Download PDF
Journal of Pediatric Neurology 2023; 21(03): 224-234
DOI: 10.1055/s-0041-1728684
Review Article

Calcium Channels Genes and Their Epilepsy Phenotypes

Giulio Pulvirenti‡   *
1   Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Martina Caccamo‡   *
1   Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Manuela Lo Bianco
1   Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Marina Mazzurco
2   Unit of Pediatrics, Avola Hospital, Avola (SR), Italy
,
Elena R. Praticò
3   Unit of Pediatrics, Carpi Hospital, Carpi, Italy
,
Alessandro Giallongo
1   Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Gloria Gangi
1   Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Antonio Zanghì
4   Department of Medical and Surgical Sciences and Advanced Technology “G.F. Ingrassia,” University of Catania, Catania, Italy
,
Raffaele Falsaperla
5   Unit of Pediatrics and Pediatric Emergency, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy
6   Unit of Neonatal Intensive Care and Neonatology, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

Calcium (Ca2+) channel gene mutations play an important role in the pathogenesis of neurological episodic disorders like epilepsy. CACNA1A and CACNA1H genes are involved in the synthesis of calcium channels. Mutations in the α1A subunit of the P/Q type voltage-gated calcium channel gene (CACNA1A) located in 19p13.13, which encodes for the transmembrane pore-forming subunit of CAV2.1 voltage-dependent calcium channel, have been correlated to a large clinical spectrum of epilepsy such as idiopathic genetic epilepsy, early infantile epilepsy, and febrile seizures. Moreover, CACNA1A mutations have been demonstrated to be involved in spinocerebellar ataxia type 6, familiar hemiplegic migraine, episodic ataxia type 2, early-onset encephalopathy, and hemiconvulsion–hemiplegia epilepsy syndrome. This wide phenotype heterogeneity associated with CACNA1A mutations is correlated to different clinical and electrophysiological manifestations. CACNA1H gene, located in 16p13.3, encodes the α1H subunit of T-type calcium channel, expressing the transmembrane pore-forming subunit Cav3.2. Despite data still remain controversial, it has been identified as an important gene whose mutations seem strictly related to the pathogenesis of childhood absence epilepsy and other generalized epilepsies. The studied variants are mainly gain-of-function, hence responsible for an increase in neuronal susceptibility to seizures. CACNA1H mutations have also been associated with autism spectrum disorder and other behavior disorders. More recently, also amyotrophic lateral sclerosis has been related to CACNA1H alterations. The aim of this review, other than describe the CACNA1A and CACNA1H gene functions, is to identify mutations reported in literature and to analyze their possible correlations with specific epileptic disorders, purposing to guide an appropriate medical treatment recommendation.

Keywords

CACNA1A - CACNA1H - calcium channel - childhood absence epilepsy - generalized epilepsy

* Both Authors have equally contributed to the present article.




Publication History

Received: 30 September 2020

Accepted: 24 February 2021

Article published online:
21 May 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Mulley JC, Scheffer IE, Petrou S, Berkovic SF. Channelopathies as a genetic cause of epilepsy. Curr Opin Neurol 2003; 16 (02) 171-176
    CrossrefPubMedGoogle Scholar
  • 2 Praticò AD, Falsaperla R, Ruggieri M, Corsello G, Pavone P. Prognostic challenges of SCN1A genetic mutations: report on two children with mild features. J Pediatr Neurol 2016; 14: 82-88
    Google Scholar
