The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.

Purpose Photon therapy has been reported to induce resets of implanted cardiac devices, but the clinical sequelae of treating patients with such devices with proton beam therapy (PBT) are not well known. We reviewed the incidence of device malfunctions among patients undergoing PBT. Methods From March 2009 through July 2012, 42 patients with implanted cardiac implantable electronic devices (CIEDs) (28 pacemakers and 14 cardioverter-defillibrators) underwent 42 courses of PBT for thoracic (23 [55%]), prostate (15 [36%]), liver (3[7%]), or base of skull (1 [2%]) tumors at a single institution. The median prescribed dose was 74 Gy(RBE) [range 46.8–87.5 Gy(RBE)], and the median distance from the treatment field to the CIED was 10 cm (range 0.8–40 cm). Maximum proton and neutron doses were estimated for each treatment course. All CIEDs were checked before radiation delivery and monitored throughout treatment. Results Median estimated peak proton and neutron doses to the CIED in all patients were 0.8 Gy (range 0.13–21 Gy) and 346 Sv (range 11–1100 mSv). Six CIED malfunctions occurred in five patients (2 pacemakers and 3 defibrillators). Five of these malfunctions were CIED resets, and one patient with a defibrillator (in a patient with a liver tumor) had an elective replacement indicator (ERI) after therapy that was not influenced by radiation. The mean distance from the proton beam to the CIED among devices that reset was 7.0 cm (range 0.9–8 cm), and the mean maximum neutron dose was 655 mSv (range 330–1100 mSv). All resets occurred in patients receiving thoracic PBT and were corrected without clinical incident. The generator for the defibrillator with the ERI message was replaced uneventfully after treatment. Conclusions The incidence of CIED resets was about 20% among patients receiving PBT to the thorax. We recommend that PBT be avoided in pacing-dependent patients and that patients with any type of CIED receiving thoracic PBT be followed closely.

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Speckle tracking strain analysis echocardiography can evaluate the LA mechanical dyssynchrony quantitatively. The severity of LA mechanical dyssynchrony by VVI can predict the outcome of PVI catheter ablation for paroxysmal AF.