A CGG‐Repeat Expansion Mutation in ZNF713 Causes FRA7A: Association with Autistic Spectrum Disorder in Two Families

We report de novo occurrence of the 7p11.2 folate‐sensitive fragile site FRA7A in a male with an autistic spectrum disorder (ASD) due to a CGG‐repeat expansion mutation (～450 repeats) in a 5′ intron of ZNF713. This expanded allele showed hypermethylation of the adjacent CpG island with reduced ZNF713 expression observed in a proband‐derived lymphoblastoid cell line (LCL). His unaffected mother carried an unmethylated premutation (85 repeats). This CGG‐repeat showed length polymorphism in control samples (five to 22 repeats). In a second unrelated family, three siblings with ASD and their unaffected father were found to carry FRA7A premutations, which were partially or mosaically methylated. In one of the affected siblings, mitotic instability of the premutation was observed. ZNF713 expression in LCLs in this family was increased in three of these four premutation carriers. A firm link cannot yet be established between ASD and the repeat expansion mutation but plausible pathogenic mechanisms are discussed.     

Orbital volume and surface after Le Fort III advancement in syndromic craniosynostosis

There are no quantitative standards for the volumetric measurements of the orbital cavity after Le Fort III advancement. Computed tomography (CT) scan images have given the opportunity to compare with accuracy the real anatomic changes and potentially the functional improvements that resulted after a surgical treatment.Three-dimensional CT scan images processed by DICOM files in Dolphin 3D Software were used to assess orbital volume and surface in 12 subjects affected by craniofacial syndromic malformations treated with Le Fort III advancement. The preoperative (T0) and postoperative (T1: 6 months after surgery) three-dimensional craniofacial CT scans of the subjects were collected and retrospectively analyzed. Image segmentation of the anatomic orbital cavity and the three-dimensional graphic rendering were done by using the Dolphin Imaging Plus 11.0 software.The orbital volume was increased after surgery, with statistical significance, from 22,267 to 22,706.3 mm(3) in the right eye and from 26,511 mm(3) to 26,256.4 mm(3) in the left eye. The surface of both bony orbits had an expansion, which is statistically significant. In conclusion, this study showed that the orbital advancement in white subjects after Le Fort III advancement was significant and produced a significant augmentation of the orbital volume and surface area with correction of the ocular bulb proptosis.     

Increased temporal dispersion of myocardial repolarization in myotonic dystrophy type 1: beyond the cardiac conduction system

Objectives

To assess ventricular dysfunction and ventricular interaction after repair of Tetralogy of Fallot (ToF) employing echocardiography speckle-tracking and cardiac magnetic resonance imaging (CMR).

Background

Severe pulmonary regurgitation and right ventricular (RV) dysfunction are common after repair of ToF and may also affect the shape and function of the left ventricle (LV). Recent studies suggest that LV dysfunction may be of particular prognostic value.

Methods and results

Twenty-one consecutive adults with repaired ToF (15 male, mean age 38 ± 11 years, 7 with severe PR) underwent a comprehensive echocardiographic exam including speckle-tracking analysis, CMR and cardiopulmonary exercise testing. Twenty-one subjects without relevant heart disease served as controls. Echocardiographically measured RV diameters correlated with RV volumes obtained from CMR (r = 0.63; p = 0.006). In addition, a close correlation was found between RV and LV function on CMR (r = 0.74, p = 0.002), speckle-tracking LV and RV peak longitudinal 2D strain (r = 0.66, p = 0.003) and mitral and tricuspid annular plain systolic excursion (r = 0.71, p = 0.0003). While LV ejection fraction was normal in the majority of patients and not different from controls, LV longitudinal strain was significantly reduced in ToF patients (− 16.5 ± 3.3 vs. -20.5 ± 2.7%, p = 0.0001).

Conclusion

Left and right ventricular function both by CMR and speckle-tracking is interrelated in adults with repaired ToF. Despite normal LV ejection fraction, 2D longitudinal strain is significantly reduced in ToF patients, suggesting subclinical LV myocardial damage. Considering the potential prognostic value of LV dysfunction in ToF, this measurement may gain importance and should be included in future outcome studies.     

Selective activation of protein kinase C∊ in mitochondria is neuroprotective in vitro and reduces focal ischemic brain injury in mice

Activation of protein kinase C? (PKC?) confers protection against neuronal ischemia/reperfusion. Activation of PKC? leads to its translocation to multiple intracellular sites, so a mitochondria‐selective PKC? activator was used to test the importance of mitochondrial activation to the neuroprotective effect of PKC?. PKC? can regulate key cytoprotective mitochondrial functions, including electron transport chain activity, reactive oxygen species (ROS) generation, mitochondrial permeability transition, and detoxification of reactive aldehydes. We tested the ability of mitochondria‐selective activation of PKC? to protect primary brain cell cultures or mice subjected to ischemic stroke. Pretreatment with either general PKC? activator peptide, TAT‐Ψ?RACK, or mitochondrial‐selective PKC? activator, TAT‐Ψ?HSP90, reduced cell death induced by simulated ischemia/reperfusion in neurons, astrocytes, and mixed neuronal cultures. The protective effects of both TAT‐Ψ?RACK and TAT‐Ψ?HSP90 were blocked by the PKC? antagonist ?V_1–2, indicating that protection requires PKC? interaction with its anchoring protein, TAT‐?RACK. Further supporting a mitochondrial mechanism for PKC?, neuroprotection by TAT‐Ψ?HSP90 was associated with a marked delay in mitochondrial membrane depolarization and significantly attenuated ROS generation during ischemia. Importantly, TAT‐Ψ?HSP90 reduced infarct size and reduced neurological deficit in C57/BL6 mice subjected to middle cerebral artery occlusion and 24 hr of reperfusion. Thus selective activation of mitochondrial PKC? preserves mitochondrial function in vitro and improves outcome in vivo, suggesting potential therapeutic value clinically when brain ischemia is anticipated, including neurosurgery and cardiac surgery. © 2013 Wiley Periodicals, Inc.     

Napping to renew learning capacity: enhanced encoding after stimulation of sleep slow oscillations

As well as consolidating memory, sleep has been proposed to serve a second important function for memory, i.e. to free capacities for the learning of new information during succeeding wakefulness. The slow wave activity (SWA) that is a hallmark of slow wave sleep could be involved in both functions. Here, we aimed to demonstrate a causative role for SWA in enhancing the capacity for encoding of information during subsequent wakefulness, using transcranial slow oscillation stimulation (tSOS) oscillating at 0.75 Hz to induce SWA in healthy humans during an afternoon nap. Encoding following the nap was tested for hippocampus‐dependent declarative materials (pictures, word pairs, and word lists) and procedural skills (finger sequence tapping). As compared with a sham stimulation control condition, tSOS during the nap enhanced SWA and significantly improved subsequent encoding on all three declarative tasks (picture recognition, cued recall of word pairs, and free recall of word lists), whereas procedural finger sequence tapping skill was not affected. Our results indicate that sleep SWA enhances the capacity for encoding of declarative materials, possibly by down‐scaling hippocampal synaptic networks that were potentiated towards saturation during the preceding period of wakefulness.