. Future studies should investigate mindfulness in longitudinal randomly controlled designs, should strive for a multi-method approach, and distinguish inmates according to personality characteristics.

Empathic distress and concern predict aggression in toddlerhood: The moderating role of sex.

Impaired empathy is an important risk factor of aggression, but results are contradictory in toddlerhood. The association between empathy and aggression may differ for empathic distress and empathic concern in response to empathy-evoking situations, and for boys and girls. Therefore, the current study investigated whether empathic distress and empathic concern at age 20 months (N = 133, 69 boys) predicted aggression at ages 20 and 30 months (N = 119, 62 boys), while taking a potential moderating effect of sex into account. Empathic behavior was observed during a distress simulation task 20 months post-partum. Physical aggression was assessed through maternal report, using the Physical Aggression Scale for Early Childhood. Linear regression analyses revealed sex differences in the associations between empathic distress and concern on the one hand and physical aggression at age 20 months on the other. Furthermore, physical aggression at age 30 months was predicted by the interaction of sex with empathic distress at age 20 months, while controlling for aggression at age 20 months. More empathic distress and concern were associated with less physical aggression in girls, but not in boys. The findings indicate that the prediction of physical aggression by empathic distress was more robust over time than for empathic concern. This study sheds new light on the intricate relationship between empathy, aggression, and sex from a developmental perspective.

Infant Parasympathetic and Sympathetic Activity during Baseline, Stress and Recovery: Interactions with Prenatal Adversity Predict Physical Aggression in Toddlerhood.

Exposure to prenatal adversity is associated with aggression later in life. Individual differences in autonomic nervous system (ANS) functioning, specifically nonreciprocal activation of the parasympathetic (PNS) and sympathetic (SNS) nervous systems, increase susceptibility to aggression, especially in the context of adversity. Previous work examining interactions between early adversity and ANS functioning in infancy is scarce and has not examined interaction between PNS and SNS. This study examined whether the PNS and SNS moderate the relation between cumulative prenatal risk and early physical aggression in 124 children (57% male). Cumulative risk (e.g., maternal psychiatric disorder, substance (ab)use, and social adversity) was assessed during pregnancy. Parasympathetic respiratory sinus arrhythmia (RSA) and sympathetic pre-ejection period (PEP) at baseline, in response to and during recovery from emotional challenge were measured at 6 months. Physical aggression and non-physical aggression/oppositional behavior were measured at 30 months. The results showed that cumulative prenatal risk predicted elevated physical aggression and non-physical aggression/oppositional behavior in toddlerhood; however, the effects on physical aggression were moderated by PNS and SNS functioning. Specifically, the effects of cumulative risk on physical aggression were particularly evident in children characterized by low baseline PNS activity and/or by nonreciprocal activity of the PNS and SNS, characterized by decreased activity (i.e., coinhibition) or increased activity (i.e., coactivation) of both systems at baseline and/or in response to emotional challenge. These findings extend our understanding of the interaction between perinatal risk and infant ANS functioning on developmental outcome.

Interaction between prenatal risk and infant parasympathetic and sympathetic stress reactivity predicts early aggression.

Nonreciprocal action of the parasympathetic (PNS) and sympathetic (SNS) nervous systems, increases susceptibility to emotional and behavioral problems in children exposed to adversity. Little is known about the PNS and SNS in interaction with early adversity during infancy. Yet this is when the physiological systems involved in emotion regulation are emerging and presumably most responsive to environmental influences. We examined whether parasympathetic respiratory sinus arrhythmia (RSA) and sympathetic pre-ejection period (PEP) response and recovery at six months, moderate the association between cumulative prenatal risk and physical aggression at 20 months (N=113). Prenatal risk predicted physical aggression, but only in infants exhibiting coactivation of PNS and SNS (i.e., increase in RSA and decrease in PEP) in response to stress. These findings indicate that coactivation of the PNS and SNS in combination with prenatal risk is a biological marker for the development of aggression.

White matter microstructure of patients with neurofibromatosis type 1 and its relation to inhibitory control.

