PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families

PURPOSE: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants. METHODS: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized. RESULTS: Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity. CONCLUSION: We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted.Accepted version (6 month embargo), submitted versio

Overview of JET results

Since the last IAEA conference, the scientific programme of JET has focused on the qualification of the integrated operating scenarios for ITER and on physics issues essential for the consolidation of design choices and the efficient exploitation of ITER. Particular attention has been given to the characterization of the edge plasma, pedestal energy and edge localized modes (ELMs), and their impact on plasma facing components (PFCs). Various ELM mitigation techniques have been assessed for all ITER operating scenarios using active methods such as resonant magnetic field perturbation, rapid variation of the radial field and pellet pacing. In particular, the amplitude and frequency of type I ELMs have been actively controlled over a wide parameter range (q95 = 3–4.8, βN <= 3.0) by adjusting the amplitude of the n = 1 external perturbation field induced by error field correction coils. The study of disruption induced heat loads on PFCs has taken advantage of a new wide-angle viewing infrared system and a fast bolometer to provide a detailed account of time, localization and form of the energy deposition. Specific ITER-relevant studies have used the unique JET capability of varying the toroidal field (TF) ripple from its normal low value δBT = 0.08% up to δBT = 1% to study the effect of TF ripple on high confinement-mode plasmas. The results suggest that δBT < 0.5% is required on ITER to maintain adequate confinement to allow QDT = 10 at full field. Physics issues of direct relevance to ITER include heat and toroidal momentum transport, with experiments using power modulation to decouple power input and torque to achieve first experimental evidence of inward momentum pinch in JET and determine the threshold for ion temperature gradient driven modes. Within the longer term JET programme in support of ITER, activities aiming at the modification of the JET first wall and divertor and the upgrade of the neutral beam and plasma control systems are being conducted. The procurement of all components will be completed by 2009 with the shutdown for the installation of the beryllium wall and tungsten divertor extending from summer 2009 to summer 2010

Overview of JET results

Since the last IAEA conference, the scientific programme of JET has focused on the qualification of the integrated operating scenarios for ITER and on physics issues essential for the consolidation of design choices and the efficient exploitation of ITER. Particular attention has been given to the characterization of the edge plasma, pedestal energy and edge localized modes (ELMs), and their impact on plasma facing components (PFCs). Various ELM mitigation techniques have been assessed for all ITER operating scenarios using active methods such as resonant magnetic field perturbation, rapid variation of the radial field and pellet pacing. In particular, the amplitude and frequency of type I ELMs have been actively controlled over a wide parameter range (q95 = 3-4.8, βN ≥ 3.0) by adjusting the amplitude of the n = 1 external perturbation field induced by error field correction coils. The study of disruption induced heat loads on PFCs has taken advantage of a new wide-angle viewing infrared system and a fast bolometer to provide a detailed account of time, localization and form of the energy deposition. Specific ITER-relevant studies have used the unique JET capability of varying the toroidal field (TF) ripple from its normal low value δBT = 0.08% up to δBT = 1% to study the effect of TF ripple on high confinement-mode plasmas. The results suggest that δBT < 0.5% is required on ITER to maintain adequate confinement to allow QDT = 10 at full field. Physics issues of direct relevance to ITER include heat and toroidal momentum transport, with experiments using power modulation to decouple power input and torque to achieve first experimental evidence of inward momentum pinch in JET and determine the threshold for ion temperature gradient driven modes. Within the longer term JET programme in support of ITER, activities aiming at the modification of the JET first wall and divertor and the upgrade of the neutral beam and plasma control systems are being conducted. The procurement of all components will be completed by 2009 with the shutdown for the installation of the beryllium wall and tungsten divertor extending from summer 2009 to summer 2010