  • 3 Ruggieri M, Polizzi A, Pavone L, Musumeci S. Thalamic syndrome in children with measles infection and selective, reversible thalamic involvement. Pediatrics 1998; 101 (1 Pt 1): 112-119
    Google Scholar
  • 4 Salpietro V, Polizzi A, Di Rosa G. et al. Adrenal disorders and the paediatric brain: pathophysiological considerations and clinical implications. Int J Endocrinol 2014; 2014: 282489
    Google Scholar
  • 5 Simms BA, Zamponi GW. Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron 2014; 82 (01) 24-45
    CrossrefPubMedGoogle Scholar
  • 6 Dunlap K, Luebke JI, Turner TJ. Exocytotic Ca2+ channels in mammalian central neurons. Trends Neurosci 1995; 18 (02) 89-98
    CrossrefPubMedGoogle Scholar
  • 7 Terwindt GM, Ophoff RA, Haan J, Sandkuijl LA, Frants RR, Ferrari MD. Dutch Migraine Genetics Research Group. Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies. Eur J Hum Genet 1998; 6 (04) 297-307
    CrossrefPubMedGoogle Scholar
  • 8 Chioza B, Wilkie H, Nashef L. et al. Association between the alpha(1a) calcium channel gene CACNA1A and idiopathic generalized epilepsy. Neurology 2001; 56 (09) 1245-1246
    CrossrefPubMedGoogle Scholar
  • 9 Sorge G, Ruggieri M, Polizzi A, Scuderi A, Di Pietro M. SHORT syndrome: a new case with probable autosomal dominant inheritance. Am J Med Genet 1996; 61 (02) 178-181
    Google Scholar
  • 10 Epi4K Consortium. De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies. Am J Hum Genet 2016; 99 (02) 287-298
    CrossrefPubMedGoogle Scholar
  • 11 Zhuchenko O, Bailey J, Bonnen P. et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet 1997; 15 (01) 62-69
    CrossrefPubMedGoogle Scholar
  • 12 Ducros A, Denier C, Joutel A. et al. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. N Engl J Med 2001; 345 (01) 17-24
    CrossrefPubMedGoogle Scholar
  • 13 Labrum RW, Rajakulendran S, Graves TD. et al. Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing. J Med Genet 2009; 46 (11) 786-791
    CrossrefPubMedGoogle Scholar
  • 14 Riant F, Lescoat C, Vahedi K. et al. Identification of CACNA1A large deletions in four patients with episodic ataxia. Neurogenetics 2010; 11 (01) 101-106
    CrossrefPubMedGoogle Scholar
  • 15 Pavone P, Praticò AD, Pavone V. et al. Ataxia in children: early recognition and clinical evaluation. Ital J Pediatr 2017; 43 (01) 6
    Google Scholar
  • 16 Ruggieri M, Rizzo R, Pavone P, Baieli S, Sorge G, Happle R. Temporal triangular alopecia in association with mental retardation and epilepsy in a mother and daughter. Arch Dermatol 2000; 136 (03) 426-427
    Google Scholar
  • 17 Chen Y, Lu J, Pan H. et al. Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol 2003; 54 (02) 239-243
    CrossrefPubMedGoogle Scholar
  • 18 Eckle VS, Shcheglovitov A, Vitko I. et al. Mechanisms by which a CACNA1H mutation in epilepsy patients increases seizure susceptibility. J Physiol 2014; 592 (04) 795-809
    CrossrefPubMedGoogle Scholar
  • 19 Heron SE, Khosravani H, Varela D. et al. Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann Neurol 2007; 62 (06) 560-568
    CrossrefPubMedGoogle Scholar
  • 20 Ruggieri M, Iannetti P, Clementi M. et al. Neurofibromatosis type 1 and infantile spasms. Childs Nerv Syst 2009; 25 (02) 211-216
    Google Scholar
  • 21 Coulter DA, Huguenard JR, Prince DA. Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons. Ann Neurol 1989; 25 (06) 582-593
    CrossrefPubMedGoogle Scholar
  • 22 Bien CG, Scheffer IE. Autoantibodies and epilepsy. Epilepsia 2011; 52 (Suppl. 03) 18-22
    CrossrefPubMedGoogle Scholar
  • 23 Celesia GG. Disorders of membrane channels or channelopathies. Clin Neurophysiol 2001; 112 (01) 2-18
    CrossrefPubMedGoogle Scholar
  • 24 Perez-Reyes E, Cribbs LL, Daud A. et al. Molecular characterization of a neuronal low-voltage-activated T-type calcium channel. Nature 1998; 391 (6670): 896-900
