{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:23:50Z","timestamp":1793319830326,"version":"4.5.0"},"reference-count":118,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T00:00:00Z","timestamp":1614643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>\n                    Ion channel dysfunction is a key pathological substrate of episodic neurological disorders. A classical gene associated to paroxysmal movement disorders is\n                    <jats:italic>CACNA1A<\/jats:italic>\n                    , which codes for the pore-forming subunit of the neuronal calcium channel P\/Q. Non-polyglutamine\n                    <jats:italic>CACNA1A<\/jats:italic>\n                    variants underlie familial hemiplegic ataxia type 1 (FHM1) and episodic ataxia type 2 (EA2). Classical paroxysmal manifestations of FHM1 are migraine attacks preceded by motor aura consisting of hemiparesis, aphasia, and disturbances of consciousness until coma. Patients with EA2 suffer of recurrent episodes of vertigo, unbalance, diplopia, and vomiting. Beyond these typical presentations, several reports highlighted manifold clinical features associated with P\/Q channelopathies, from chronic progressive cerebellar ataxia to epilepsy and psychiatric disturbances. These manifestations may often outlast the burden of classical episodic symptoms leading to pitfalls in the diagnostic work-up. Lately, the spreading of next generation sequencing techniques linked\n                    <jats:italic>de novo CACNA1A<\/jats:italic>\n                    variants to an even broader phenotypic spectrum including early developmental delay, autism spectrum disorders, epileptic encephalopathy, and early onset paroxysmal dystonia. The age-dependency represents a striking new aspect of these phenotypes und highlights a pivotal role for P\/Q channels in the development of the central nervous system in a defined time window. While several reviews addressed the clinical presentation and treatment of FHM1 and EA2, an overview of the newly described age-dependent manifestations is lacking. In this Mini-Review we present a clinical update, delineate genotype-phenotype correlations as well as summarize evidence on the pathophysiological mechanisms underlying the expanded phenotype associated with\n                    <jats:italic>CACNA1A<\/jats:italic>\n                    variants.\n                  <\/jats:p>","DOI":"10.3389\/fneur.2021.639994","type":"journal-article","created":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T00:13:11Z","timestamp":1614643991000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":109,"title":["From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing"],"prefix":"10.3389","volume":"12","author":[{"given":"Elisabetta","family":"Indelicato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Boesch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2577","DOI":"10.1113\/jphysiol.2011.224204","article-title":"Voltage-gated sodium channels at 60: structure, function and pathophysiology","volume":"590","author":"Catterall","year":"2012","journal-title":"J Physiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1016\/S0092-8674(00)81373-2","article-title":"Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4","volume":"87","author":"Ophoff","year":"1996","journal-title":"Cell."},{"key":"B3","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/S1474-4422(11)70048-5","article-title":"Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and management","volume":"10","author":"Russell","year":"2011","journal-title":"Lancet Neurol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1212\/01.WNL.0000101675.61074.50","article-title":"Clinical spectrum of episodic ataxia type 2","volume":"62","author":"Jen","year":"2004","journal-title":"Neurology."},{"key":"B5","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/ng0197-62","article-title":"Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel","volume":"15","author":"Zhuchenko","year":"1997","journal-title":"Nat Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1212\/WNL.49.5.1247","article-title":"Spinocerebellar ataxia type 6. Frequency of the mutation and genotype-phenotype correlations","volume":"49","author":"Geschwind","year":"1997","journal-title":"Neurology."