Overview of JET results

High density and high confinement operation in ELMy H-mode is confirmed at or above the normalized parameters foreseen for the ITER operating point (H98(y,2) 3c 1, n/nGW 3c 1, \u3b2N > 1.8 at q95 3c 3). The scaling of the ELMy H-mode with \u3b2N could be more favourable than that predicted by the IPB98(y,2) scaling. In ELMy H-mode, ion cyclotron current drive (ICCD) control of large sawteeth stabilized by fast particle has been demonstrated and the underlying neo-classical tearing modes (NTMs) and sawtooth physics is being refined. At high-density, Type I ELMy H-modes show trends that would lead to marginally acceptable ELMs on ITER. Type II ELM regime has been produced, though under very restrictive conditions. Type III ELMy operation with radiation fractions up to 95% has been demonstrated by seeding of N2 in H-modes and could extrapolate to Q = 10 ITER operation, albeit at high current (17 MA). The mitigation of Type I ELMs, nevertheless, remains a challenge. Considerable progress has been obtained in internal transport barrier (ITB) plasmas, with operation at central densities close to the Greenwald density or/and low toroidal rotation or/and high triangularity. Demonstrations of full current drive and successful simultaneous real time control of safety factor and temperature profiles have been achieved in ITB plasmas. Physics of resistive wall modes (RWMs) has been compared with theory, showing favourable scaling for ITER. High \u3b2N 3c 2.8 operation of hybrid modes (also called improved H-modes) has been obtained with dominant neutral beam heating. Hybrid modes with dominant ion cyclotron resonance heating (ICRH) have also been achieved. Trace tritium experiments yielded valuable information on particle transport in H-mode, ITB and hybrid regimes. In Type I ELMy plasmas, successful tests of the conjugate-T ICRH scheme have been achieved as well as lower hybrid coupling at ITER-relevant 10\u201311 cm distances. Reduced D and T fuel retention has been observed, which could relate to operation with vertical targets in the divertor and/or lower (ITER-like) vessel temperature. It is confirmed that erosion occurs predominantly on the main chamber surfaces, with possible benefits for T retention in ITER, although consequences for the metallic first wall lifetime need to be assessed. Disruption and ELM studies indicate that transient power deposition could be less constraining than expected for the ITER divertor, but more challenging for the metallic first wall. Alpha particle tomography and direct observation of alpha particle slowing down have been made possible by \u3b3 -spectroscopy. Measurements of Alfve \u301n cascades have been improved by a new interferometric technique. Promising tests of ITER relevant neutron counting detectors have been conducted

Analysis of ELM stability with extended MHD models in JET, JT-60U and future JT-60SA tokamak plasmas

The stability with respect to a peelingballooning mode (PBM) was investigated numerically with extended MHD simulation codes in JET, JT-60U and future JT-60SA plasmas. The MINERVA-DI code was used to analyze the linear stability, including the effects of rotation and ion diamagnetic drift (w∗i), in JET-ILW and JT-60SA plasmas, and the JOREK code was used to simulate nonlinear dynamics with rotation, viscosity and resistivity in JT-60U plasmas. It was validated quantitatively that the ELM trigger condition in JET-ILW plasmas can be reasonably explained by taking into account both the rotation and w∗i effects in the numerical analysis. When deuterium poloidal rotation is evaluated based on neoclassical theory, an increase in the effective charge of plasma destabilizes the PBM because of an acceleration of rotation and a decrease in w∗i. The difference in the amount of ELM energy loss in JT-60U plasmas rotating in opposite directions was reproduced qualitatively with JOREK. By comparing the ELM affected areas with linear eigenfunctions, it was confirmed that the difference in the linear stability property, due not to the rotation direction but to the plasma density profile, is thought to be responsible for changing the ELM energy loss just after the ELM crash. A predictive study to determine the pedestal profiles in JT-60SA was performed by updating the EPED1 model to include the rotation and w∗i effects in the PBM stability analysis. It was shown that the plasma rotation predicted with the neoclassical toroidal viscosity degrades the pedestal performance by about 10% by destabilizing the PBM, but the pressure pedestal height will be high enough to achieve the target parameters required for the ITER-like shape inductive scenario in JT-60SA