Patients with complex congenital heart disease are at risk for neurodevelopmental impairments. Evidence suggests that brain maturation can be delayed and pre- and postoperative brain injury may occur, and there is limited information on the long-term effect of congenital heart disease on brain development and function in adolescent patients. At a mean age of 13.8 years, 39 adolescent survivors of childhood cardiopulmonary bypass surgery with no structural brain lesions evident through conventional cerebral magnetic resonance imaging and 32 healthy control subjects underwent extensive neurodevelopmental assessment and cerebral magnetic resonance imaging. Cerebral scans were analysed quantitatively using surface-based and voxel-based morphometry. Compared with control subjects, patients had lower total brain (P = 0.003), white matter (P = 0.004) and cortical grey matter (P = 0.005) volumes, whereas cerebrospinal fluid volumes were not different. Regional brain volume reduction ranged from 5.3% (cortical grey matter) to 11% (corpus callosum). Adolescents with cyanotic heart disease showed more brain volume loss than those with acyanotic heart disease, particularly in the white matter, thalami, hippocampi and corpus callosum (all P-values < 0.05). Brain volume reduction correlated significantly with cognitive, motor and executive functions (grey matter: P < 0.05, white matter: P < 0.01). Our findings suggest that there are long-lasting cerebral changes in adolescent survivors of cardiopulmonary bypass surgery for congenital heart disease and that these changes are associated with functional outcome.

X-linked infantile spinal muscular atrophy (XL-SMA) is an X-linked disorder presenting with the clinical features hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and infantile death. To identify the XL-SMA disease gene, we performed large-scale mutation analysis in genes located between markers DXS8080 and DXS7132 (Xp11.3-Xq11.1). This resulted in detection of three rare novel variants in exon 15 of UBE1 that segregate with disease: two missense mutations (c.1617 G-->T, p.Met539Ile; c.1639 A-->G, p.Ser547Gly) present each in one XL-SMA family, and one synonymous C-->T substitution (c.1731 C-->T, p.Asn577Asn) identified in another three unrelated families. Absence of the missense mutations was demonstrated for 3550 and absence of the synonymous mutation was shown in 7914 control X chromosomes; therefore, these results yielded statistical significant evidence for the association of the synonymous substitution and the two missense mutations with XL-SMA (p = 2.416 x 10(-10), p = 0.001815). We also demonstrated that the synonymous C-->T substitution leads to significant reduction of UBE1 expression and alters the methylation pattern of exon 15, implying a plausible role of this DNA element in developmental UBE1 expression in humans. Our observations indicate first that XL-SMA is part of a growing list of neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway and second that synonymous C-->T transitions might have the potential to affect gene expression.

Aim The aim of this study was to examine neurodevelopment, psychological adjustment, and health‐related quality of life (HRQoL) in adolescents after bypass surgery for congenital heart disease (CHD) during early childhood. Method Fifty‐nine adolescents (34 females, 25 males) with CHD were examined at a median age of 13 years 8 months (range 11y 5mo–16y 11mo). Outcome was assessed with the Wechsler Intelligence Scale for Children, (fourth edition); the Beery Test of Visual‐Motor Integration; the Rey–Osterrieth Complex Figure Test; the Zurich Neuromotor Assessment; the Strengths and Difficulties Questionnaire; and the KIDSCREEN questionnaires. Results were compared with those of 40 age‐ and sex‐matched healthy comparison individuals. Results Outcome with regard to full‐scale IQ, perceptual reasoning, and the working memory scale was poorer in patients with CHD than in the comparison group (all p≤0.001). Visual perception, visuomotor integration (p≤0.001), and executive functions (Rey figure copy: p=0.05) were also affected. Patients with CHD also had lower scores on all motor domains (p<0.02) except static balance. Psychological adjustment was affected only in the ‘peer relationship’ domain (p=0.05). Quality of life was similar to that of typically developing peers. Interpretation Adolescents with CHD may manifest persistent cognitive and motor impairments, while psychological adjustment and self‐reported HRQoL are mostly typical. Thus, long‐term neurodevelopmental evaluations are necessary to provide early educational and therapeutic support.

A conditional independence graph is a concise representation of pairwise conditional independence among many variables. Graphical Random Forests (GRaFo) are a novel method for estimating pairwise conditional independence relationships among mixed-type, i.e. continuous and discrete, variables. The number of edges is a tuning parameter in any graphical model estimator and there is no obvious number that constitutes a good choice. Stability Selection helps choosing this parameter with respect to a bound on the expected number of false positives (error control).The performance of GRaFo is evaluated and compared with various other methods for p = 50, 100, and 200 possibly mixed-type variables while sample size is n = 100 (n = 500 for maximum likelihood). Furthermore, GRaFo is applied to data from the Swiss Health Survey in order to evaluate how well it can reproduce the interconnection of functional health components, personal, and environmental factors, as hypothesized by the World Health Organization's International Classification of Functioning, Disability and Health (ICF). Finally, GRaFo is used to identify risk factors which may be associated with adverse neurodevelopment of children who suffer from trisomy 21 and experienced open-heart surgery.GRaFo performs well with mixed data and thanks to Stability Selection * Corresponding author. it provides an error control mechanism for false positive selection.