},{"key":"B7","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1111\/ene.13765","article-title":"The neuropsychiatric phenotype in CACNA1A mutations: a retrospective single center study and review of the literature","volume":"26","author":"Indelicato","year":"2019","journal-title":"Eur J Neurol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1111\/dmcn.14261","article-title":"Cognitive impairment in children with CACNA1A mutations","volume":"62","author":"Humbertclaude","year":"2020","journal-title":"Dev Med Child Neurol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1111\/j.1469-8749.2002.tb00311.x","article-title":"Benign paroxysmal torticollis of infancy: four new cases and linkage to CACNA1A mutation","volume":"44","author":"Giffin","year":"2002","journal-title":"Dev Med Child Neurol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1600","DOI":"10.1007\/s00415-008-0982-8","article-title":"Benign paroxysmal tonic upgaze, benign paroxysmal torticollis, episodic ataxia and CACNA1A mutation in a family","volume":"255","author":"Roubertie","year":"2008","journal-title":"J Neurol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.ejpn.2013.12.011","article-title":"A loss-of-function CACNA1A mutation causing benign paroxysmal torticollis of infancy","volume":"18","author":"Vila-Pueyo","year":"2014","journal-title":"Eur J Paediatr Neurol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/S0140-6736(01)05971-2","article-title":"Human epilepsy associated with dysfunction of the brain P\/Q-type calcium channel","volume":"358","author":"Jouvenceau","year":"2001","journal-title":"Lancet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1905","DOI":"10.1113\/jphysiol.2009.186437","article-title":"Genetic and functional characterisation of the P\/Q calcium channel in episodic ataxia with epilepsy","volume":"588","author":"Rajakulendran","year":"2010","journal-title":"J Physiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1038\/ejhg.2015.21","article-title":"CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms","volume":"23","author":"Damaj","year":"2015","journal-title":"Eur J Hum Genet."},{"key":"B15","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.ajhg.2016.06.003","article-title":"De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies","volume":"99","author":"Epi","year":"2016","journal-title":"Am J Hum Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/j.pediatrneurol.2008.07.030","article-title":"Stepwise developmental regression associated with novel CACNA1A mutation","volume":"39","author":"Guerin","year":"2008","journal-title":"Pediatr Neurol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"a003947","DOI":"10.1101\/cshperspect.a003947","article-title":"Voltage-gated calcium channels","volume":"3","author":"Catterall","year":"2011","journal-title":"Cold Spring Harb Perspect Biol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/nrneurol.2011.228","article-title":"Neuronal P\/Q-type calcium channel dysfunction in inherited disorders of the CNS","volume":"8","author":"Rajakulendran","year":"2012","journal-title":"Nat Rev Neurol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/0896-6273(95)90155-8","article-title":"Calcium control of transmitter release at a cerebellar synapse","volume":"15","author":"Mintz","year":"1995","journal-title":"Neuron."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1016\/j.cell.2007.11.028","article-title":"Calcium signaling","volume":"131","author":"Clapham","year":"2007","journal-title":"Cell."},{"key":"B21","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1016\/j.pneurobio.2006.02.006","article-title":"Cerebellar circuitry as a neuronal machine","volume":"78","author":"Ito","year":"2006","journal-title":"Prog Neurobiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1016\/j.neuron.2008.08.020","article-title":"Calcium signaling in dendrites and spines: practical and functional considerations","volume":"59","author":"Higley","year":"2008","journal-title":"Neuron."},{"key":"B23","doi-asserted-by":"publisher","first-page":"18694","DOI":"10.1073\/pnas.1009500107","article-title":"Contribution of calcium-dependent facilitation to synaptic plasticity revealed by migraine mutations in the P\/Q-type calcium channel","volume":"107","author":"Adams","year":"2010","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B24","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/j.neuroscience.2020.05.032","article-title":"Ion channels involvement in neurodevelopmental disorders","volume":"440","author":"D'Adamo","year":"2020","journal-title":"Neuroscience."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2735","DOI":"10.3390\/ijms19092735","article-title":"Voltage-dependent calcium channels, calcium binding proteins, and their interaction in the pathological process of epilepsy","volume":"19","author":"Xu","year":"2018","journal-title":"Int J Mol Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1016\/j.neuron.2018.03.017","article-title":"Calcium channels, synaptic plasticity, and neuropsychiatric disease","volume":"98","author":"Nanou","year":"2018","journal-title":"Neuron."},{"key":"B27","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1016\/j.tins.2013.06.008","article-title":"Control of neuronal voltage-gated calcium ion channels from RNA to protein","volume":"36","author":"Lipscombe","year":"2013","journal-title":"Trends Neurosci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e1003709","DOI":"10.1371\/journal.pgen.1003709","article-title":"Genic intolerance to functional variation and the interpretation of personal genomes","volume":"9","author":"Petrovski","year":"2013","journal-title":"PLoS Genet."