OBJECTIVES: To determine the long-term neurodevelopmental outcome for children after hypoxic-ischemic encephalopathy (HIE) without major disability, and to examine neonatal injury patterns detected on cerebral magnetic resonance imaging (MRI) in relation to later deficits. STUDY DESIGN: Prospectively enrolled children with HIE and neonatal cerebral MRI data (n = 68) were examined at a mean age of 11.2 years (range, 8.2-15.7 years). Eleven children had a major disability (ie, cerebral palsy or mental retardation). Brain injury was scored according to the region and extent of injury. RESULTS: Children without major disability (n = 57) had lower full-scale and performance IQ scores compared with norms (P = .02 and .01, respectively), and the proportion of children with an IQ <85 was higher than expected (P = .04). Motor performance on the Zurich Neuromotor Assessment was affected in the pure motor, adaptive fine motor, and gross motor domains, as well as in the movement quality domain (all P < .001). Watershed injury pattern on neonatal MRI correlated with full-scale and verbal IQ scores (P = .006 and <.001, respectively), but neonatal MRI pattern did not correlate with motor performance in children without major disability. CONCLUSION: Children who sustained neonatal HIE without major disability are at increased risk for long-term intellectual, verbal, and motor deficits. The severity of watershed injury is correlated with later intellectual performance. Long-term follow-up examinations are necessary for early detection of neurodevelopmental impairment and early initiation of adequate therapies. AbstractObjectives: To determine the long-term neurodevelopmental outcome for children after hypoxic-ischemic encephalopathy without major disability and to examine the role of neonatal cerebral MRI injury patterns in relation to later deficits.Study design: Sixty-eight prospectively enrolled children with hypoxic-ischemic encephalopathy and neonatal cerebral MRI were examined at a mean age of 11.2 years (range 8.2 -15.7 years). Eleven children had a major disability (cerebral palsy or mental retardation). Brain injury was scored according to region and extent of injury.Results: Children without major disability (n=57) had lower total and performance IQ scores compared to the norm (p=0.02 and 0.01, respectively) and the proportion of children with an IQ < 85 was higher than that expected (p= 0.04). Motor performance on the Zurich Neuromotor Assessment was affected in the domains 'pure motor', 'adaptive fine' and 'gross motor' as well as in the domain 'movement quality' (all p-values< 0.001). Watershed injury pattern on neonatal MRI correlated with total and verbal IQ (p=0.006 and < 0.001, respectively), while neonatal MRI pattern did not correlated with motor performance in children without major disability. Conclusions:Children after neonatal hypoxic-ischemic encephalopathy without major disability are at higher risk for long-term intellectual, verbal and motor deficits. Severity of watershed injury correlates ...

BackgroundDespite abundant evidence for pathogenicity of large copy number variants (CNVs) in neurodevelopmental disorders (NDDs), the individual significance of genome-wide rare CNVs <500 kb has not been well elucidated in a clinical context.MethodsBy high-resolution chromosomal microarray analysis, we investigated the clinical significance of all rare non-polymorphic exonic CNVs sizing 1–500 kb in a cohort of 714 patients with undiagnosed NDDs.ResultsWe detected 96 rare CNVs <500 kb affecting coding regions, of which 58 (60.4%) were confirmed. 6 of 14 confirmed de novo, one of two homozygous and four heterozygous inherited CNVs affected the known microdeletion regions 17q21.31, 16p11.2 and 2p21 or OMIM morbid genes (CASK, CREBBP, PAFAH1B1, SATB2; AUTS2, NRXN3, GRM8). Two further de novo CNVs affecting single genes (MED13L, CTNND2) were instrumental in delineating novel recurrent conditions. For the first time, we here report exonic deletions of CTNND2 causing low normal IQ with learning difficulties with or without autism spectrum disorder. Additionally, we discovered a homozygous out-of-frame deletion of ACOT7 associated with features comparable to the published mouse model. In total, 24.1% of the confirmed small CNVs were categorised as pathogenic or likely pathogenic (median size 130 kb), 17.2% as likely benign, 3.4% represented incidental findings and 55.2% remained unclear.ConclusionsThese results verify the diagnostic relevance of genome-wide rare CNVs <500 kb, which were found pathogenic in ∼2% (14/714) of cases (1.1% de novo, 0.3% homozygous, 0.6% inherited) and highlight their inherent potential for discovery of new conditions.