    CrossrefPubMedGoogle Scholar
  • 25 Cribbs LL, Lee JH, Yang J. et al. Cloning and characterization of alpha1H from human heart, a member of the T-type Ca2+ channel gene family. Circ Res 1998; 83 (01) 103-109
    CrossrefPubMedGoogle Scholar
  • 26 Zamponi GW. A crash course in calcium channels. ACS Chem Neurosci 2017; 8 (12) 2583-2585
    CrossrefPubMedGoogle Scholar
  • 27 Rajakulendran S, Kaski D, Hanna MG. Neuronal P/Q-type calcium channel dysfunction in inherited disorders of the CNS. Nat Rev Neurol 2012; 8 (02) 86-96
    CrossrefPubMedGoogle Scholar
  • 28 Noebels JL. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV. eds. The Voltage-Gated Calcium Channel and Absence Epilepsy.” Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition.. Bethesda (MD): National Center for Biotechnology Information (US); 2012
  • 29 Bomben VC, Aiba I, Qian J, Mark MD, Herlitze S, Noebels JL. Isolated P/Q calcium channel deletion in layer VI corticothalamic neurons generates absence epilepsy. J Neurosci 2016; 36 (02) 405-418
    CrossrefPubMedGoogle Scholar
  • 30 Krovetz HS, Helton TD, Crews AL, Horne WA. C-Terminal alternative splicing changes the gating properties of a human spinal cord calcium channel alpha 1A subunit. J Neurosci 2000; 20 (20) 7564-7570
    CrossrefPubMedGoogle Scholar
  • 31 Trettel F, Mantuano E, Calabresi V. et al. A fine physical map of the CACNA1A gene region on 19p13.1-p13.2 chromosome. Gene 2000; 241 (01) 45-50
    CrossrefPubMedGoogle Scholar
  • 32 Ophoff RA, Terwindt GM, Vergouwe MN. et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996; 87 (03) 543-552
    CrossrefPubMedGoogle Scholar
  • 33 Takamori M, Maruta T, Komai K. Lambert-Eaton myasthenic syndrome as an autoimmune calcium-channelopathy. Neurosci Res 2000; 36 (03) 183-191
    CrossrefPubMedGoogle Scholar
  • 34 Adams PJ, Snutch TP. Calcium channelopathies: voltage-gated calcium channels. Subcell Biochem 2007; 45: 215-251
    CrossrefPubMedGoogle Scholar
  • 35 Kordasiewicz HB, Thompson RM, Clark HB, Gomez CM. C-termini of P/Q-type Ca2+ channel alpha1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity. Hum Mol Genet 2006; 15 (10) 1587-1599
    CrossrefPubMedGoogle Scholar
  • 36 Hirano M, Takada Y, Wong CF. et al. C-terminal splice variants of P/Q-type Ca2+ channel CaV2.1 α1 subunits are differentially regulated by Rab3-interacting molecule proteins. J Biol Chem 2017; 292 (22) 9365-9381
    CrossrefPubMedGoogle Scholar
  • 37 Gazulla J, Tintore M. [P/Q-type voltage-dependent calcium channels in neurological disease]. Neurologia 2007; 22 (08) 511-516
    PubMedGoogle Scholar
  • 38 Burgess DL, Noebels JL. Single gene defects in mice: the role of voltage-dependent calcium channels in absence models. Epilepsy Res 1999; 36 (2-3): 111-122
    CrossrefPubMedGoogle Scholar
  • 39 Pietrobon D. Calcium channels and channelopathies of the central nervous system. Mol Neurobiol 2002; 25 (01) 31-50
    CrossrefPubMedGoogle Scholar
  • 40 Kim TY, Maki T, Zhou Y. et al. Absence-like seizures and their pharmacological profile in tottering-6j mice. Biochem Biophys Res Commun 2015; 463 (1-2): 148-153
    CrossrefPubMedGoogle Scholar
  • 41 Tokuda S, Kuramoto T, Tanaka K. et al. The ataxic groggy rat has a missense mutation in the P/Q-type voltage-gated Ca2+ channel alpha1A subunit gene and exhibits absence seizures. Brain Res 2007; 1133 (01) 168-177
    CrossrefPubMedGoogle Scholar
  • 42 Zamponi GW, Lory P, Perez-Reyes E. Role of voltage-gated calcium channels in epilepsy. Pflugers Arch 2010; 460 (02) 395-403
    CrossrefPubMedGoogle Scholar
  • 43 Zhang Y, Mori M, Burgess DL, Noebels JL. Mutations in high-voltage-activated calcium channel genes stimulate low-voltage-activated currents in mouse thalamic relay neurons. J Neurosci 2002; 22 (15) 6362-6371