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e1006905","DOI":"10.1371\/journal.pgen.1006905","article-title":"Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially","volume":"13","author":"Luo","year":"2017","journal-title":"PLoS Genet."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2514","DOI":"10.1038\/s41598-017-02554-x","article-title":"Mutation spectrum in the CACNA1A gene in 49 patients with episodic ataxia","volume":"7","author":"Sintas","year":"2017","journal-title":"Sci Rep."},{"key":"B31","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1136\/jmg.2009.067967","article-title":"Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing","volume":"46","author":"Labrum","year":"2009","journal-title":"J Med Genet."},{"key":"B32","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1001\/archneur.65.6.817","article-title":"Large CACNA1A deletion in a family with episodic ataxia type 2","volume":"65","author":"Riant","year":"2008","journal-title":"Arch Neurol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1212\/01.wnl.0000169020.82223.dd","article-title":"New calcium channel mutations predict aberrant RNA splicing in episodic ataxia","volume":"65","author":"Eunson","year":"2005","journal-title":"Neurology."},{"key":"B34","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1177\/0883073809351316","article-title":"Congenital ataxia, mental retardation, and dyskinesia associated with a novel CACNA1A mutation","volume":"25","author":"Blumkin","year":"2010","journal-title":"J Child Neurol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1111\/dmcn.13033","article-title":"Eye movement disorders are an early manifestation of CACNA1A mutations in children","volume":"58","author":"Tantsis","year":"2016","journal-title":"Dev Med Child Neurol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.pediatrneurol.2013.04.011","article-title":"Possible effect of corticoids on hemiplegic attacks in severe hemiplegic migraine","volume":"49","author":"Sanchez-Albisua","year":"2013","journal-title":"Pediatr Neurol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"332","DOI":"10.3390\/biomedicines8090332","article-title":"Targeting alternative splicing as a potential therapy for episodic ataxia type 2","volume":"8","author":"Jaudon","year":"2020","journal-title":"Biomedicines."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3810","DOI":"10.3390\/ijms21113810","article-title":"Association of a novel splice site mutation in P\/Q-type calcium channels with childhood epilepsy and late-onset slowly progressive non-episodic cerebellar ataxia","volume":"21","author":"Stendel","year":"2020","journal-title":"Int J Mol Sci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1056\/NEJM200107053450103","article-title":"The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel","volume":"345","author":"Ducros","year":"2001","journal-title":"N Engl J Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.nurt.2007.01.014","article-title":"Episodic ataxia type 2","volume":"4","author":"Strupp","year":"2007","journal-title":"Neurotherapeutics."},{"key":"B41","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1007\/s12311-008-0023-2","article-title":"The clinical diagnosis of autosomal dominant spinocerebellar ataxias","volume":"7","author":"Klockgether","year":"2008","journal-title":"Cerebellum."},{"key":"B42","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.cell.2013.05.059","article-title":"Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6","volume":"154","author":"Du","year":"2013","journal-title":"Cell."},{"key":"B43","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1016\/j.neuron.2019.02.036","article-title":"\u03b11ACT is essential for survival and early cerebellar programming in a critical neonatal window","volume":"102","author":"Du","year":"2019","journal-title":"Neuron."},{"key":"B44","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1177\/0333102413485658","article-title":"The International Classification of Headache Disorders, 3rd edition (beta version)","volume":"33","year":"2013","journal-title":"Cephalalgia."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1177\/0333102417715229","article-title":"Ten years of follow-up in a large family with familial hemiplegic migraine type 1: clinical course and implications for treatment","volume":"38","author":"Indelicato","year":"2017","journal-title":"Cephalalgia."},{"key":"B46","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1007\/s00415-014-7310-2","article-title":"Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature","volume":"261","author":"Nachbauer","year":"2014","journal-title":"J Neurol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.jns.2010.01.010","article-title":"Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2","volume":"291","author":"Mantuano","year":"2010","journal-title":"J Neurol Sci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1002\/ana.10756","article-title":"Novel CACNA1A mutation causes febrile episodic ataxia with interictal cerebellar deficits","volume":"54","author":"Subramony","year":"2003","journal-title":"Ann Neurol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.ejpn.2014.10.005","article-title":"Novel frameshift mutation in the CACNA1A gene causing a mixed phenotype of episodic ataxia and familiar hemiplegic migraine","volume":"19","author":"Kinder","year":"2015","journal-title":"Eur J Paediatr Neurol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1136\/jnnp.2008.159103","article-title":"Episodic ataxia type 2: unusual aspects in clinical and genetic presentation. Special emphasis in childhood","volume":"80","author":"Bertholon","year":"2009","journal-title":"J Neurol Neurosurg Psychiatry."