BackgroundHereditary Tyrosinemia type 1 (HT1) is a rare metabolic disorder caused by a defect in the enzyme Fumarylacetoacetate Hydrolase. Due to this defect, toxic products accumulate which, in turn, cause liver and kidney dysfunction. Treatment with 2-(2-nitro-4-trifluoromethylbenoyl)-1,3-cyclohexanedione (NTBC) and diet has diminished these problems, but recent data indicate that HT1 patients have neurocognitive problems. However, the neuropsychological profile of these patients is unknown. Therefore, this study aimed to investigate this neuropsychological profile by comparing HT1 patients with healthy controls.MethodsNeurocognitive testing was performed in a heterogeneous group of 19 NTBC and dietary treated HT1 patients (five female, fourteen male; mean age 12.9 ± 4.8 years; range 7.9–23.6 years) and 19 age and gender matched controls (five female, fourteen male; mean age 13.2 ± 4.6 years; range 8.1–24.8 years). IQ scores were estimated and all participants performed the Amsterdam Neuropsychological Tasks, measuring executive functions (inhibition, cognitive flexibility and working memory) and social cognition (face recognition and identification of facial emotions).ResultsHT1 patients showed poorer estimated IQ, executive functioning (working memory and cognitive flexibility), and social cognition compared to healthy controls. Lower IQ scores in HT1 patients were mostly unrelated to scores on executive function- and social cognition tasks and therefore did not account for group differences in these domains. Further analyses within the HT1 patient group (comparing different groups of patients based on the age at diagnosis and the clinical symptoms at diagnosis) did not reveal any significant results. The duration of NTBC treatment was negatively correlated with IQ.ConclusionsDespite the heterogeneity of the patient group, these data clearly show that IQ, executive functioning and social cognition are affected in HT1 patients, and that IQ screening is not sufficient for cognitive monitoring of these patients. Further research should focus on the underlying pathophysiological mechanisms of these impairments to consequently try to improve treatment strategies.

AIM To examine social information processing in children and adolescents with neurofibromatosis type 1 (NF1).METHOD Thirty-two children with NF1 (12 males, 20 females; mean age 12y 4mo, SD 4y) and 32 comparison children (12 males, 20 females; mean age 13y 1mo, SD 3y 11mo) completed face recognition, identification of facial emotions (IFE), and matching facial emotions (MFE) tasks. A series of general linear model analyses of variance were used to compare performance between children with NF1 and comparison children. RESULTSChildren with NF1 performed less accurately than comparison children in the face recognition task when faces were presented 'in profile' (p=0.05), when fearful expressions had to be identified in IFE (p=0.017), and across conditions in MFE (p=0.009). When quality of cognitive control (i.e. mean standardized scores on tasks measuring working memory and inhibitory control) was introduced to the analyses, differences in face recognition were no longer significant and differences in MFE were largely reduced (p=0.048). Differences in IFE between the comparison group and children with NF1 remained largely intact (fear: p=0.047).INTERPRETATION Children with NF1 have problems in social information processing, which, in part, appear to be caused by cognitive control deficits. Some of the deficits, however, appear to be caused by deficient bottom-up processing of social signals (e.g. fear recognition).Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with an incidence of approximately 1 in every 3000 individuals. 1,2 Clinical manifestations of NF1 include café-au-lait spots, intertriginous freckling, Lisch nodules (i.e. pigmented iris hamartomas or freckling in the iris), neurofibromas (i.e. benign Schwann cell tumours, divided into four types: (1) focal or diffuse cutaneous, (2) subcutaneous, (3) spinal, and (4) nodular or diffuse plexiform neurofibromas, which develop from nerves and extend into surrounding structures, and which can transform into malignant tumours), optic pathway gliomas, and distinctive bone lesions (e.g. short stature or dystrophic scoliosis). 3 The NF1 gene is located on chromosome 17 (17q11.2). Neurofibromin, the protein product of this gene, inhibits Ras, which in turn stimulates cell proliferation and differentiation. Therefore, lack of neurofibromin might result in the inability to control the formation, migration, and differentiation of neurons. 4 Magnetic resonance imaging studies have shown widespread abnormalities in the brains of children with NF1, including T2 hyperintensities, reduced grey matter and increased white matter volumes, and reduced integrity of white matter. [5][6][7][8] Cognitive impairment is the most common complication in children with NF1. 9 Several studies reported deficits in specific cognitive domains, such as visuospatial skills or motor control, 10,11 whereas others provided evidence for more general executive function or cognitive control deficits affecting different cognitive domains when control demands increase. 12,13 Soc...

ObjectiveEarly 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.MethodsNinety 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.ResultsPKU-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.ConclusionPKU-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.

Adult patients had lower IQ and poorer executive functions than controls, resembling problems observed in younger patients with phenylketonuria, as well as more internalizing problems. Group differences and phenylalanine-outcome associations were smaller than those observed in younger populations. A subset of nontetrahydrobiopterin users, matched for childhood phenylalanine level, had a poorer outcome on some tests than tetrahydrobiopterin users, which might indicate an impact of tetrahydrobiopterin treatment beyond lowering phenylalanine. However, clinical relevance needs further investigation. (PsycINFO Database Record