    CrossrefPubMedGoogle Scholar
  • 44 Song I, Kim D, Choi S, Sun M, Kim Y, Shin HS. Role of the alpha1G T-type calcium channel in spontaneous absence seizures in mutant mice. J Neurosci 2004; 24 (22) 5249-5257
    CrossrefPubMedGoogle Scholar
  • 45 Kros L, Eelkman Rooda OH, Spanke JK. et al. Cerebellar output controls generalized spike-and-wave discharge occurrence. Ann Neurol 2015; 77 (06) 1027-1049
    CrossrefPubMedGoogle Scholar
  • 46 Rossignol E, Kruglikov I, van den Maagdenberg AM, Rudy B, Fishell G. CaV 2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures. Ann Neurol 2013; 74 (02) 209-222
    CrossrefPubMedGoogle Scholar
  • 47 Chioza B, Nashef L, Asherson P, Makoff A. CACNA1A and P/Q-type calcium channels in epilepsy. Lancet 2002; 359 (9302): 258
    CrossrefPubMedGoogle Scholar
  • 48 Hino-Fukuyo N, Kikuchi A, Arai-Ichinoi N. et al. Genomic analysis identifies candidate pathogenic variants in 9 of 18 patients with unexplained West syndrome. Hum Genet 2015; 134 (06) 649-658
    CrossrefPubMedGoogle Scholar
  • 49 Pavone P, Falsaperla R, Ruggieri M, Praticò AD, Pavone L. West syndrome treatment: new roads for an old syndrome. Front Neurol 2013; 4: 113
    Google Scholar
  • 50 Chioza B, Osei-Lah A, Nashef L. et al. Haplotype and linkage disequilibrium analysis to characterise a region in the calcium channel gene CACNA1A associated with idiopathic generalised epilepsy. Eur J Hum Genet 2002; 10 (12) 857-864
    CrossrefPubMedGoogle Scholar
  • 51 Sander T, Toliat MR, Heils A, Becker C, Nürnberg P. Failure to replicate an allelic association between an exon 8 polymorphism of the human alpha(1A) calcium channel gene and common syndromes of idiopathic generalized epilepsy. Epilepsy Res 2002; 49 (02) 173-177
    CrossrefPubMedGoogle Scholar
  • 52 Danzer SC. Double agent mTOR. Epilepsy Curr 2019; 19 (01) 44-46
    CrossrefPubMedGoogle Scholar
  • 53 Jiang X, Lupien-Meilleur A, Tazerart S. et al. Remodeled cortical inhibition prevents motor seizures in generalized epilepsy. Ann Neurol 2018; 84 (03) 436-451
    CrossrefPubMedGoogle Scholar
  • 54 Loonen ICM, Jansen NA, Cain SM. et al. Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1a S218L mice. Brain 2019; 142 (02) 412-425
    CrossrefPubMedGoogle Scholar
  • 55 Ruggieri M, Milone P, Pavone P. et al. Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke-Davidoff-Masson type in two patients. Am J Med Genet A 2012; 158A (11) 2870-2880
    Google Scholar
  • 56 Carbone E, Lux HD. A low voltage-activated, fully inactivating Ca channel in vertebrate sensory neurones. Nature 1984; 310 (5977): 501-502
    CrossrefPubMedGoogle Scholar
  • 57 Nilius B, Hess P, Lansman JB, Tsien RW. A novel type of cardiac calcium channel in ventricular cells. Nature 1985; 316 (6027): 443-446
    CrossrefPubMedGoogle Scholar
  • 58 Jagannathan S, Punt EL, Gu Y. et al. Identification and localization of T-type voltage-operated calcium channel subunits in human male germ cells. Expression of multiple isoforms. J Biol Chem 2002; 277 (10) 8449-8456
    CrossrefPubMedGoogle Scholar
  • 59 Wolfe JT, Wang H, Howard J, Garrison JC, Barrett PQ. T-type calcium channel regulation by specific G-protein betagamma subunits. Nature 2003; 424 (6945): 209-213
    CrossrefPubMedGoogle Scholar
  • 60 Dunham I, Shimizu N, Roe BA. et al. The DNA sequence of human chromosome 22. Nature 1999; 402 (6761): 489-495
    CrossrefPubMedGoogle Scholar
  • 61 Zhong X, Liu JR, Kyle JW, Hanck DA, Agnew WS. A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies. Hum Mol Genet 2006; 15 (09) 1497-1512
    CrossrefPubMedGoogle Scholar
  • 62 Yalçın O. Genes and molecular mechanisms involved in the epileptogenesis of idiopathic absence epilepsies. Seizure 2012; 21 (02) 79-86