},{"key":"B51","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1212\/WNL.0b013e3181f25e8f","article-title":"De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine","volume":"75","author":"Riant","year":"2010","journal-title":"Neurology."},{"key":"B52","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/S0887-8994(01)00371-X","article-title":"Wide clinical variability in a family with a CACNA1A T666m mutation: hemiplegic migraine, coma, and progressive ataxia","volume":"26","author":"Wada","year":"2002","journal-title":"Pediatr Neurol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/j.jns.2010.09.032","article-title":"A novel mutation in CACNA1A associated with hemiplegic migraine, cerebellar dysfunction and late-onset cognitive decline","volume":"300","author":"Freilinger","year":"2011","journal-title":"J Neurol Sci."},{"key":"B54","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1007\/s10048-013-0375-8","article-title":"Diagnostic utility of whole exome sequencing in patients showing cerebellar and\/or vermis atrophy in childhood","volume":"14","author":"Ohba","year":"2013","journal-title":"Neurogenetics."},{"key":"B55","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.pediatrneurol.2015.10.014","article-title":"Whole exome sequencing and heterologous cellular electrophysiology studies elucidate a novel Loss-of-Function mutation in the CACNA1A-encoded neuronal P\/Q-type calcium channel in a child with congenital hypotonia and developmental delay","volume":"55","author":"Weyhrauch","year":"2016","journal-title":"Pediatr Neurol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1016\/j.braindev.2019.05.007","article-title":"Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders","volume":"41","author":"Yamamoto","year":"2019","journal-title":"Brain Dev."},{"key":"B57","doi-asserted-by":"publisher","first-page":"e78598","DOI":"10.1371\/journal.pone.0078598","article-title":"Ablation of Ca(V)2.1 voltage-gated Ca(2)(+) channels in mouse forebrain generates multiple cognitive impairments.","volume":"8","author":"Mallmann","year":"2013","journal-title":"PLoS One."},{"key":"B58","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.tics.2017.02.005","article-title":"The cerebellum: adaptive prediction for movement and cognition","volume":"21","author":"Sokolov","year":"2017","journal-title":"Trends Cogn Sci."},{"key":"B59","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.neulet.2018.07.005","article-title":"The cerebellum and cognition","volume":"688","author":"Schmahmann","year":"2019","journal-title":"Neurosci Lett."},{"key":"B60","doi-asserted-by":"publisher","first-page":"2501","DOI":"10.1111\/j.1528-1167.2009.02189.x","article-title":"Array-CGH detection of a de novo 0.7-Mb deletion in 19p13.13 including CACNA1A associated with mental retardation and epilepsy with infantile spasms.","volume":"50","author":"Auvin","year":"2009","journal-title":"Epilepsia."},{"key":"B61","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1002\/ajmg.a.35790","article-title":"Apparent germline mosaicism for a novel 19p13.13 deletion disrupting NFIX and CACNA1A.","author":"Nimmakayalu","year":"2013","journal-title":"Am J Med Genet A."},{"key":"B62","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1097\/MCD.0000000000000185","article-title":"Two patients with 19p13.2 deletion (Malan syndrome) involving NFIX and CACNA1A with overgrowth, developmental delay, and epilepsy.","volume":"26","author":"Kuroda","year":"2017","journal-title":"Clin Dysmorphol."},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-021-10415-x","article-title":"The electrophysiological footprint of CACNA1A disorders","author":"Indelicato","year":"2021","journal-title":"J Neurol"},{"key":"B64","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1007\/s10072-015-2157-6","article-title":"Exercise-induced downbeat nystagmus in a Korean family with a nonsense mutation in CACNA1A","volume":"36","author":"Choi","year":"2015","journal-title":"Neurol Sci."},{"key":"B65","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1212\/01.wnl.0000176069.64200.28","article-title":"Late-onset episodic ataxia type 2 due to an in-frame insertion in CACNA1A","volume":"65","author":"Imbrici","year":"2005","journal-title":"Neurology."