A lifetime with Phenylketonuria:Towards a better understanding of therapeutic targets

Dit proefschrift ‘A lifetime with Phenylketonuria. Towards a better understanding of therapeutic targets’ bevat de eerste bevindingen van het Nederlandse multicenter Phenylketonurie-COBESO onderzoek, uitgevoerd tussen 2012-2015. COBESO staat voor de cognitieve (COgnitive), gedrags- (BEhavioral) en sociale (SOcial) maten die onderzocht zijn in deze studie. 108 Patiënten met phenylketonurie (PKU) uit zes universitair medische centra en 112 gezonde controles van verschillende leeftijden zijn geïncludeerd. De doelstelling was het onderzoeken van cognitief functioneren, mentale gezondheid, sociaal cognitief functioneren en sociale vaardigheden bij vroeg en continu behandelde PKU patiënten in relatie tot hun metabole controle (gemeten aan de hand van phenylalaninewaarden in het bloed), behandeling en behandelrichtlijnen. Cognitieve en internaliserende gedragsproblemen zijn met name gevonden bij volwassen PKU patiënten. Adolescenten met PKU hadden ook problemen met sociale cognitie, maar deze problemen waren het meest uitgesproken bij volwassen patiënten. Problemen op alle gebieden waren gerelateerd aan hoge phenylalaninewaarden tijdens verschillende levensfasen. Er zijn meerdere belangrijke bevindingen betreffende behandelrichtlijnen. Patiënten met phenylalanine concentraties onder de 360 µmol/L in de kindertijd en boven de 360 µmol/L vanaf adolescentie hadden betere cognitieve uitkomsten in volwassenheid dan degenen met phenylalanine boven de 360 µmol/L gedurende hun leven. Phenylalanine in de kindertijd lijkt het meest belangrijk voor cognitieve en gedragsuitkomsten in volwassenheid. Verder lijkt een grotere toename van phenylalanine in de adolescentie ook belangrijk voor cognitieve uitkomsten in de volwassenheid. Bovendien, een phenylalanine level van 240 µmol/ L in de kindertijd is mogelijk een betere behandelrichtlijn voor beter cognitief functioneren vergeleken met de meest geadviseerde phenylalanine bovengrens van 360 µmol/L

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 mu mol/L) and proportion below lower target level (120 mu mol/L) during this period, diagnostic phenylalanine levels, number of days until phenylalanine levels were 360 mu mol/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

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

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. Qu

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 value

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 mmol/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 mmol/L and healthy controls performed equally well. Patients with Phe levels between 240 and 360 mmol/L and $360 mmol/L performed more poorly than did controls across tasks. Patients with Phe levels #240 mmol/L performed significantly better than patients with levels between 240 and 360 mmol/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