    CrossrefPubMedGoogle Scholar
  • 63 Llinás RR, Ribary U, Jeanmonod D, Kronberg E, Mitra PP. Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc Natl Acad Sci U S A 1999; 96 (26) 15222-15227
    CrossrefPubMedGoogle Scholar
  • 64 Gomora JC, Daud AN, Weiergräber M, Perez-Reyes E. Block of cloned human T-type calcium channels by succinimide antiepileptic drugs. Mol Pharmacol 2001; 60 (05) 1121-1132
    CrossrefPubMedGoogle Scholar
  • 65 Lionetti E, Leonardi S, Franzonello C, Mancardi M, Ruggieri M, Catassi C. Gluten psychosis: confirmation of a new clinical Entity. Nutrients 2015; 7 (07) 5532-5539
    Google Scholar
  • 66 Tsakiridou E, Bertollini L, de Curtis M, Avanzini G, Pape HC. Selective increase in T-type calcium conductance of reticular thalamic neurons in a rat model of absence epilepsy. J Neurosci 1995; 15 (04) 3110-3117
    CrossrefPubMedGoogle Scholar
  • 67 Talley EM, Solórzano G, Depaulis A, Perez-Reyes E, Bayliss DA. Low-voltage-activated calcium channel subunit expression in a genetic model of absence epilepsy in the rat. Brain Res Mol Brain Res 2000; 75 (01) 159-165
    CrossrefPubMedGoogle Scholar
  • 68 Lee CG, Lee J, Lee M. Multi-gene panel testing in Korean patients with common genetic generalized epilepsy syndromes. PLoS One 2018; 13 (06) e0199321
    CrossrefPubMedGoogle Scholar
  • 69 Sander T, Peters C, Janz D. et al. The gene encoding the alpha1A-voltage-dependent calcium channel (CACN1A4) is not a candidate for causing common subtypes of idiopathic generalized epilepsy. Epilepsy Res 1998; 29 (02) 115-122
    CrossrefPubMedGoogle Scholar
  • 70 International League Against Epilepsy Consortium on Complex Epilepsies. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat Commun 2018; 9 (01) 5269
    CrossrefPubMedGoogle Scholar
  • 71 Jiang X, Raju PK, D'Avanzo N. et al. Both gain-of-function and loss-of-function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox-Gastaut syndrome. Epilepsia 2019; 60 (09) 1881-1894
    CrossrefPubMedGoogle Scholar
  • 72 Lv Y, Wang Z, Liu C, Cui L. Identification of a novel CACNA1A mutation in a Chinese family with autosomal recessive progressive myoclonic epilepsy. Neuropsychiatr Dis Treat 2017; 13: 2631-2636
    CrossrefPubMedGoogle Scholar
  • 73 Graves TD. Response to the paper titled “Identification of a novel CACNA1A mutation in a Chinese family with autosomal recessive progressive myoclonic epilepsy”. Neuropsychiatr Dis Treat 2018; 14: 2329
    CrossrefPubMedGoogle Scholar
  • 74 Hayashida T, Saito Y, Ishii A. et al. CACNA1A-related early-onset encephalopathy with myoclonic epilepsy: a case report. Brain Dev 2018; 40 (02) 130-133
    CrossrefPubMedGoogle Scholar
  • 75 Reinson K, Õiglane-Shlik E, Talvik I. et al. Biallelic CACNA1A mutations cause early onset epileptic encephalopathy with progressive cerebral, cerebellar, and optic nerve atrophy. Am J Med Genet A 2016; 170 (08) 2173-2176
    CrossrefPubMedGoogle Scholar
  • 76 Epperson MV, Haws ME, Standridge SM, Gilbert DL. An atypical Rett syndrome phenotype due to a novel missense mutation in CACNA1A. J Child Neurol 2018; 33 (04) 286-289
    CrossrefPubMedGoogle Scholar
  • 77 Salafia S, Praticò AD, Pizzo E, Greco F, Di Bella D. Hemiconvulsion-hemiplegia-epilepsy syndrome. Magnetic resonance findings in a 3-year-old boy. Neurol Neurochir Pol 2013; 47 (06) 584-589
    Google Scholar
  • 78 Yamazaki S, Ikeno K, Abe T, Tohyama J, Adachi Y. Hemiconvulsion-hemiplegia-epilepsy syndrome associated with CACNA1A S218L mutation. Pediatr Neurol 2011; 45 (03) 193-196
    CrossrefPubMedGoogle Scholar
  • 79 Haan J, van den Maagdenberg AM, Brouwer OF, Ferrari MD. Migraine and epilepsy: genetically linked?. Expert Rev Neurother 2008; 8 (09) 1307-1311
