Search

Summary Objective Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available. Methods We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had “epilepsy plus,” defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51‐6.68; P = 2.34 × 10−9). Meta‐analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. Significance The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large‐scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.

Objective: The common single nucleotide polymorphism (SNP) rs9939609 in the fat mass and obesity-associated gene (FTO) is associated with obesity. As genetic variants associated with weight regulation might also be implicated in the etiology of eating disorders, we evaluated whether SNP rs9939609 is associated with bulimia nervosa (BN) and anorexia nervosa (AN). Methods: Association of rs9939609 with BN and AN was assessed in 689 patients with AN, 477 patients with BN, 984 healthy non-population-based controls, and 3,951 population-based controls (KORA-S4). Based on the familial and premorbid occurrence of obesity in patients with BN, we hypothesized an association of the obesity risk A-allele with BN. Results: In accordance with our hypothesis, we observed evidence for association of the rs9939609 A-allele with BN when compared to the non-population-based controls (unadjusted odds ratio (OR) = 1.142, one-sided 95% confidence interval (CI) 1.001-infinity; one-sided p = 0.049) and a trend in the population-based controls (OR = 1.124, one-sided 95% CI 0.932-infinity; one-sided p = 0.056). Interestingly, compared to both control groups, we further detected a nominal association of the rs9939609 A-allele to AN (OR = 1.181, 95% CI 1.027-1.359, two-sided p = 0.020 or OR = 1.673, 95% CI 1.101-2.541, two-sided p = 0.015,). Conclusion: Our data suggest that the obesity-predisposing FTO allele might be relevant in both AN and BN. Copyright (C) 2012 S. Karger GmbH, Freiburg

The objective of this study was to examine whether there is an association between individual and family eating patterns during childhood and early adolescence and the likelihood of developing a subsequent eating disorder (ED). A total of 1664 participants took part in the study. The ED cases (n 879) were referred for assessment and treatment to specialized ED units in five different European countries and were compared to a control group of healthy individuals (n 785). Participants completed the Early Eating Environmental Subscale of the Cross-Cultural (Environmental) Questionnaire, a retrospective measure, which has been developed as part of a European multicentre trial in order to detect dimensions associated with ED in different countries. In the control group, also the General Health Questionnaire-28 (GHQ-28), the semi-structured clinical interview (SCID-I) and the Eating Attitudes Test (EAT-26) were used. Five individually Categorical Principal Components Analysis (CatPCA) procedures were adjusted, one for each theoretically expected factor. Logistic regression analyses indicated that the domains with the strongest effects from the CatPCA scores in the total sample were: food used as individualization, and control and rules about food. Oil the other hand, healthy eating was negatively related to a subsequent ED. When differences between countries were assessed, results indicated that the pattern of associated ED factors did vary between countries. There was very little difference in early eating behaviour on the subtypes of ED. These findings suggest that the fragmentation of meals within the family and an excessive importance given to food by the individual and the family are linked to the later development of an ED.

Objectives: To assess the differences in comorbid lifetime and current substance use (tobacco, alcohol and drug use) between eating disorder (ED) patients and healthy controls in five different European countries. Method: A total of 1664 participants took part in the present study. ED cases (n=879) were referred to specialized ED units in five European countries. The ED cases were compared to a balanced control group of 785 healthy individuals. Assessment: Participants completed the Substance Use Subscale of the Cross Cultural (Environmental) Questionnaire (CCQ), a measure of lifetime tobacco, alcohol and drug use. In the control group, also the GHQ-28, the SCID-1 interview and the EAT-26 were used. Results: ED patients had higher lifetime and current tobacco and general drug use. The only non-significant result was obtained for lifetime and current alcohol use. Significant differences across ED subdiagnoses and controls also emerged, with BN and AN-BP generally presenting the highest and AN-R and controls the lowest rates. The only exception was detected for alcohol use where EDNOS demonstrated the highest values. Only a few cultural differences between countries emerged. Conclusions: With the exception of alcohol consumption, tobacco and drug use appear to be more prevalent in ED patients than healthy controls. The differential risk observed in patients with bulimic features might be related to differences in temperament or might be the result of increased sensitivity to reward. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

A Tyrrhenian coastal area in southern Italy was flooded on July 2006. This event caused the spread of mud, detritus and the spill of industrial wastes into the sea water. Surficial sediment samples were collected and analysed for polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and polychlorinated dibenzop- dioxins and –furans (PCDD/Fs) in order to evaluate current contamination status and risk assessment by means of Toxic Equivalency Factors (TEF). Data analysis showed that PCBs and OCPs levels were low and homogeneous in the three areas while PCDD/F fingerprint showed an heterogeneous distribution, suggesting for these molecules different sources of pollution.

