Cardiac phenotype in ATP1A3-related syndromes: A multicentre cohort study.

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 had at least one 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: 98 AHC, nine RDP, and three CAPOS patients (63 females, mean age 17 years) were included. Resting EKG abnormalities were found in 52/87 (60%) AHC, 2/3 (67%) CAPOS, and 6/9 (67%) RDP patients. Serial EKGs showed dynamic changes in 10/18 AHC patients. The first Holter EKG was abnormal in 24/65 (37%) AHC and RDP cases, with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3/98 (∼3%) AHC patients. In the mouse model, resting EKGs showed intra-cardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of EKG 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 as well as neurological 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

Cleavage of Na+ channels by calpain increases persistent Na+ current and promotes spasticity after spinal cord injury

International audienceUpregulation of the persistent sodium current (INaP) in motoneurons contributes to spasticity following spinal cord injury (SCI). We investigated the mechanisms that regulate INaP and observed elevated expression of Nav1.6 channels in spinal lumbar motoneurons of adult rats with SCI. Furthermore, immunoblot revealed a proteolysis of Nav channels and biochemical assays identified calpain as the main proteolytic factor. Calpain-dependent cleavage of Nav channels following neonatal SCI was associated with an upregulation of INaP in motoneurons. Likewise, calpain-dependent cleavage of Nav1.6 channels expressed in HEK-293 cells caused elevation of INaP. Pharmacological inhibition of calpain by MDL28170 reduced the cleavage of Nav channels, INaP in motoneurons and spasticity in rats with SCI. Similarly, blockade of INaP by riluzole alleviated spasticity. This study demonstrates that Nav channel expression in lumbar motoneurons is altered after SCI and shows a tight relationship between the calpain-dependent proteolysis of Nav1.6 channels, the upregulation of INaP and spasticity