    CrossrefPubMedGoogle Scholar
  • 80 Haan J, Terwindt GM, van den Maagdenberg AM, Stam AH, Ferrari MD. A review of the genetic relation between migraine and epilepsy. Cephalalgia 2008; 28 (02) 105-113
    PubMedGoogle Scholar
  • 81 Salpietro V, Mankad K, Kinali M. et al. Pediatric idiopathic intracranial hypertension and the underlying endocrine-metabolic dysfunction: a pilot study. J Pediatr Endocrinol Metab 2014; 27 (1-2): 107-115
    Google Scholar
  • 82 Pavone P, Praticò AD, Vitaliti G. et al. Hydranencephaly: cerebral spinal fluid instead of cerebral mantles. Ital J Pediatr 2014; 40: 79
    Google Scholar
  • 83 Zangaladze A, Asadi-Pooya AA, Ashkenazi A, Sperling MR. Sporadic hemiplegic migraine and epilepsy associated with CACNA1A gene mutation. Epilepsy Behav 2010; 17 (02) 293-295
    CrossrefPubMedGoogle Scholar
  • 84 Auvin S, Holder-Espinasse M, Lamblin MD, Andrieux J. 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. Epilepsia 2009; 50 (11) 2501-2503
    CrossrefPubMedGoogle Scholar
  • 85 Pavone P, Briuglia S, Falsaperla R. et al. Wide spectrum of congenital anomalies including choanal atresia, malformed extremities, and brain and spinal malformations in a girl with a de novo 5.6-Mb deletion of 13q12.11-13q12.13. Am J Med Genet A 2014; 164A (07) 1734-1743
    Google Scholar
  • 86 Rajakulendran S, Graves TD, Labrum RW. et al. Genetic and functional characterisation of the P/Q calcium channel in episodic ataxia with epilepsy. J Physiol 2010; 588 (Pt 11): 1905-1913
    CrossrefPubMedGoogle Scholar
  • 87 Du X, Chen Y, Zhao Y, Luo W, Cen Z, Hao W. Dramatic response to pyridoxine in a girl with absence epilepsy with ataxia caused by a de novo CACNA1A mutation. Seizure 2017; 45: 189-191
    CrossrefPubMedGoogle Scholar
  • 88 Lance S, Mossman S, Poke G. A novel CACNA1A nonsense variant [c.4054C>T (p.Arg1352*)] causing episodic ataxia type 2. Case Rep Neurol Med 2018; 2018: 5802650
    PubMedGoogle Scholar
  • 89 Balck A, Tunc S, Schmitz J, Hollstein R, Kaiser FJ, Brüggemann N. A novel frameshift CACNA1A mutation causing episodic ataxia type 2. Cerebellum 2018; 17 (04) 504-506
    CrossrefPubMedGoogle Scholar
  • 90 Park D, Kim SH, Lee YJ, Song GJ, Park JS. A novel CACNA1A mutation associated with episodic ataxia 2 presenting with periodic paralysis. Acta Neurol Belg 2018; 118 (01) 137-139
    CrossrefPubMedGoogle Scholar
  • 91 Ruggieri M, Iannetti P, Pavone L. Delineation of a newly recognized neurocutaneous malformation syndrome with “cutis tricolor”. Am J Med Genet A 2003; 120A (01) 110-116
    Google Scholar
  • 92 Polizzi A, Pavone P, Ciancio E, La Rosa C, Sorge G, Ruggieri M. Hypertrichosis cubiti (hairy elbow syndrome): a clue to a malformation syndrome. J Pediatr Endocrinol Metab 2005; 18 (10) 1019-1025
    CrossrefPubMedGoogle Scholar
  • 93 Polizzi A, Pavone P, Parano E, Incorpora G, Ruggieri M. Lack of progression of brain atrophy in Aicardi-Goutières syndrome. Pediatr Neurol 2001; 24 (04) 300-302
    Google Scholar
  • 94 Polizzi A, Coghill S, McShane MA, Squier W. Acute ataxia complicating Langerhans cell histiocytosis. Arch Dis Child 2002; 86 (02) 130-131
    Google Scholar
  • 95 Ruggieri M, Praticò AD, Scuderi A, Sorge G, Polizzi A. The multiple faces of artwork diagnoses. Lancet Neurol 2017; 16 (06) 417-418
    Google Scholar
  • 96 Global Variome shared LOVD (Leiden Open Variation Database) CACNA1A. https://databases.lovd.nl/shared/genes/CACNA1A. Accessed March 18, 2021
    PubMedGoogle Scholar
  • 97 Angelini C, Van Gils J, Bigourdan A. et al. Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant. Eur J Med Genet 2019; 62 (06) 103530
    CrossrefPubMedGoogle Scholar
