{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:50:37Z","timestamp":1760147437003,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T00:00:00Z","timestamp":1675382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Calcium channels are an integral component in maintaining cellular function. Alterations may lead to channelopathies, primarily manifested in the central nervous system. This study describes the clinical and genetic features of a unique 12-year-old boy harboring two congenital calcium channelopathies, involving the CACNA1A and CACNA1F genes, and provides an unadulterated view of the natural history of sporadic hemiplegic migraine type 1 (SHM1) due to the patient\u2019s inability to tolerate any preventative medication. The patient presents with episodes of vomiting, hemiplegia, cerebral edema, seizure, fever, transient blindness, and encephalopathy. He is nonverbal, nonambulatory, and forced to have a very limited diet due to abnormal immune responses. The SHM1 manifestations apparent in the subject are consistent with the phenotype described in the 48 patients identified as part of a systematic literature review. The ocular symptoms of CACNA1F align with the family history of the subject. The presence of multiple pathogenic variants make it difficult to identify a clear phenotype\u2013genotype correlation in the present case. Moreover, the detailed case description and natural history along with the comprehensive review of the literature contribute to the understanding of this complex disorder and point to the need for comprehensive clinical assessments of SHM1.<\/jats:p>","DOI":"10.3390\/genes14020400","type":"journal-article","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T05:09:20Z","timestamp":1675400960000},"page":"400","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Concomitant Calcium Channelopathies Involving CACNA1A and CACNA1F: A Case Report and Review of the Literature"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1132-3097","authenticated-orcid":false,"given":"Donna","family":"Schaare","sequence":"first","affiliation":[{"name":"Ph.D. Program in Healthcare Genetics and Genomics, School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University, Clemson, SC 29634, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1625-7404","authenticated-orcid":false,"given":"Sara M.","family":"Sarasua","sequence":"additional","affiliation":[{"name":"Ph.D. Program in Healthcare Genetics and Genomics, School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University, Clemson, SC 29634, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laina","family":"Lusk","sequence":"additional","affiliation":[{"name":"Division of Neurology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shridhar","family":"Parthasarathy","sequence":"additional","affiliation":[{"name":"Division of Neurology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liangjiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Genetics and Biochemistry, College of Science, Clemson University, Clemson, SC 29634, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingo","family":"Helbig","sequence":"additional","affiliation":[{"name":"Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2017-4270","authenticated-orcid":false,"given":"Luigi","family":"Boccuto","sequence":"additional","affiliation":[{"name":"Ph.D. Program in Healthcare Genetics and Genomics, School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University, Clemson, SC 29634, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1016\/j.bbamcr.2006.08.049","article-title":"Voltage-gated calcium channels in genetic diseases","volume":"1763","author":"Bidaud","year":"2006","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.pneurobio.2015.09.002","article-title":"Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders","volume":"134","author":"Heyes","year":"2015","journal-title":"Prog. Neurobiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1002\/mgg3.24","article-title":"Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: Clinical, genetic, and functional studies","volume":"1","author":"Carreno","year":"2013","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.jns.2014.04.027","article-title":"Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A","volume":"342","author":"Gautschi","year":"2014","journal-title":"J. Neurol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"577544","DOI":"10.3389\/fped.2020.577544","article-title":"CACNA1A Gene Variants in Eight Chinese Patients with a Wide Range of Phenotypes","volume":"8","author":"Zhang","year":"2020","journal-title":"Front. Pediatr."},{"key":"ref_6","doi-asserted-by":"crossref","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":"ref_7","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.pediatrneurol.2005.08.033","article-title":"Minor head trauma-induced sporadic hemiplegic migraine coma","volume":"34","author":"Curtain","year":"2006","journal-title":"Pediatr. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","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":"ref_9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13041-021-00745-2","article-title":"The de novo CACNA1A pathogenic variant Y1384C associated with hemiplegic migraine, early onset cerebellar atrophy and developmental delay leads to a loss of Cav2.1 channel function","volume":"14","author":"Gandini","year":"2021","journal-title":"Mol. Brain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.ejpn.2016.11.005","article-title":"Missense mutations of CACNA1A are a frequent cause of autosomal dominant nonprogressive congenital ataxia","volume":"21","author":"Travaglini","year":"2017","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1177\/0333102416686347","article-title":"Epilepsy in hemiplegic migraine: Genetic mutations and clinical implications","volume":"38","author":"Prontera","year":"2018","journal-title":"Cephalalgia"},{"key":"ref_12","doi-asserted-by":"crossref","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":"ref_13","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1007\/s00424-021-02570-x","article-title":"Cav1.4 dysfunction and congenital stationary night blindness type 2","volume":"473","author":"Koschak","year":"2021","journal-title":"Pfl\u00fcgers Arch.-Eur. J. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1523\/JNEUROSCI.4846-03.2004","article-title":"The CACNA1F gene encodes an L-type calcium channel with unique biophysical properties and tissue distribution","volume":"24","author":"McRory","year":"2004","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Mahmood, U., Mejecase, C., Ali, S.M.A., Moosajee, M., and Kozak, I. (2021). A Novel Splice-Site Variant in CACNA1F Causes a Phenotype Synonymous with angstrom land Island Eye Disease and Incomplete Congenital Stationary Night Blindness. Genes, 12.","DOI":"10.3390\/genes12020171"},{"key":"ref_16","first-page":"607","article-title":"Diagnosis of an X-linked type 2 congenital stationary night blindness using electroretinography and CACNA1F sequencing","volume":"95","year":"2020","journal-title":"Arch. Soc. Espa\u00f1ola Oftalmol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/947","article-title":"Loss-of-function mutations in a calcium-channel \u03b11-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness","volume":"19","author":"Naylor","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.4049\/jimmunol.1800837","article-title":"What\u2019s Bred in the Bone: Calcium Channels in Lymphocytes","volume":"202","author":"Fenninger","year":"2019","journal-title":"J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"243","DOI":"10.3389\/fimmu.2013.00243","article-title":"Emerging Roles of L-Type Voltage-Gated and Other Calcium Channels in T Lymphocytes","volume":"4","author":"Badou","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"ra103","DOI":"10.1126\/scisignal.aac7538","article-title":"Essential roles for Cav\u03b22 and Cav1 channels in thymocyte development and T cell homeostasis","volume":"8","author":"Jha","year":"2015","journal-title":"Sci. Signal."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.immuni.2011.07.011","article-title":"The CaV1.4 Calcium Channel Is a Critical Regulator of T Cell Receptor Signaling and Naive T Cell Homeostasis","volume":"35","author":"Omilusik","year":"2011","journal-title":"Immunity"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1016\/j.molimm.2005.01.014","article-title":"Molecular characterization of L-type calcium channel splice variants expressed in human T lymphocytes","volume":"42","author":"Kotturi","year":"2005","journal-title":"Mol. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.braindev.2011.11.002","article-title":"Sporadic hemiplegic migraine presenting as acute encephalopathy","volume":"34","author":"Ohmura","year":"2012","journal-title":"Brain Dev."},{"key":"ref_24","doi-asserted-by":"crossref","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":"Lerche","year":"2013","journal-title":"Pediatr. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1177\/0333102413513182","article-title":"Rare clinical findings in a patient with sporadic hemiplegic migraine: FDG-PET provides diminished brain metabolism at 10-year follow-up","volume":"34","author":"Topakian","year":"2014","journal-title":"Cephalalgia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1177\/0333102416668655","article-title":"Combined early treatment in hemiplegic attacks related to CACNA1A encephalopathy with brain oedema: Blocking the cascade?","volume":"37","author":"Camia","year":"2017","journal-title":"Cephalalgia"},{"key":"ref_28","doi-asserted-by":"crossref","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":"ref_29","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1159\/000512275","article-title":"R1352Q CACNA1A Variant in a Patient with Sporadic Hemiplegic Migraine, Ataxia, Seizures and Cerebral Oedema: A Case Report","volume":"13","author":"Stubberud","year":"2021","journal-title":"Case Rep. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1111\/dmcn.13935","article-title":"Benign paroxysmal torticollis, benign paroxysmal vertigo, and benign tonic upward gaze are not benign disorders","volume":"60","author":"Humbertclaude","year":"2018","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","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":"ref_32","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1111\/j.1468-2982.2008.01596.x","article-title":"CACNA1A mutation linking hemiplegic migraine and alternating hemiplegia of childhood","volume":"28","author":"Stam","year":"2008","journal-title":"Cephalalgia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ejpn.2021.05.010","article-title":"CACNA1A-associated epilepsy: Electroclinical findings and treatment response on seizures in 18 patients","volume":"33","author":"Barth","year":"2021","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","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":"ref_35","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.3928\/01913913-20171129-01","article-title":"Ocular