{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T16:40:11Z","timestamp":1782837611932,"version":"3.54.5"},"reference-count":31,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,5,27]],"date-time":"2020-05-27T00:00:00Z","timestamp":1590537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Episodic ataxia type 2 (EA2) is characterized by paroxysmal attacks of ataxia with typical onset in childhood or early adolescence. The disease is associated with mutations in the voltage-gated calcium channel alpha 1A subunit (Cav2.1) that is encoded by the CACNA1A gene. However, previously unrecognized atypical symptoms and the genetic overlap existing between EA2, spinocerebellar ataxia type 6, familial hemiplegic migraine type 1, and other neurological diseases blur the genotype\/phenotype correlations, making a differential diagnosis difficult to formulate correctly and delaying early therapeutic intervention. Here we report a new clinical phenotype of a CACNA1A-associated disease characterized by absence epilepsy occurring during childhood. However, much later in life the patient displayed non-episodic, slowly progressive gait ataxia. Gene panel sequencing for hereditary ataxias led to the identification of a novel heterozygous CACNA1A mutation (c.1913 + 2T &gt; G), altering the donor splice site of intron 14. This genetic defect was predicted to result in an in-frame deletion removing 44 amino acids from the voltage-gated calcium channel Cav2.1. An RT-PCR analysis of cDNA derived from patient skin fibroblasts confirmed the skipping of the entire exon 14. Furthermore, two-electrode voltage-clamp recordings performed from Xenopus laevis oocytes expressing a wild-type versus mutant channel showed that the genetic defect caused a complete loss of channel function. This represents the first description of distinct clinical manifestations that remarkably expand the genetic and phenotypic spectrum of CACNA1A-related diseases and should be considered for an early diagnosis and effective therapeutic intervention.<\/jats:p>","DOI":"10.3390\/ijms21113810","type":"journal-article","created":{"date-parts":[[2020,5,28]],"date-time":"2020-05-28T10:02:45Z","timestamp":1590660165000},"page":"3810","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"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"],"prefix":"10.3390","volume":"21","author":[{"given":"Claudia","family":"Stendel","sequence":"first","affiliation":[{"name":"Friedrich Baur Institute at the Department of Neurology, University Hospital, Ludwig\u2013Maximilians\u2013University Munich, 80336 Munich, Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cristina","family":"D\u2019Adamo","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Physiology &amp; Biochemistry, University of Malta, MSD 2080 Msida, Malta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Wiessner","sequence":"additional","affiliation":[{"name":"Friedrich Baur Institute at the Department of Neurology, University Hospital, Ludwig\u2013Maximilians\u2013University Munich, 80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Dusl","sequence":"additional","affiliation":[{"name":"Friedrich Baur Institute at the Department of Neurology, University Hospital, Ludwig\u2013Maximilians\u2013University Munich, 80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Cenciarini","sequence":"additional","affiliation":[{"name":"Section of Physiology &amp; Biochemistry, Department of Experimental Medicine, University of Perugia School of Medicine, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Belia","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Biotechnology, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9674-6138","authenticated-orcid":false,"given":"Ehsan","family":"Nematian-Ardestani","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Physiology &amp; Biochemistry, University of Malta, MSD 2080 Msida, Malta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Bauer","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Senderek","sequence":"additional","affiliation":[{"name":"Friedrich Baur Institute at the Department of Neurology, University Hospital, Ludwig\u2013Maximilians\u2013University Munich, 80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Klopstock","sequence":"additional","affiliation":[{"name":"Friedrich Baur Institute at the Department of Neurology, University Hospital, Ludwig\u2013Maximilians\u2013University Munich, 80336 Munich, Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany"},{"name":"Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2857-6795","authenticated-orcid":false,"given":"Mauro","family":"Pessia","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Physiology &amp; Biochemistry, University of Malta, MSD 2080 Msida, Malta"},{"name":"Department of Physiology, United Arab Emirates University, Al Ain Po Box 17666, UAE"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,27]]},"reference":[{"key":"ref_1","first-page":"105","article-title":"A review of the genetic relation between migraine and epilepsy","volume":"28","author":"Haan","year":"2008","journal-title":"Cephalalgia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/S0140-6736(02)07355-5","article-title":"Human epilepsy, episodic ataxia type 2, and migraine","volume":"359","author":"Holtmann","year":"2002","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","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. 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