  • 98 Kuroda Y, Mizuno Y, Mimaki M. et al. Two patients with 19p13.2 deletion (Malan syndrome) involving NFIX and CACNA1A with overgrowth, developmental delay, and epilepsy. Clin Dysmorphol 2017; 26 (04) 224-227
    CrossrefPubMedGoogle Scholar
  • 99 Ruggieri M, Pavone V, De Luca D, Franzò A, Tiné A, Pavone L. Congenital bone malformations in patients with neurofibromatosis type 1 (Nf1). J Pediatr Orthop 1999; 19 (03) 301-305
    Google Scholar
  • 100 Pavone V, Signorelli SS, Praticò AD. et al. Total hemi-overgrowth in pigmentary mosaicism of the (Hypomelanosis of) Ito type: eight case reports. Medicine (Baltimore) 2016; 95 (10) e2705
    Google Scholar
  • 101 Holtmann M, Opp J, Tokarzewski M, Korn-Merker E. Human epilepsy, episodic ataxia type 2, and migraine. Lancet 2002; 359 (9301): 170-171
    CrossrefPubMedGoogle Scholar
  • 102 Ruggieri M, Praticò AD, Serra A. et al. Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies. Acta Otorhinolaryngol Ital 2016; 36 (05) 345-367
    PubMedGoogle Scholar
  • 103 Jouvenceau A, Eunson LH, Spauschus A. et al. Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet 2001; 358 (9284): 801-807
    CrossrefPubMedGoogle Scholar
  • 104 Damaj L, Lupien-Meilleur A, Lortie A. et al. CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms. Eur J Hum Genet 2015; 23 (11) 1505-1512
    CrossrefPubMedGoogle Scholar
  • 105 Ohmori I, Ouchida M, Kobayashi K. et al. CACNA1A variants may modify the epileptic phenotype of Dravet syndrome. Neurobiol Dis 2013; 50: 209-217
    CrossrefPubMedGoogle Scholar
  • 106 Nelson MT, Todorovic SM, Perez-Reyes E. The role of T-type calcium channels in epilepsy and pain. Curr Pharm Des 2006; 12 (18) 2189-2197
    CrossrefPubMedGoogle Scholar
  • 107 Pavone P, Praticò AD, Ruggieri M. et al. Acquired peripheral neuropathy: a report on 20 children. Int J Immunopathol Pharmacol 2012; 25 (02) 513-517
    Google Scholar
  • 108 Splawski I, Yoo DS, Stotz SC, Cherry A, Clapham DE, Keating MT. CACNA1H mutations in autism spectrum disorders. J Biol Chem 2006; 281 (31) 22085-22091
    CrossrefPubMedGoogle Scholar
  • 109 Steinberg KM, Yu B, Koboldt DC, Mardis ER, Pamphlett R. Exome sequencing of case-unaffected-parents trios reveals recessive and de novo genetic variants in sporadic ALS. Sci Rep 2015; 5: 9124
    CrossrefPubMedGoogle Scholar
  • 110 Gargus JJ. Unraveling monogenic channelopathies and their implications for complex polygenic disease. Am J Hum Genet 2003; 72 (04) 785-803
    CrossrefPubMedGoogle Scholar
  • 111 Vadlamudi L, Andermann E, Lombroso CT. et al. Epilepsy in twins: insights from unique historical data of William Lennox. Neurology 2004; 62 (07) 1127-1133
    CrossrefPubMedGoogle Scholar
  • 112 Sander T. The genetics of idiopathic generalized epilepsy: implications for the understanding of its aetiology. Mol Med Today 1996; 2 (04) 173-180
    CrossrefPubMedGoogle Scholar
  • 113 Tan NC, Mulley JC, Berkovic SF. Genetic association studies in epilepsy: “the truth is out there”. Epilepsia 2004; 45 (11) 1429-1442
    CrossrefPubMedGoogle Scholar
  • 114 Chourasia N, Ossó-Rivera H, Ghosh A, Von Allmen G, Koenig MK. Expanding the phenotypic spectrum of CACNA1H mutations. Pediatr Neurol 2019; 93: 50-55
    CrossrefPubMedGoogle Scholar
  • 115 Falsaperla R, Perciavalle V, Pavone P. et al. Unilateral eye blinking arising from the ictal ipsilateral occipital area. Clin EEG Neurosci 2016; 47 (03) 243-246
    Google Scholar
  • 116 Incorpora G, Pavone P, Castellano-Chiodo D, Praticò AD, Ruggieri M, Pavone L. Gelastic seizures due to hypothalamic hamartoma: rapid resolution after endoscopic tumor disconnection. Neurocase 2013; 19 (05) 458-461
    Google Scholar
  • 117 Scheffer IE, Berkovic S, Capovilla G. et al. ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia 2017; 58 (04) 512-521
    Google Scholar
