Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients

Background: Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC), Hypokaliemic type II (HypoPP2), and Hyperkaliemic/Normokaliemic periodic paralysis (HyperPP/NormoPP); in addition, rare phenotypes associated with mutations in SCN4A are congenital myasthenic syndrome and congenital myopathy. However, only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis. Methods: We retrospectively investigated clinical and molecular features of 80 patients fulfilling the following criteria: (1) clinical and neurophysiological diagnosis of myotonia, or clinical diagnosis of PP, and (2) presence of a pathogenic SCN4A gene variant. Patients presenting at birth with episodic laryngospasm or congenital myopathy-like phenotype with later onset of myotonia were considered as neonatal SCN4A. Results: PMC was observed in 36 (45%) patients, SCM in 30 (37.5%), Hyper/NormoPP in 7 (8.7%), HypoPP2 in 3 (3.7%), and neonatal SCN4A in 4 (5%). The median age at onset was significantly earlier in PMC than in SCM (p < 0.01) and in Hyper/NormoPP than in HypoPP2 (p = 0.02). Cold-induced myotonia was more frequently observed in PMC (n = 34) than in SCM (n = 23) (p = 0.04). No significant difference was found in age at onset of episodes of paralysis among PMC and PP or in frequency of permanent weakness between PP (n = 4), SCM (n = 5), and PMC (n = 10). PP was more frequently associated with mutations in the S4 region of the NaV1.4 channel protein compared to SCM and PMC (p < 0.01); mutations causing PMC were concentrated in the C-terminal region of the protein, while SCM-associated mutations were detected in all the protein domains. Conclusions: Our data suggest that skeletal muscle channelopathies associated with mutations in SCN4A represent a continuum in the clinical spectrum

First results on the SPS beam collimation with bent crystals

Experiments were performed at the CERN SPS with 120 GeV/c stored proton beams to assess the possibility of beam halo collimation assisted by bent crystals. A bent crystal was used to deflect horizontally by an angle of about 170 mu rad the beam halo protons in channeling states directing them into a 60 cm long tungsten absorber. The halo loss rate due to nuclear inelastic interactions of protons in the aligned crystal was up to five times smaller than for its amorphous orientation. Channeled fractions, (75 +/- 4)% and (85 +/- 5)% for the two tested silicon crystals, were measured by intercepting the deflected beam with another collimator located between the crystals and the absorber. The pixel detector (MEDIPIX) installed in a Roman pot inside the beam pipe was used to obtain visual images of the deflected beam

Advances in the development of pixel detector for the SuperB Silicon Vertex Tracker

The latest advances in the design and characterization of several pixel sensors developed to satisfy the very demanding requirements of the innermost layer of the SuperB Silicon Vertex Tracker will be presented in this paper. The SuperB machine is an electron positron collider operating at the ϒ(4S)ϒ(4S) peak to be built in the very near future by the Cabibbo Lab consortium. A pixel detector based on extremely thin, radiation hard devices able to cope with rate in the tens of MHz/cm^2 range will be the optimal solution for the upgrade of the inner layer of the SuperB tracking system. At present several options with different levels of maturity are being investigated to understand advantages and potential issues of the different technologies: thin hybrid pixels, Deep N-Well CMOS MAPS, INMAPS CMOS MAPS featuring a quadruple well and high resistivity substrates and CMOS MAPS realized with Vertical Integration technology. The newest results from beam test, the outcomes of the radiation damage studies and the laboratory characterization of the latest prototypes will be reported

The SuperB Silicon Vertex Tracker

SuperB is an asymmetric electron-positron collider planned to operate at very high luminosity (>10^36cm−2s−1) around the Υ(4S) peak and in an energy range from the τ/charm threshold to the Υ(5S). It is an evolution of the SLAC PEP-II collider and its detector, BaBar. This paper describes the Silicon Vertex Tracker (SVT), one of the key elements of the SuperB detector, concentrating on the modifications and improvements adopted on the strip sensors for the external layers and on the baseline option for the innermost layer (Layer0), a thin (200 μm) double-sided silicon detector with short strips ("Striplets"), oriented at ±45◦ angle to the detector’s edge

The front-end chip of the SuperB SVT detector

The asymmetric e(+) e(-) collider SuperB is designed to deliver a high luminosity, greater than 10(36) cm(-2) S-1, with moderate beam currents and a reduced center of mass boost with respect to earlier B-Factories. The innermost detector is the Silicon Vertex Tracker which is made of 5 layers of double sided silicon strip sensors plus a layer 0, that can be equipped with short striplets detectors in a first phase of the experiment. In order to achieve an overall track reconstruction efficiency above 98% it is crucial to optimize both analog and digital readout circuits. The readout architecture being developed for the front-end chips will be able to cope with the very high rates expected in the first layer. The digital readout will be optimized to be fully efficient for hit rates up to 2 MHz/strip, including large margins on the maximum expected background rates, but can potentially accommodate higher rates with a proper tuning of the buffer depth. The readout is based on a triggered architecture where each of the 128 strip channel is provided with a dedicated digital buffer. Each buffer collects the digitized charge information by means of a 4-bit TOT, storing it in conjunction with the related time stamp. The depth of buffers was dimensioned considering the expected trigger latency and hit rate including suitable safety margins. Every buffer is connected to a highly parallelized circuit handling the trigger logic, rejecting expired data in the buffers and channeling the parallel stream of triggered hits to the common output of the chip. The presented architecture has been modeled by HDL language and investigated with a Monte Carlo hit generator emulating the analog front-end behavior. The simulations showed that even applying the highest stressing conditions, about 2 MHz per strip, the efficiency of the digital readout remained above 99.8%

Recent developments on CMOS MAPS for the SuperB Silicon Vertex Tracker

In the design of the Silicon Vertex Tracker for the high luminosity SuperB collider, very challenging requirements are set by physics and background conditions on its innermost Layer0: small radius (about 1.5 cm), resolution of 10–15um in both coordinates, low material budget <1%X0, and the ability to withstand a background hit rate of several tens of MHz/cm2. Thanks to an intense R&D program the development of Deep NWell CMOS MAPS (with the ST Microelectronics 130 nm process) has reached a good level of maturity and allowed for the first time the implementation of thin CMOS sensors with similar functionalities as in hybrid pixels, such as pixel-level sparsification and fast time stamping. Further MAPS performance improvements are currently under investigation with two different approaches: the INMAPS CMOS process, featuring a quadruple well and a high resistivity substrate, and 3D CMOS MAPS, realized with vertical integration technology. In both cases specific features of the processes chosen can improve charge collection efficiency, with respect to a standard DNW MAPS design, and allow to implement a more complex in-pixel logic in order to develop a faster readout architecture. Prototypes of MAPS matrix, suitable for application in the SuperB Layer0, have been realized with the INMAPS 180 nm process and the 130 nm Chartered/Tezzaron 3D process and results of their characterization will be presented in this paper