},{"key":"B66","doi-asserted-by":"publisher","first-page":"2682","DOI":"10.1093\/brain\/awh301","article-title":"Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia.","volume":"127","author":"Imbrici","year":"2004","journal-title":"Brain."},{"key":"B67","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1159\/000315145","article-title":"Phenotypic variability of episodic ataxia type 2 mutations: a family study","volume":"64","author":"Jung","year":"2010","journal-title":"Eur Neurol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1016\/j.jocn.2007.01.013","article-title":"Electroencephalographic changes and seizures in familial hemiplegic migraine patients with the CACNA1A gene S218L mutation","volume":"15","author":"Chan","year":"2008","journal-title":"J Clin Neurosci."},{"key":"B69","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1159\/000079546","article-title":"New CACNA1A gene mutation in a case of familial hemiplegic migraine with status epilepticus","volume":"52","author":"Beauvais","year":"2004","journal-title":"Eur Neurol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1111\/j.1468-2982.2009.01884.x","article-title":"The FHM1 mutation S218L: a severe clinical phenotype? A case report and review of the literature","volume":"29","author":"Debiais","year":"2009","journal-title":"Cephalalgia."},{"key":"B71","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1002\/ana.1031","article-title":"Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine","volume":"49","author":"Kors","year":"2001","journal-title":"Ann Neurol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1111\/j.1469-8749.2009.03493.x","article-title":"Sporadic hemiplegic migraine and delayed cerebral oedema after minor head trauma: a novel de novo CACNA1A gene mutation","volume":"52","author":"Malpas","year":"2010","journal-title":"Dev Med Child Neurol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1136\/jnnp.2009.177279","article-title":"Early seizures and cerebral oedema after trivial head trauma associated with the CACNA1A S218L mutation","volume":"80","author":"Stam","year":"2009","journal-title":"J Neurol Neurosurg Psychiatry."},{"key":"B74","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1212\/WNL.55.7.1040","article-title":"CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy","volume":"55","author":"Vahedi","year":"2000","journal-title":"Neurology."},{"key":"B75","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1001\/archneur.60.4.610","article-title":"Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family","volume":"60","author":"Alonso","year":"2003","journal-title":"Arch Neurol."},{"key":"B76","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1136\/jnnp.2008.163402","article-title":"A wide spectrum of clinical, neurophysiological and neuroradiological abnormalities in a family with a novel CACNA1A mutation","volume":"81","author":"Romaniello","year":"2010","journal-title":"J Neurol Neurosurg Psychiatry."},{"key":"B77","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1111\/j.1399-0004.2008.00996.x","article-title":"CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine","volume":"74","author":"Stam","year":"2008","journal-title":"Clin Genet."},{"key":"B78","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1093\/brain\/awz365","article-title":"Adult loss of Cacna1a in mice recapitulates childhood absence epilepsy by distinct thalamic bursting mechanisms","volume":"143","author":"Miao","year":"2020","journal-title":"Brain."},{"key":"B79","doi-asserted-by":"publisher","first-page":"17819","DOI":"10.1073\/pnas.0707945104","article-title":"Gamma-band deficiency and abnormal thalamocortical activity in P\/Q-type channel mutant mice","volume":"104","author":"Llinas","year":"2007","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B80","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/B978-0-444-63326-2.00012-0","article-title":"Monogenic models of absence epilepsy: windows into the complex balance between inhibition and excitation in thalamocortical microcircuits","volume":"213","author":"Maheshwari","year":"2014","journal-title":"Prog Brain Res."},{"key":"B81","doi-asserted-by":"publisher","first-page":"5654","DOI":"10.1523\/JNEUROSCI.20-15-05654.2000","article-title":"Reduced voltage sensitivity of activation of P\/Q-type Ca2+ channels is associated with the ataxic mouse mutation rolling Nagoya (tg(rol))","volume":"20","author":"Mori","year":"2000","journal-title":"J Neurosci."},{"key":"B82","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.1126\/science.572084","article-title":"Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering","volume":"204","author":"Noebels","year":"1979","journal-title":"Science."},{"key":"B83","doi-asserted-by":"publisher","first-page":"15245","DOI":"10.1073\/pnas.96.26.15245","article-title":"Ablation of P\/Q-type Ca(2+) channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the alpha(1A)-subunit","volume":"96","author":"Jun","year":"1999","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B84","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1523\/JNEUROSCI.2555-15.2016","article-title":"Isolated P\/Q calcium channel deletion in layer VI corticothalamic neurons generates absence epilepsy","volume":"36","author":"Bomben","year":"2016","journal-title":"J Neurosci."