  • 118 Goetz CG, Pappert EJ. Textbook of Clinical Neurology. Philadelphia: W. B. Saunders; 1999
    Google Scholar
  • 119 Khosravani H, Altier C, Simms B. et al. Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy. J Biol Chem 2004; 279 (11) 9681-9684
    CrossrefPubMedGoogle Scholar
  • 120 Vitko I, Chen Y, Arias JM, Shen Y, Wu XR, Perez-Reyes E. Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel. J Neurosci 2005; 25 (19) 4844-4855
    CrossrefPubMedGoogle Scholar
  • 121 Liang J, Zhang Y, Wang J. et al. New variants in the CACNA1H gene identified in childhood absence epilepsy. Neurosci Lett 2006; 406 (1-2): 27-32
    CrossrefPubMedGoogle Scholar
  • 122 Ruggieri M, Polizzi A, Marceca GP, Catanzaro S, Praticò AD, Di Rocco C. Introduction to phacomatoses (neurocutaneous disorders) in childhood. Childs Nerv Syst 2020; 36 (10) 2229-2268
    Google Scholar
  • 123 Sadamatsu M, Kanai H, Xu X, Liu Y, Kato N. Review of animal models for autism: implication of thyroid hormone. Congenit Anom (Kyoto) 2006; 46 (01) 1-9
    CrossrefPubMedGoogle Scholar
  • 124 Han JY, Jang JH, Park J, Lee IG. Targeted next-generation sequencing of Korean patients with developmental delay and/or intellectual disability. Front Pediatr 2018; 6: 391
    CrossrefPubMedGoogle Scholar
  • 125 Rzhepetskyy Y, Lazniewska J, Blesneac I, Pamphlett R, Weiss N. CACNA1H missense mutations associated with amyotrophic lateral sclerosis alter Cav3.2 T-type calcium channel activity and reticular thalamic neuron firing. Channels (Austin) 2016; 10 (06) 466-477
    CrossrefPubMedGoogle Scholar
  • 126 Gören MZ, Onat F. Ethosuximide: from bench to bedside. CNS Drug Rev 2007; 13 (02) 224-239
    CrossrefPubMedGoogle Scholar
  • 127 Hughes JR. Absence seizures: a review of recent reports with new concepts. Epilepsy Behav 2009; 15 (04) 404-412
    CrossrefPubMedGoogle Scholar
  • 128 Byers HM, Beatty CW, Hahn SH, Gospe Jr SM. Dramatic response after lamotrigine in a patient with epileptic encephalopathy and a de novoCACNA1A variant. Pediatr Neurol 2016; 60: 79-82
    CrossrefPubMedGoogle Scholar
  • 129 Strupp M, Kalla R, Freilinger T, Dichgans M, Brandt T. Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia--a comment. Brain 2005;128(Pt 6):E32, author reply E33
    PubMedGoogle Scholar
  • 130 Pratico AD, Longo L, Mansueto S. et al. Off-label use of drugs and adverse drug reactions in pediatric units: a prospective, multicenter study. Curr Drug Saf 2018; 13 (03) 200-207
    Google Scholar
  • 131 Coulter DA, Huguenard JR, Prince DA. Calcium currents in rat thalamocortical relay neurones: kinetic properties of the transient, low-threshold current. J Physiol 1989; 414: 587-604
    CrossrefPubMedGoogle Scholar
  • 132 Praticò AD, Pavone P, Scuderi MG. et al. Symptomatic hypocalcemia in an epileptic child treated with valproic acid plus lamotrigine: a case report. Cases J 2009; 2: 7394
    PubMedGoogle Scholar
  • 133 Pratico AD, Ruggieri M, Falsaperla R, Pavone P. A probable topiramate-induced limbs paraesthesia and rigid fingers flexion. Curr Drug Saf 2018; 13 (02) 131-136
    Google Scholar
  • 134 Glauser TA, Holland K, O'Brien VP. et al; Childhood Absence Epilepsy Study Group. Pharmacogenetics of antiepileptic drug efficacy in childhood absence epilepsy. Ann Neurol 2017; 81 (03) 444-453
    CrossrefPubMedGoogle Scholar
  • 135 Kürtüncü M, Kaya D, Zuliani L. et al. CACNA1H antibodies associated with headache with neurological deficits and cerebrospinal fluid lymphocytosis (HaNDL). Cephalalgia 2013; 33 (02) 123-129
    CrossrefPubMedGoogle Scholar
  • 136 Tektürk P, Baykan B, Ekizoğlu E. et al. Calcium channel antibodies in patients with absence epilepsy. Int J Neurosci 2014; 124 (07) 486-490
    CrossrefPubMedGoogle Scholar