BackgroundAlbeit several studies pointed out the pivotal role that CD4+T cells have in Multiple Sclerosis, the CD8+ T cells involvement in the pathology is still in its early phases of investigation. Proteasome degradation is the key step in the production of MHC class I-restricted epitopes and therefore its activity could be an important element in the activation and regulation of autoreactive CD8+ T cells in Multiple Sclerosis.Methodology/principal findingsImmunoproteasomes and PA28-alphabeta regulator are present in MS affected brain area and accumulated in plaques. They are expressed in cell types supposed to be involved in MS development such as neurons, endothelial cells, oligodendrocytes, macrophages/macroglia and lymphocytes. Furthermore, in a genetic study on 1262 Italian MS cases and 845 controls we observed that HLA-A*02+ female subjects carrying the immunoproteasome LMP2 codon 60HH variant have a reduced risk to develop MS. Accordingly, immunoproteasomes carrying the LMP2 60H allele produce in vitro a lower amount of the HLA-A*0201 restricted immunodominant epitope MBP(111-119).Conclusion/significanceThe immunoproteasome LMP2 60HH variant reduces the risk to develop MS amongst Italian HLA-A*02+ females. We propose that such an effect is mediated by the altered proteasome-dependent production of a specific MBP epitope presented on the MHC class I. Our observations thereby support the hypothesis of an involvement of immunoproteasome in the MS pathogenesis.

Plastic is everywhere—increasing evidence suggests that plastic pollution is ubiquitous and persistent in ecosystems worldwide. Microplastic pollution in marine environments is particularly insidious, as small fragmentation can increase interaction with biota and food chain access. Of particular concern is the Mediterranean Sea, which has become a large area of accumulation of plastic debris, including microplastics, whose polymeric composition is still largely unknown. In this study, we analyzed the polymeric composition, particle size distribution, shape, and color of small plastic particles (ranging from 50 to 5000 µm) collected from the sea surface in six stations at the center of the Mediterranean Sea. We also described, for the first time, the different distribution of microplastics from coastal areas up to 12 nautical miles offshore. The microplastic density was 0.13 ± 0.19 particles/m2, with a marked prevalence of smaller particles (73% &lt, 3 mm) and a peak between 1 and 2 mm (34.74%). Microplastics composition analysis showed that the most abundant material was polyethylene (69%), followed by polypropylene (24%). Moreover, we reported a comparison of the two Calabrian coasts providing the first characterization of a great difference in microplastic concentration between the Tyrrhenian and Ionian sides (87% vs. 13%, respectively), probably due to the complex marine and atmospheric circulation, which make the Tyrrhenian side an area of accumulation of materials originating even from faraway places. We demonstrate, for the first time, a great difference in microplastic concentration between Tyrrhenian and Ionian Calabrian coasts, providing a full characterization and highlighting that microplastic pollution is affected by both local release and hydrography of the areas.

A wide phenotypic spectrum of neurological diseases is associated with KCNA1 (Kv1.1) variants. To investigate the molecular basis of such a heterogeneous clinical presentation and identify the possible correlation with in vitro phenotypes, we compared the functional consequences of three heterozygous de novo variants (p.P403S, p.P405L, and p.P405S) in Kv1.1 pore region found in four patients with severe developmental and epileptic encephalopathy (DEE), with those of a de novo variant in the voltage sensor (p.A261T) identified in two patients with mild, carbamazepine-responsive, focal epilepsy. Patch-clamp electrophysiology was used to investigate the functional properties of mutant Kv1.1 subunits, both expressed as homomers and heteromers with wild-type Kv1.1 subunits. KCNA1 pore mutations markedly decreased (p. P405S) or fully suppressed (p. P403S, p. P405L) Kv1.1-mediated currents, exerting loss-of-function (LoF) effects. By contrast, channels carrying the p.A261T variant exhibited a hyperpolarizing shift of the activation process, consistent with a gain-of-function (GoF) effect. The present results unveil a novel correlation between in vitro phenotype (GoF vs LoF) and clinical course (mild vs severe) in KCNA1-related phenotypes. The excellent clinical response to carbamazepine observed in the patients carrying the A261T variant suggests an exquisite sensitivity of KCNA1 GoF to sodium channel inhibition that should be further explored.