Browsing by Subject "Hemiplegia"

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    ItemOpen Access
    Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.
    (Neurology, 2020-11) Balestrini, Simona; Mikati, Mohamad A; Álvarez-García-Rovés, Reyes; Carboni, Michael; Hunanyan, Arsen S; Kherallah, Bassil; McLean, Melissa; Prange, Lyndsey; De Grandis, Elisa; Gagliardi, Alessandra; Pisciotta, Livia; Stagnaro, Michela; Veneselli, Edvige; Campistol, Jaume; Fons, Carmen; Pias-Peleteiro, Leticia; Brashear, Allison; Miller, Charlotte; Samões, Raquel; Brankovic, Vesna; Padiath, Quasar S; Potic, Ana; Pilch, Jacek; Vezyroglou, Aikaterini; Bye, Ann ME; Davis, Andrew M; Ryan, Monique M; Semsarian, Christopher; Hollingsworth, Georgina; Scheffer, Ingrid E; Granata, Tiziana; Nardocci, Nardo; Ragona, Francesca; Arzimanoglou, Alexis; Panagiotakaki, Eleni; Carrilho, Inês; Zucca, Claudio; Novy, Jan; Dzieżyc, Karolina; Parowicz, Marek; Mazurkiewicz-Bełdzińska, Maria; Weckhuysen, Sarah; Pons, Roser; Groppa, Sergiu; Sinden, Daniel S; Pitt, Geoffrey S; Tinker, Andrew; Ashworth, Michael; Michalak, Zuzanna; Thom, Maria; Cross, J Helen; Vavassori, Rosaria; Kaski, Juan P; Sisodiya, Sanjay M

    Objective

    To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes.

    Methods

    Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death.

    Results

    Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death.

    Conclusions

    We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.
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    ATP1A3-Encoded Sodium-Potassium ATPase Subunit Alpha 3 D801N Variant Is Associated With Shortened QT Interval and Predisposition to Ventricular Fibrillation Preceded by Bradycardia.
    (Journal of the American Heart Association, 2021-09) Moya-Mendez, Mary E; Ogbonna, Chiagoziem; Ezekian, Jordan E; Rosamilia, Michael B; Prange, Lyndsey; de la Uz, Caridad; Kim, Jeffrey J; Howard, Taylor; Garcia, John; Nussbaum, Robert; Truty, Rebecca; Callis, Thomas E; Funk, Emily; Heyes, Matthew; Dear, Guy de Lisle; Carboni, Michael P; Idriss, Salim F; Mikati, Mohamad A; Landstrom, Andrew P
    Background Pathogenic variation in the ATP1A3-encoded sodium-potassium ATPase, ATP1A3, is responsible for alternating hemiplegia of childhood (AHC). Although these patients experience a high rate of sudden unexpected death in epilepsy, the pathophysiologic basis for this risk remains unknown. The objective was to determine the role of ATP1A3 genetic variants on cardiac outcomes as determined by QT and corrected QT (QTc) measurements. Methods and Results We analyzed 12-lead ECG recordings from 62 patients (male subjects=31, female subjects=31) referred for AHC evaluation. Patients were grouped according to AHC presentation (typical versus atypical), ATP1A3 variant status (positive versus negative), and ATP1A3 variant (D801N versus other variants). Manual remeasurements of QT intervals and QTc calculations were performed by 2 pediatric electrophysiologists. QTc measurements were significantly shorter in patients with positive ATP1A3 variant status (P<0.001) than in patients with genotype-negative status, and significantly shorter in patients with the ATP1A3-D801N variant than patients with other variants (P<0.001). The mean QTc for ATP1A3-D801N was 344.9 milliseconds, which varied little with age, and remained <370 milliseconds throughout adulthood. ATP1A3 genotype status was significantly associated with shortened QTc by multivariant regression analysis. Two patients with the ATP1A3-D801N variant experienced ventricular fibrillation, resulting in death in 1 patient. Rare variants in ATP1A3 were identified in a large cohort of genotype-negative patients referred for arrhythmia and sudden unexplained death. Conclusions Patients with AHC who carry the ATP1A3-D801N variant have significantly shorter QTc intervals and an increased likelihood of experiencing bradycardia associated with life-threatening arrhythmias. ATP1A3 variants may represent an independent cause of sudden unexplained death. Patients with AHC should be evaluated to identify risk of sudden death.