Neurofibromatosis Type 1 (NF1) is commonly associated with deficits in executive functions such as working memory and inhibitory control. A valid biomarker to describe the pathological basis of these deficits in NF1 is not available. The aim of this study was to investigate whether any abnormalities in white matter integrity of the executive function related anterior thalamic radiation (ATR), cingulate bundle (CB), and superior longitudinal fasciculus (SLF) may be regarded as a pathological basis for inhibitory control deficits in adolescents with NF1. Sixteen NF1 patients and 32 healthy controls underwent 3 T DTI MRI scanning. Whole brain-, ATR-, CB-, and SLF-white matter integrity were studied using fractional anisotropy, mean (MD), radial, and axial (DA) diffusivity. Correlation analyses between white matter metrics and inhibitory control (as measured with a computerized task) were performed. Also, verbal and performance abilities (IQ-estimates) were assessed and correlated with white matter metrics. Patients showed significant whole brain- and local microstructural pathology when compared to healthy controls in all measures. In NF1-patients, whole-brain (MD: r = .646 and DA: r = .673) and ATR- (r-range: -.405-.771), but not the CB- (r-range: -.307-.472) and SLF- (r-range: -.187-.406) white matter integrity, were correlated with inhibitory control. Verbal and performance abilities were not associated with white matter pathology. In NF1, white matter abnormalities are observed throughout the brain, but damage to the ATR seems specifically, or at least most strongly related to inhibitory control. Future studies should examine whether reduced white matter integrity in other brain regions or tracts is (more strongly) associated with different aspects of the cognitive-behavioral phenotype associated with NF1.

Prenatal Reflective Functioning and Development of Aggression in Infancy: the Roles of Maternal Intrusiveness and Sensitivity.

Maternal reflective functioning (RF) has been associated with quality of parent-child interactions and child development. This study investigated whether prenatal RF predicted the development of infant physical aggression and whether maternal sensitivity and/or intrusiveness mediated or moderated this association. The sample consisted of 96 first-time mothers (M = 22.57 years, SD = 2.13) and their infants (54 % male). Prenatal RF was measured with an interview, maternal behavior was observed during free play at 6 months post-partum, and infant physical aggression was assessed at 6, 12, and 20 months using maternal reports. Multivariate analyses of variance showed that relatively poor prenatal RF was related to relatively high infant physical aggression. These associations were moderated by maternal intrusiveness, with significant differences in physical aggression between RF-groups reportedly only in the absence of intrusiveness. Generally, mothers reported an increase in physical aggression between 6 and 12 months, except when they had both low RF-skills and were relatively less sensitive. It is concluded that prenatal RF is associated with (development of) infant physical aggression, and may be targeted in intervention programs aimed at reducing early physical aggression. Less adequate parenting, however, may counteract the beneficial effects of good RF, or obscure insight into children's behavioral development.

The complete European guidelines on phenylketonuria: diagnosis and treatment.

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.

Interrelations Between Maternal Smoking During Pregnancy, Birth Weight and Sociodemographic Factors in the Prediction of Early Cognitive Abilities.

Maternal prenatal smoking, birth weight and sociodemographic factors were investigated in relation to cognitive abilities of 1544 children (aged 3.5 years) participating in the Québec Longitudinal Study of Children's Development. The Peabody Picture Vocabulary Test (PPVT) was used to assess verbal ability, the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R) block design test to assess visuospatial ability, and the Visually Cued Recall (VCR) task to assess short-term memory. Prenatal smoking was related to performance on the WPPSI-R, the PPVT, and the VCR, although it did not independently predict any cognitive ability after maternal education was taken into account. Birth weight was a more robust predictor of all outcome measures and independently predicted VCR-performance. Birth weight interacted significantly with family income and maternal education in predicting visuospatial ability, indicating a greater influence of birth weight under relatively poor socio-economic conditions. Parenting and family functioning mediated associations between maternal education/family income and cognitive task performance under different birth weight conditions, although there were indications for stronger effects under relatively low birth weight. We conclude that investigations of moderating and mediating effects can provide insights into which children are most at risk of cognitive impairment and might benefit most from interventions.

Maternal reflective functioning as a multidimensional construct: Differential associations with children's temperament and externalizing behavior.