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Major depression increases cardiovascular risk despite lower cholesterol levels. Little is known about effects of antidepressants on metabolic risk factors. We studied lipoprotein composition, insulin sensitivity (quantitative insulin sensitivity check index), and saliva cortisol in 78 depressed patients before and after 35 days of amitriptyline or paroxetin treatment. Data were analyzed by principal component factor analyses and analysis of variance (ANOVA). At baseline, quantitative insulin sensitivity check index was inversely correlated with cortisol (r = -0.46; P = 0.005) in normal weight patients, with body mass index in overweight patients (r = -0.50; P < 0.001). In overweight patients, hypercortisolemia correlated inversely with total and low density lipoprotein cholesterol (eg, cortisol at 4:00 PM and low density lipoprotein cholesterol: r = -0.49, P = 0.002). After treatment, quantitative insulin sensitivity check index was unchanged. Triglycerides increased in responders to amitriptyline only (P < 0.05). Parameters of cholesterol metabolism improved slightly without differences between treatment groups (eg, high density lipoprotein: pre 43.5 +/- 12.0; post 47.6 +/- 13.0 mg/dL; P = 0.01; low density lipoprotein triglycerides, a measure of low density lipoprotein atherogenicity: pre 458 +/- 120; post 415 +/- 130 mg/g; P < 0,01). The inverse correlation of cortisol and cholesterol, at least in the obese subgroup, proposes a mechanism for the known association of depression with low cholesterol. As determinants of plasma lipids in major depression, we identified body mass index, insulin sensitivity, and cortisol. Although uncontrolled, our data suggest that treatment of depression exerts a mainly beneficial effect on lipid regulation.

Developmental delay (DD) in children is a common socioeconomic problem with a prevalence of 1-2%. The cause of DD in children is often unknown, and magnetic resonance imaging plays an important role in evaluating children with DD, estimating long-term prognosis, and guiding therapeutic options. The aim of our study on children with DD was to elucidate 1) whether magnetic resonance spectroscopy (MRS) reveals abnormalities in cerebral metabolism and 2) whether there is a correlation between the cognitive performance and the concentration of brain metabolites, especially N-acetylaspartate (NAA), named in the literature a neuronal marker. Using proton MRS of deep gray and central white matter, we measured concentrations of brain metabolites in 48 children, who were aged 1 mo to 13 y and had unexplained DD [developmental quotient (DQ) between Ͻ50 and 85] and normal magnetic resonance imaging examinations, and compared them with those of 23 age-matched normal control children. Children with DD were divided into three groups: mild (DQ 76 -85), moderate (DQ 51-75), and severe (DQ Ͻ50). We found no significant differences in metabolite concentrations, neither among the three groups of children with DD nor between patients and age-matched normal control children. Independent of the degree of mental retardation, the NAA concentrations of handicapped patients and normal children were comparable. We conclude that 1) brain metabolites, especially NAA, in children with unexplained DD are within normal limits, and 2) in most cases, proton MRS adds little information concerning cause of unexplained DD. Developmental delay (DD) in children includes mental retardation (IQ Ͻ70) and borderline intellectual functioning (IQ between 71 and 85). DD is a common socioeconomic problem with an estimated prevalence of 1-2% in the child population, with most cases in the middle range of IQ (50 -75) (1). Whereas congenital defects-genetic or early acquired-are often the cause of severe mental disability, up to 15% of school-aged children may present with some form of DD (2).The primary care pediatrician, the pediatric neurologist, and the developmental pediatrician, therefore, are frequently confronted with children with unexplained DD. The consensus conference of the American College of Medical Genetics has established guidelines regarding the evaluation of children with mental retardation (3,4). An important aspect in the search of possible causes for the child's delay is the characterization of the type of DD, e.g. global delay or isolated forms, because they afford different evaluation strategies (5-7). Global delay is defined as significant delay in two or more of the following domains: motor (gross/fine), speech/language, cognition, personal/social, and activities of daily living. There is general agreement that magnetic resonance imaging (MRI) plays an important role in the evaluation of children with DD in certain clinical settings (8) and that MRI seems to be more sensitive than computed tomography, with abnormalities found in 48.6 -6...