},{"key":"B85","doi-asserted-by":"publisher","first-page":"1615","DOI":"10.1523\/JNEUROSCI.2081-08.2009","article-title":"Genetic enhancement of thalamocortical network activity by elevating alpha 1g-mediated low-voltage-activated calcium current induces pure absence epilepsy","volume":"29","author":"Ernst","year":"2009","journal-title":"J Neurosci."},{"key":"B86","doi-asserted-by":"publisher","first-page":"4311","DOI":"10.1523\/JNEUROSCI.5342-10.2011","article-title":"Delayed postnatal loss of P\/Q-type calcium channels recapitulates the absence epilepsy, dyskinesia, and ataxia phenotypes of genomic Cacna1a mutations","volume":"31","author":"Mark","year":"2011","journal-title":"J Neurosci."},{"key":"B87","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/S1474-4422(15)00250-1","article-title":"The genetic landscape of the epileptic encephalopathies of infancy and childhood","volume":"15","author":"McTague","year":"2016","journal-title":"Lancet Neurol."},{"key":"B88","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1086\/320609","article-title":"De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy","volume":"68","author":"Claes","year":"2001","journal-title":"Am J Hum Genet."},{"key":"B89","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/nature12439","article-title":"De novo mutations in epileptic encephalopathies","volume":"501","author":"Epi","year":"2013","journal-title":"Nature."},{"key":"B90","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1177\/0883073818754987","article-title":"An atypical rett syndrome phenotype due to a novel missense mutation in CACNA1A","volume":"33","author":"Epperson","year":"2018","journal-title":"J Child Neurol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"106398","DOI":"10.1016\/j.eplepsyres.2020.106398","article-title":"Genotype-phenotype correlates of infantile-onset developmental & epileptic encephalopathy syndromes in South India: a single centre experience","volume":"166","author":"Mitta","year":"2020","journal-title":"Epilepsy Res."},{"key":"B92","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.braindev.2017.08.006","article-title":"CACNA1A-related early-onset encephalopathy with myoclonic epilepsy: a case report","volume":"40","author":"Hayashida","year":"2018","journal-title":"Brain Dev."},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.3389\/fnsyn.2021.634760","article-title":"Voltage-gated Ca2+-channel de novo missense mutations: gain or loss of function - implications for potential therapies","author":"Striessnig","year":"2020","journal-title":"Front Synaptic Neurosci."},{"key":"B94","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1016\/j.ajhg.2017.09.008","article-title":"High rate of recurrent de novo mutations in developmental and epileptic encephalopathies","volume":"101","author":"Hamdan","year":"2017","journal-title":"Am J Hum Genet."},{"key":"B95","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1007\/s00415-017-8494-z","article-title":"Adult-onset ataxia or developmental disorder with seizures: two sides of missense changes in CACNA1A","volume":"264","author":"Balck","year":"2017","journal-title":"J Neurol."},{"key":"B96","doi-asserted-by":"publisher","first-page":"1881","DOI":"10.1111\/epi.16316","article-title":"Both gain-of-function and loss-of-function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox-Gastaut syndrome","volume":"60","author":"Jiang","year":"2019","journal-title":"Epilepsia."},{"key":"B97","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1093\/brain\/awy325","article-title":"Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1a S218L mice","volume":"142","author":"Loonen","year":"2019","journal-title":"Brain."},{"key":"B98","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1002\/ana.21815","article-title":"High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1 S218L mice.","volume":"67","author":"van den Maagdenberg","year":"2010","journal-title":"Ann Neurol."},{"key":"B99","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1111\/j.1468-2982.2008.01645.x","article-title":"Genetic analysis of 27 Spanish patients with hemiplegic migraine, basilar-type migraine and childhood periodic syndromes","volume":"28","author":"Cuenca-Leon","year":"2008","journal-title":"Cephalalgia."},{"key":"B100","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.ejpn.2019.11.002","article-title":"Paroxysmal tonic upgaze: A heterogeneous clinical condition responsive to carbonic anhydrase inhibition","volume":"25","author":"Quade","year":"2020","journal-title":"Eur J Paediatr Neurol."},{"key":"B101","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.ejpn.2014.12.018","article-title":"Paroxysmal tonic upward gaze as a presentation of de-novo mutations in CACNA1A","volume":"19","author":"Blumkin","year":"2015","journal-title":"Eur J Paediatr Neurol."