Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies

Background: Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogeneous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with multisystemic involvement. Methods: We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives (n = 43) and particularly focused on the associated multisystemic symptoms. Results: We identified 14 heterozygous mutations (diagnostic yield of 37%), among them the novel p.Pro209Gln mutation in the BAG3 gene, which was associated with onset in adulthood, a mild phenotype and an axonal sensorimotor polyneuropathy, in the absence of giant axons at the nerve biopsy. We revealed several novel clinical phenotypes and unusual multisystemic presentations with previously described mutations: hearing impairment with a FLNC mutation, dysphonia with a mutation in DES and the first patient with a FLNC mutation presenting respiratory insufficiency as the initial symptom. Moreover, we described for the first time respiratory insufficiency occurring in a patient with the p.Gly154Ser mutation in CRYAB. Interestingly, we detected a polyneuropathy in 28% of the MFM patients, including a BAG3 and a MYOT case, and hearing impairment in 13%, including one patient with a FLNC mutation and two with mutations in the DES gene. In four index patients with a mutation in one of the MFM genes, typical histological findings were only identified at the ultrastructural level (29%). Conclusions: We conclude that extraskeletal symptoms frequently occur in MFM, particularly cardiac and respiratory involvement, polyneuropathy and/or deafness. BAG3 mutations should be considered even in cases with a mild phenotype or an adult onset. We identified a genetic defect in one of the known genes in less than half of the MFM patients, indicating that more causative genes are still to be found. Next generation sequencing techniques should be helpful in achieving this aim

Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy

Nemaline myopathy (NM) is a skeletal muscle disorder caused by mutations in genes that are generally involved in muscle contraction, in particular those related to the structure and/or regulation of the thin filament. Many pathogenic aspects of this disease remain largely unclear. Here, we report novel pathological defects in skeletal muscle fibres of mouse models and patients with NM: irregular spacing and morphology of nuclei; disrupted nuclear envelope; altered chromatin arrangement; and disorganisation of the cortical cytoskeleton. Impairments in contractility are the primary cause of these nuclear defects. We also establish the role of microtubule organisation in determining nuclear morphology, a phenomenon which is likely to contribute to nuclear alterations in this disease. Our results overlap with findings in diseases caused directly by mutations in nuclear envelope or cytoskeletal proteins. Given the important role of nuclear shape and envelope in regulating gene expression, and the cytoskeleton in maintaining muscle fibre integrity, our findings are likely to explain some of the hallmarks of NM, including contractile filament disarray, altered mechanical properties and broad transcriptional alterations

Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy

Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies

Grouping by feature of cross-modal flankers in temporal ventriloquism

Signals in one sensory modality can influence perception of another, for example the bias of visual timing by audition: temporal ventriloquism. Strong accounts of temporal ventriloquism hold that the sensory representation of visual signal timing changes to that of the nearby sound. Alternatively, underlying sensory representations do not change. Rather, perceptual grouping processes based on spatial, temporal, and featural information produce best-estimates of global event properties. In support of this interpretation, when feature-based perceptual grouping conflicts with temporal information-based in scenarios that reveal temporal ventriloquism, the effect is abolished. However, previous demonstrations of this disruption used long-range visual apparent-motion stimuli. We investigated whether similar manipulations of feature grouping could also disrupt the classical temporal ventriloquism demonstration, which occurs over a short temporal range. We estimated the precision of participants’ reports of which of two visual bars occurred first. The bars were accompanied by different cross-modal signals that onset synchronously or asynchronously with each bar. Participants’ performance improved with asynchronous presentation relative to synchronous - temporal ventriloquism - however, unlike the long-range apparent motion paradigm, this was unaffected by different combinations of cross-modal feature, suggesting that featural similarity of cross-modal signals may not modulate cross-modal temporal influences in short time scales

Oxygenated-Blood Colour Change Thresholds for Perceived Facial Redness, Health, and Attractiveness

Blood oxygenation level is associated with cardiovascular fitness, and raising oxygenated blood colouration in human faces increases perceived health. The current study used a two-alternative forced choice (2AFC) psychophysics design to quantify the oxygenated blood colour (redness) change threshold required to affect perception of facial colour, health and attractiveness. Detection thresholds for colour judgments were lower than those for health and attractiveness, which did not differ. The results suggest redness preferences do not reflect a sensory bias, rather preferences may be based on accurate indications of health status. Furthermore, results suggest perceived health and attractiveness may be perceptually equivalent when they are assessed based on facial redness. Appearance-based motivation for lifestyle change can be effective; thus future studies could assess the degree to which cardiovascular fitness increases face redness and could quantify changes in aerobic exercise needed to increase facial attractiveness

Changing Human Visual Field Organization from Early Visual to Extra-Occipital Cortex

BACKGROUND: The early visual areas have a clear topographic organization, such that adjacent parts of the cortical surface represent distinct yet adjacent parts of the contralateral visual field. We examined whether cortical regions outside occipital cortex show a similar organization. METHODOLOGY/PRINCIPAL FINDINGS: The BOLD responses to discrete visual field locations that varied in both polar angle and eccentricity were measured using two different tasks. As described previously, numerous occipital regions are both selective for the contralateral visual field and show topographic organization within that field. Extra-occipital regions are also selective for the contralateral visual field, but possess little (or no) topographic organization. A regional analysis demonstrates that this weak topography is not due to increased receptive field size in extra-occipital areas. CONCLUSIONS/SIGNIFICANCE: A number of extra-occipital areas are identified that are sensitive to visual field location. Neurons in these areas corresponding to different locations in the contralateral visual field do not demonstrate any regular or robust topographic organization, but appear instead to be intermixed on the cortical surface. This suggests a shift from processing that is predominately local in visual space, in occipital areas, to global, in extra-occipital areas. Global processing fits with a role for these extra-occipital areas in selecting a spatial locus for attention and/or eye-movements

Testing a dynamic field account of interactions between spatial attention and spatial working memory

Studies examining the relationship between spatial attention and spatial working memory (SWM) have shown that discrimination responses are faster for targets appearing at locations that are being maintained in SWM, and that location memory is impaired when attention is withdrawn during the delay. These observations support the proposal that sustained attention is required for successful retention in SWM: if attention is withdrawn, memory representations are likely to fail, increasing errors. In the present study, this proposal is reexamined in light of a neural process model of SWM. On the basis of the model’s functioning, we propose an alternative explanation for the observed decline in SWM performance when a secondary task is performed during retention: SWM representations drift systematically toward the location of targets appearing during the delay. To test this explanation, participants completed a color-discrimination task during the delay interval of a spatial recall task. In the critical shifting attention condition, the color stimulus could appear either toward or away from the memorized location relative to a midline reference axis. We hypothesized that if shifting attention during the delay leads to the failure of SWM representations, there should be an increase in the variance of recall errors but no change in directional error, regardless of the direction of the shift. Conversely, if shifting attention induces drift of SWM representations—as predicted by the model—there should be systematic changes in the pattern of spatial recall errors depending on the direction of the shift. Results were consistent with the latter possibility—recall errors were biased toward the location of discrimination targets appearing during the delay

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p