Maternal reflective functioning (RF) has been associated with children's behavioral development. This study examined maternal prenatal and postnatal RF, as measured by the Pregnancy Interview and Parent Development Interview, as multidimensional constructs. It was also examined whether the RF-dimensions were associated with children's temperament and externalizing behavior, as assessed by several questionnaires. The sample consisted of 123 first-time mothers (M age=22.85years, SD=2.21) and their children (M age=19.97months, SD=0.85, 56% male). Two related but distinct dimensions were found for prenatal RF, termed self-focused and child-focused mentalization. Three dimensions were observed for postnatal RF, termed self-focused, child-focused, and relation-focused mentalization. Results showed that prenatal RF negatively related to reported child physical aggression. Postnatal self-focused RF was positively linked to externalizing behavior and negative emotionality in offspring, while relation-focused RF scores were negatively associated with child physical aggression. Findings show that it is important to also look at the specific RF-dimensions when examining the effects of maternal RF on children's behavioral development, as differential associations with behavioral outcomes exist. Discussion further focuses on the importance of these findings in prevention and clinical practice, and suggestions are being made to further improve the measurement of maternal RF-dimensions.

The neuropsychological profile of early and continuously treated phenylketonuria: orienting, vigilance, and maintenance versus manipulation-functions of working memory.

In this paper, we review neuropsychological test results of early and continuously treated Phenylketonuria (PKU) patients. To increase insight into the neuropsychological profile of this population, we have attempted to place the results within an attentional network model [Images of the mind, 1994], which proposes interacting but dissociable attentional networks for orienting, vigilance, and executive control of attention. Executive control of attention is discussed against the background of the process-specific theory of working memory (WM) [Handbook of neuropsychology, 1994], which postulates a distinction between the 'maintenance'-function of WM and the 'manipulation and monitoring'-function. Neuropsychological results are presented for 67 early and continuously treated PKU patients and 73 controls aged 7-14 years. Four neuropsychological tasks were employed to measure orienting, mnemonic processing, interference suppression, and top-down control in visual search. No differences were found in orienting and the maintenance-function of WM. In addition to previously reported impairments in sustained attention/vigilance and inhibition of prepotent responding, PKU patients exhibited deficits when top-down control was required in a visual search task, but showed no impairment when interference suppression was required. It is discussed how the specific neuropsychological impairments in PKU may be a consequence of mid-dorsolateral prefrontal cortex (DLPFC) dysfunctioning due to deficiencies in catecholamine modulation.

Sustained attention and inhibition of cognitive interference in treated phenylketonuria: associations with concurrent and lifetime phenylalanine concentrations.

Fifty-seven 7-14-year-old early- and continuously treated phenylketonuria (PKU) patients and 65 matched controls performed a sustained attention task. PKU patients with plasma phenylalanine (phe) levels higher than 360 micromol/l at the time of testing exhibited, compared to controls, lower speed of information processing, a lower ability to inhibit task-induced cognitive interference, less consistent performance, and a stronger decrease of performance level over time. Patients with concurrent phe levels lower than 360 micromol/l did not differ from controls and were significantly better than patients with levels higher than 360 micromol/l. Strong relationships were found with task performance for phe levels during the pre-school years and between ages 5 and 7. These correlations were stronger than those between concurrent phe level and task performance. Significant multiple regression models were found with age accounting for the largest proportion of variance of tempo and tempo fluctuation, and lifetime phe levels (particularly phe level between ages 5 and 7) accounting for the largest proportion of variance of the relative number of inhibition errors and its increase over time. Phe level between ages 5 and 7 also contributed significantly to the variance of tempo and tempo fluctuation. Neuropsychological outcome was independent of IQ. The results indicate that strict dietary adherence during these periods is beneficial to attentional control later in life. We suggest that phe levels should be maintained under 360 micromol/l until approximately age 12, when development of attentional control approaches an adult level.

Motor function under lower and higher controlled processing demands in early and continuously treated phenylketonuria.

This study examined motor control in 61 early and continuously treated patients with phenylketonuria (PKU) and 69 control participants, aged 7 to 14 years. The pursuit task demanded concurrent planning and execution of unpredictable movements, whereas the tracking task required a highly automated circular movement that could be planned in advance. PKU patients showed significantly poorer motor control in both tasks compared with control participants. Deficits were particularly observed for younger patients (age < 11 years). Differences between control participants and PKU patients were significantly greater in the pursuit task compared with the tracking task, indicating more serious deficits when a higher level of controlled processing is required. Correlations with historical phenylalanine levels indicated a later maturation of the level of control required by the pursuit task compared with the tracking task.