},{"key":"B102","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1177\/0883073808322338","article-title":"The neurology of benign paroxysmal torticollis of infancy: report of 10 new cases and review of the literature","volume":"24","author":"Rosman","year":"2009","journal-title":"J Child Neurol."},{"key":"B103","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1177\/0883073816636226","article-title":"The genetics of benign paroxysmal torticollis of infancy: is there an association with mutations in the CACNA1A gene?","volume":"31","author":"Shin","year":"2016","journal-title":"J Child Neurol."},{"key":"B104","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1177\/088307388800300305","article-title":"Benign paroxysmal tonic upgaze of childhood","volume":"3","author":"Ouvrier","year":"1988","journal-title":"J Child Neurol."},{"key":"B105","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1002\/ana.410430416","article-title":"Paroxysmal tonic upgaze: a reappraisal of outcome","volume":"43","author":"Hayman","year":"1998","journal-title":"Ann Neurol."},{"key":"B106","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1684\/epd.2007.0119","article-title":"Paroxysmal tonic upgaze of childhood with co-existent absence epilepsy","volume":"9","author":"Luat","year":"2007","journal-title":"Epileptic Disord."},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2020.10.004","article-title":"Clinical phenotypes of infantile onset CACNA1A-related disorder","author":"Gur-Hartman","year":"2020","journal-title":"Eur J Neurol Paedriatr Neurol."},{"key":"B108","doi-asserted-by":"publisher","first-page":"e56362","DOI":"10.1371\/journal.pone.0056362","article-title":"Identification of a novel nonsense mutation p.Tyr1957Ter of CACNA1A in a Chinese family with episodic ataxia 2.","volume":"8","author":"Hu","year":"2013","journal-title":"PLoS One."},{"key":"B109","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.jns.2009.01.005","article-title":"Late-onset episodic ataxia type 2 associated with a novel loss-of-function mutation in the CACNA1A gene","volume":"280","author":"Cuenca-Leon","year":"2009","journal-title":"J Neurol Sci."},{"key":"B110","doi-asserted-by":"publisher","first-page":"116909","DOI":"10.1016\/j.jns.2020.116909","article-title":"Novel CACNA1A variant may cause cervical dystonia and cerebellar ataxia syndrome","volume":"415","author":"Fuerte-Hortigon","year":"2020","journal-title":"J Neurol Sci."},{"key":"B111","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1001\/archneur.62.2.314","article-title":"Two novel CACNA1A gene mutations associated with episodic ataxia type 2 and interictal dystonia","volume":"62","author":"Spacey","year":"2005","journal-title":"Arch Neurol."},{"key":"B112","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1016\/B978-0-12-374105-9.00095-2","article-title":"Dystonia: Animal Models","author":"Hess","year":"2017","journal-title":"EncyclMov Disord."},{"key":"B113","doi-asserted-by":"publisher","first-page":"e575","DOI":"10.1212\/WNL.0000000000004966","article-title":"Clinical spectrum of hemiplegic migraine and chances of finding a pathogenic mutation","volume":"90","author":"Pelzer","year":"2018","journal-title":"Neurology."},{"key":"B114","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s11940-012-0208-3","article-title":"Familial and sporadic hemiplegic migraine: diagnosis and treatment","volume":"15","author":"Pelzer","year":"2013","journal-title":"Curr Treat Options Neurol."},{"key":"B115","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1212\/01.WNL.0000125691.74109.53","article-title":"Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine","volume":"62","author":"Strupp","year":"2004","journal-title":"Neurology."},{"key":"B116","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1007\/s00415-003-1020-5","article-title":"Positional vertigo and macroscopic downbeat positioning nystagmus in spinocerebellar ataxia type 6 (SCA6)","volume":"250","author":"Yabe","year":"2003","journal-title":"J Neurol."},{"key":"B117","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1136\/bmj.1.4968.650","article-title":"Acetazolamide in treatment of epilepsy","volume":"1","author":"Ansell","year":"1956","journal-title":"Br Med J."},{"key":"B118","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1046\/j.1528-1157.2001.33600.x","article-title":"Acetazolamide in women with catamenial epilepsy","volume":"42","author":"Lim","year":"2001","journal-title":"Epilepsia."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2021.639994\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T00:13:15Z","timestamp":1614643995000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2021.639994\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,2]]},"references-count":118,"alternative-id":["10.3389\/fneur.2021.639994"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2021.639994","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,2]]},"article-number":"639994"}}