Next-generation sequencing in X-linked intellectual disability

X-linked intellectual disability (XLID) is a genetically heterogeneous disorder with more than 100 genes known to date. Most genes are responsible for a small proportion of patients only, which has hitherto hampered the systematic screening of large patient cohorts. We performed targeted enrichment and next-generation sequencing of 107 XLID genes in a cohort of 150 male patients. Hundred patients had sporadic intellectual disability, and 50 patients had a family history suggestive of XLID. We also analysed a sporadic female patient with severe ID and epilepsy because she had strongly skewed X-inactivation. Target enrichment and high parallel sequencing allowed a diagnostic coverage of >10 reads for ~96% of all coding bases of the XLID genes at a mean coverage of 124 reads. We found 18 pathogenic variants in 13 XLID genes (AP1S2, ATRX, CUL4B, DLG3, IQSEC2, KDM5C, MED12, OPHN1, SLC9A6, SMC1A, UBE2A, UPF3B and ZDHHC9) among the 150 male patients. Thirteen pathogenic variants were present in the group of 50 familial patients (26%), and 5 pathogenic variants among the 100 sporadic patients (5%). Systematic gene dosage analysis for low coverage exons detected one pathogenic hemizygous deletion. An IQSEC2 nonsense variant was detected in the female ID patient, providing further evidence for a role of this gene in encephalopathy in females. Skewed X-inactivation was more frequently observed in mothers with pathogenic variants compared with those without known X-linked defects. The mutation rate in the cohort of sporadic patients corroborates previous estimates of 5–10% for X-chromosomal defects in male ID patients.     

Neural Substrates of Psychotic Depression: Findings From the Global ECT-MRI Research Collaboration

Psychotic major depression (PMD) is hypothesized to be a distinct clinical entity from nonpsychotic major depression (NPMD). However, neurobiological evidence supporting this notion is scarce. The aim of this study is to identify gray matter volume (GMV) differences between PMD and NPMD and their longitudinal change following electroconvulsive therapy (ECT). Structural magnetic resonance imaging (MRI) data from 8 independent sites in the Global ECT-MRI Research Collaboration (GEMRIC) database (n = 108; 56 PMD and 52 NPMD; mean age 71.7 in PMD and 70.2 in NPMD) were analyzed. All participants underwent MRI before and after ECT. First, cross-sectional whole-brain voxel-wise GMV comparisons between PMD and NPMD were conducted at both time points. Second, in a flexible factorial model, a main effect of time and a group-by-time interaction were examined to identify longitudinal effects of ECT on GMV and longitudinal differential effects of ECT between PMD and NPMD, respectively. Compared with NPMD, PMD showed lower GMV in the prefrontal, temporal and parietal cortex before ECT; PMD showed lower GMV in the medial prefrontal cortex (MPFC) after ECT. Although there was a significant main effect of time on GMV in several brain regions in both PMD and NPMD, there was no significant group-by-time interaction. Lower GMV in the MPFC was consistently identified in PMD, suggesting this may be a trait-like neural substrate of PMD. Longitudinal effect of ECT on GMV may not explain superior ECT response in PMD, and further investigation is needed.     

Fiber connections between the cerebral cortex and the corpus callosum in Alzheimer's disease: a diffusion tensor imaging and voxel-based morphometry study

Regional cortical atrophy in Alzheimer's disease (AD) most likely reflects the loss of cortical neurons. Several diffusion tensor imaging studies reported reduced fractional anisotropy (FA) in the corpus callosum in AD. The aim of this study was to investigate the association between reduced FA in the corpus callosum and gray matter atrophy in AD. Thirteen patients with AD with a mean (+/-standard deviation) age of 68.3 years (+/-11.5) and mean Mini Mental State Examination (MMSE) score of 21.8 (+/-4.8) were recruited. There were 13 control subjects with a mean age of 66.7 years (+/-6.4) and MMSE of 29.1 (+/-0.7). We used voxel-based morphometry of gray matter maps and region of interest-based analysis of FA in the corpus callosum. FA values of the anterior corpus callosum in AD patients were significantly correlated with gray matter volume in the prefrontal cortex and left parietal lobes. FA values of the posterior corpus callosum were significantly correlated with gray matter volume in the bilateral frontal, temporal, right parietal, and occipital lobes. In control subjects, no correlations were detected. Our findings suggest that decline of FA in the corpus callosum may be related to neuronal degeneration in corresponding cortical areas.     

