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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. (C) 2014 Elsevier Inc. All rights reserved.

Background: Phenylketonuria (PKU) is a rare inborn error of metabolism caused by phenylalanine hydroxylase enzyme (PAH) deficiency. Treatment constitutes a strict Phe restricted diet with unpalatable amino acid supplements. Residual PAH activity enhancement with its cofactor tetrahydrobiopterin (BH4) is a novel treatment which increases dietary tolerance in some patients and permits dietary relaxation. Relaxation of diet may improve health related quality of life (HRQoL). This prospective cohort study aims to evaluate HRQoL of patients with PKU and effects of BH4 treatment on HRQoLMethods: Patients aged 4 years and older, diagnosed through newborn screening and early and continuously treated, were recruited from eight metabolic centers. Patients and mothers completed validated generic and chronic health-conditions HRQoL questionnaires (PedsQL, TAAQOL, and DISABKIDS) twice: before and after testing BH4 responsivity. Baseline results were compared to the general population. Data collected after BH4 testing was used to find differences in HRQoL between BH4 unresponsive patients and BH4 responsive patients after one year of treatment with BH4. Also a within patient comparison was performed to find differences in HRQoL before and after treatment with BH4.Results: 69/81 (85%) patients completed the questionnaires before BH4 responsivity testing, and 45/69 (65%) participated again after testing. Overall PKU patients demonstrated normal HRQoL However, some significant differences were found when compared to the general population. A significantly higher (thus better) score on the PedsQL was reported by children 8-12 years on physical functioning and by children 13-17 years on total and psychosocial functioning. Furthermore, adult patients reported significantly lower (thus worse) scores in the TAAQOL cognitive domain. 10 patients proved to be responsive to BH4 treatment; however improvement in their HRQoL after relaxation of diet could not be demonstrated. (C) 2013 Elsevier Inc. All rights reserved.

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 33) 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. (C) 2013 Elsevier Inc. All rights reserved.

Endocrine abnormalities in classical galactosemia, female hypergonadotropic hypogonadism and low thyroxin in neonates, have been reported. Galactosemia is a secondary glycosylation disorder and hypoglycosylation of glycoproteins has a role in this dysfunction. Hypoglycosylation, improves but does not completely disappear with dietary treatment. Our aim was to evaluate the endocrine system in treated patients (n = 37, 25 females, 12 males, age 5-19 years). Endocrine determinations were compared to age and gender matched reference ranges. Sample t-test (to test differences with reference population) and linear regression analysis between hGH (growth hormone), IGF-1 (insulin-like growth factor), IGFBP-3 (insulin growth factor binding protein), FSH (follicle stimulating hormone), LH (luteinizing hormone) and GALT activity, and soy intake, was carried out. Mean IGF-1 Z-score was -0.98 +/- 0.84 (range -2.59 to 1.21) (P < 0.001) in females and 0.03 +/- 0.55 (range -1.0 to 0.89) (P = 0.84) in males. Mean IGFBP-3 Z-score was -0.98 +/- 1.3 (range -3.0 to 2.0) (P < 0.001) in females and 0.26 +/- 0.93 (range -0.94 to 2.0) (P = 0.35) in males. IGF-1 and IGFBP-3 were positively correlated (P < 0.001). IGF-1 or IGFBP-3 Z-scores and age, hGH, estradiol, GALT activity or soy intake were not correlated. FSH was elevated in females, other axes were normal. Besides the hypergonadotropic hypogonadism in females, IGF-1 and IGFBP-3 are in the low to normal ranges in girls. Hypoglycosylation in galactosemia is diet dependent and could worsen when galactose intake increases either because of poor compliance or diet liberalization.

Despite life-long galactose restriction, long-term complications generally occur in classical galactosemia. We report an adult male with classical galactosemia (Q188R homozygosity, severely reduced erythrocyte galactose-1-phosphate uridyltransferase activity) who has a surprisingly mild phenotype despite genotype and enzyme activity associated with severe phenotype. Moreover he has a normal galactose intake from the age of 3 years. This case is probably an example of the important role of yet unknown susceptibility and or modifier genes.