Dipping in a Patient With Hemiplegic Migraine","volume":"55","author":"Gray","year":"2018","journal-title":"J. Pediatr. Ophthalmol. Strabismus"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s10194-012-0444-7","article-title":"R583Q CACNA1A variant in SHM1 and ataxia: Case report and literature update","volume":"13","author":"Fusi","year":"2012","journal-title":"J. Headache Pain"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e14","DOI":"10.1161\/STROKEAHA.110.600023","article-title":"Recurrent stroke due to a novel voltage sensor mutation in Cav2.1 responds to verapamil","volume":"42","author":"Knierim","year":"2011","journal-title":"Stroke"},{"key":"ref_38","doi-asserted-by":"crossref","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":"ref_39","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.yebeh.2009.12.017","article-title":"Sporadic hemiplegic migraine and epilepsy associated with CACNA1A gene mutation","volume":"17","author":"Zangaladze","year":"2010","journal-title":"Epilepsy Behav."},{"key":"ref_40","doi-asserted-by":"crossref","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":"ref_41","doi-asserted-by":"crossref","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":"ref_42","unstructured":"Boat, T.F., Wu, J.T., and National Academies of Sciences, Engineering, and Medicine (2022, December 08). Clinical Characteristics of Intellectual Disabilities, Mental Disorders and Disabilities among Low-Income Children, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK332877\/."},{"key":"ref_43","first-page":"695","article-title":"The importance of genetic testing as demonstrated by two cases of CACNA1F-associated retinal generation misdiagnosed as LCA","volume":"23","author":"Men","year":"2017","journal-title":"Mol. Vis."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Birtel, J., Gliem, M., Hess, K., Birtel, T., Holz, F.G., Zechner, U., Bolz, H.J., and Herrmann, P. (2020). Comprehensive Geno- and Phenotyping in a Complex Pedigree Including Four Different Inherited Retinal Dystrophies. Genes, 11.","DOI":"10.3390\/genes11020137"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/ejhg.2017.44","article-title":"Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing","volume":"25","author":"Thomas","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Kim, H.M., Joo, K., Han, J., and Woo, S.J. (2021). Clinical and Genetic Characteristics of Korean Congenital Stationary Night Blindness Patients. Genes, 12.","DOI":"10.3390\/genes12060789"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/S0002-9394(02)02109-8","article-title":"A novel CACNA1F mutation in a french family with the incomplete type of X-linked congenital stationary night blindness","volume":"135","author":"Jacobi","year":"2003","journal-title":"Am. J. Ophthalmol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1002\/humu.9106","article-title":"Mutations in the CACNA1F and NYX genes in British CSNBX families","volume":"21","author":"Zito","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_49","first-page":"3262","article-title":"A novel p.Gly603Arg mutation in CACNA1F causes \u00c5land island eye disease and incomplete congenital stationary night blindness phenotypes in a family","volume":"17","author":"Vincent","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1136\/bjo.87.11.1413","article-title":"Genotype-phenotype correlation in British families with X linked congenital stationary night blindness","volume":"87","author":"Allen","year":"2003","journal-title":"Br. J. Ophthalmol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1080\/13816810.2019.1681008","article-title":"An Ashkenazi Jewish founder mutation in CACNA1F causes retinal phenotype in both hemizygous males and heterozygous female carriers","volume":"40","author":"Kimchi","year":"2019","journal-title":"Ophthalmic Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1080\/13816810.2021.1938138","article-title":"Diagnostic yield of targeted next-generation sequencing in infantile nystagmus syndrome","volume":"42","author":"Choi","year":"2021","journal-title":"Ophthalmic Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1080\/13816810.2018.1520263","article-title":"Novel truncating mutation in CACNA1F in a young male patient diagnosed with optic atrophy","volume":"39","author":"Pasutto","year":"2018","journal-title":"Ophthalmic Genet."},{"key":"ref_54","first-page":"477","article-title":"Mutation analysis in 129 genes associated with other forms of retinal dystrophy in 157 families with retinitis pigmentosa based on exome sequencing","volume":"21","author":"Xu","year":"2015","journal-title":"Mol. Vis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1186\/s13023-021-01850-0","article-title":"Calcium channelopathies and intellectual disability: A systematic review","volume":"16","author":"Kessi","year":"2021","journal-title":"Orphanet J. Rare Dis."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/400\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:23:19Z","timestamp":1760120599000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/400"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,3]]},"references-count":55,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["genes14020400"],"URL":"https:\/\/doi.org\/10.3390\/genes14020400","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2023,2,3]]}}}