The use of HIV post-exposure prophylaxis in forensic medicine following incidents of sexual violence in Hamburg,Germany: a retrospective study

In Hamburg, Germany, the initiation of HIV post-exposure prophylaxis (HIV PEP) in cases of sexual violence is often carried out by forensic medical specialists (FMS) using the city’s unique Hamburg Model. FMS-provided three-day HIV PEP starter packs include a combination of raltegravir and emtricitabine/tenofovir. This study aimed to investigate the practice of offering HIV PEP, reasons for discontinuing treatment, patient compliance, and whether or not potential perpetrators were tested for HIV. We conducted a retrospective study of forensic clinical examinations carried out by the Hamburg Department of Legal Medicine following incidents of sexual violence from 2009 to 2016. One thousand two hundred eighteen incidents of sexual violence were reviewed. In 18% of these cases, HIV PEP was initially prescribed by the FMS. HIV PEP indication depended on the examination occurring within 24 h after the incident, no/unknown condom use, the occurrence of ejaculation, the presence of any injury, and the perpetrator being from population at high risk for HIV. Half of the HIV PEP recipients returned for a reevaluation of the HIV PEP indication by an infectious disease specialist, and just 16% completed the full month of treatment. Only 131 potential perpetrators were tested for HIV, with one found to be HIV positive. No HIV seroconversion was registered among the study sample. Provision of HIV PEP by an FMS after sexual assault ensures appropriate and prompt care for victims. However, patient compliance and completion rates are low. HIV testing of perpetrators must be carried out much more rigorously.     

Expression mapping of tetracycline-responsive prion protein promoter: digital atlasing for generating cell-specific disease models

We present a digital atlas system that allows mapping of molecular expression patterns at cellular resolution through large series of histological sections. Using this system, we have mapped the distribution of a distinct marker, encoded by the LacZ reporter gene driven by the tetracycline-responsive prion protein promoter in double transgenic mice. The purpose is to evaluate the suitability of this promoter mouse line for targeting genes of interest to specific brain regions, essential for construction of inducible transgenic disease models. Following processing to visualize the promoter expression, sections were counterstained to simultaneously display cytoarchitectonics. High-resolution mosaic images covering entire coronal sections were collected through the mouse brain at intervals of 200 microm. A web-based application provides access to a customized virtual microscopy tool for viewing and navigation within and across the section images. For each section image, the nearest section in a standard atlas is defined, and annotations of key structures and regions inserted. Putative categorization of labeled cells was performed with use of distribution patterns, followed by cell size and shape, as parameters that were compared to legacy data. Among the ensuing results were expression of this promoter in putative glial cells in the cerebellum (and not in Purkinje cells), in putative glial cells in the substantia nigra, in pallidal glial cells or interneurons, and in distinct cell layers and regions of the hippocampus. The study serves as a precursor for a database resource allowing evaluation of the suitability of different promoter mouse lines for generating disease models.     

EEG synchronization to modulated auditory tones in schizophrenia, schizoaffective disorder, and schizotypal personality disorder

OBJECTIVE: The authors tested whether neural synchronization deficits were present in subjects with schizophrenia and schizotypal personality disorder. METHOD: Amplitude-modulated tones were used to evaluate auditory steady-state evoked potential entrainment in a combined group of 21 subjects with schizophrenia or schizoaffective disorder, 11 subjects with schizotypal personality disorder, and 22 nonpsychiatric comparison subjects. RESULTS: The schizophrenia or schizoaffective disorder group exhibited decreased power compared to the schizotypal personality disorder and nonpsychiatric comparison groups. There were no differences between groups in N100 amplitude. CONCLUSIONS: Subjects with schizophrenia but not subjects with schizotypal personality disorder have deficits in steady-state responses to periodic stimuli, despite an intact response to sensory-evoked potentials (N100). These deficits reflect aberrant neural synchronization or resolution and may contribute to disturbed perceptual and cognitive integration in schizophrenia.     

Value of myocardial viability estimation using dobutamine stress echocardiography in assessing risk preoperatively before noncardiac vascular surgery in patients with left ventricular ejection fraction <35%

Patients with heart failure (HF) scheduled for vascular surgery have an increased risk of adverse postoperative outcome, and stratification usually depends on dichotomous risk factors. A quantitative prognostic model for patients with HF was developed using wall motion patterns during dobutamine stress echocardiography (DSE). A total of 295 consecutive patients (mean age 67 +/- 12 years) with ejection fraction < or =35% were studied. During DSE, wall motion patterns of dysfunctional segments were scored as scar, ischemia, or sustained improvement. Cardiac death and myocardial infarction were noted perioperatively and during 5 years of follow-up. Of 4,572 dysfunctional segments; 1,783 (39%) had ischemia, 1,280 (28%) had sustained improvement, and 1,509 (33%) had scar. In 212 patients, > or =1 ischemic segment was present; 83 had only sustained improvement. Perioperative and late cardiac event rates were 20% and 30%, respectively. Using multivariate analysis, number of ischemic segments was associated with perioperative cardiac events (odds ratio per segment 1.6, 95% confidence interval 1.05 to 1.8), whereas number of segments with sustained improvement was associated with improved outcome (odds ratio per segment 0.2, 95% confidence interval 0.04 to 0.7). Multivariate independent predictors of late cardiac events were age and ischemia. Sustained improvement was associated with improved survival. In conclusion, DSE provides accurate risk stratification of patients with HF undergoing vascular surgery.