Artykuły w czasopismach: „CACNA1A gene”

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Gawel, Kinga, Waldemar A. Turski, Wietske van der Ent, Benan J. Mathai, Karolina J. Kirstein-Smardzewska, Anne Simonsen i Camila V. Esguerra. "Phenotypic Characterization of Larval Zebrafish (Danio rerio) with Partial Knockdown of the cacna1a Gene". Molecular Neurobiology 57, nr 4 (26.12.2019): 1904–16. http://dx.doi.org/10.1007/s12035-019-01860-x.

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AbstractThe CACNA1A gene encodes the pore-forming α1 subunit of voltage-gated P/Q type Ca2+ channels (Cav2.1). Mutations in this gene, among others, have been described in patients and rodents suffering from absence seizures and episodic ataxia type 2 with/without concomitant seizures. In this study, we aimed for the first time to assess phenotypic and behavioral alterations in larval zebrafish with partial cacna1aa knockdown, placing special emphasis on changes in epileptiform-like electrographic discharges in larval brains. Whole-mount in situ hybridization analysis revealed expression of cacna1aa in the optic tectum and medulla oblongata of larval zebrafish at 4 and 5 days post-fertilization. Next, microinjection of two antisense morpholino oligomers (individually or in combination) targeting all splice variants of cacna1aa into fertilized zebrafish eggs resulted in dose-dependent mortality and decreased or absent touch response. Over 90% knockdown of cacna1aa on protein level induced epileptiform-like discharges in the optic tectum of larval zebrafish brains. Incubation of morphants with antiseizure drugs (sodium valproate, ethosuximide, lamotrigine, topiramate) significantly decreased the number and, in some cases, cumulative duration of epileptiform-like discharges. In this context, sodium valproate seemed to be the least effective. Carbamazepine did not affect the number and duration of epileptiform-like discharges. Altogether, our data indicate that cacna1aa loss-of-function zebrafish may be considered a new model of absence epilepsy and may prove useful both for the investigation of Cacna1a-mediated epileptogenesis and for in vivo drug screening.

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Miao, Qing-Long, Stefan Herlitze, Melanie D. Mark i Jeffrey L. Noebels. "Adult loss of Cacna1a in mice recapitulates childhood absence epilepsy by distinct thalamic bursting mechanisms". Brain 143, nr 1 (4.12.2019): 161–74. http://dx.doi.org/10.1093/brain/awz365.

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Abstract Inborn errors of CACNA1A-encoded P/Q-type calcium channels impair synaptic transmission, producing early and lifelong neurological deficits, including childhood absence epilepsy, ataxia and dystonia. Whether these impairments owe their pathologies to defective channel function during the critical period for thalamic network stabilization in immature brain remains unclear. Here we show that mice with tamoxifen-induced adult-onset ablation of P/Q channel alpha subunit (iKOp/q) display identical patterns of dysfunction, replicating the inborn loss-of-function phenotypes and, therefore demonstrate that these neurological defects do not rely upon developmental abnormality. Unexpectedly, unlike the inborn model, the adult-onset pattern of excitability changes believed to be pathogenic within the thalamic network is non-canonical. Specifically, adult ablation of P/Q channels does not promote Cacna1g-mediated burst firing or T-type calcium current (IT) in the thalamocortical relay neurons; however, burst firing in thalamocortical relay neurons remains essential as iKOp/q mice generated on a Cacna1g deleted background show substantially diminished seizure generation. Moreover, in thalamic reticular nucleus neurons, burst firing is impaired accompanied by attenuated IT. Interestingly, inborn deletion of thalamic reticular nucleus-enriched, human childhood absence epilepsy-linked gene Cacna1h in iKOp/q mice reduces thalamic reticular nucleus burst firing and promotes rather than reduces seizure, indicating an epileptogenic role for loss-of-function Cacna1h gene variants reported in human childhood absence epilepsy cases. Together, our results demonstrate that P/Q channels remain critical for maintaining normal thalamocortical oscillations and motor control in the adult brain, and suggest that the developmental plasticity of membrane currents regulating pathological rhythmicity is both degenerate and age-dependent.

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Bolte, Kristen N., Melissa Assaf, Tamara Zach i Shubhangi Peche. "Two Children with Early-Onset Strokes and Intractable Epilepsy, Both with CACNA1A Mutations". Child Neurology Open 9 (styczeń 2022): 2329048X2210949. http://dx.doi.org/10.1177/2329048x221094977.

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Background: Mutations in the CACNA1A gene have been associated phenotypically with Familial Hemiplegic Migraine Type 1, Episodic Ataxia Type 2, Idiopathic Generalized Epilepsy, and Developmental and Epileptic Encephalopathy 42. Only six cases have linked ischemic strokes to mutations in the CACNA1A gene. Summary of Cases: We describe two unrelated patients who were found to have different mutations of the CACNA1A gene, one being a novel mutation, as shown by whole exome sequencing. One presented with seizures at birth and the other with seizures at 17 months old, both eventually exhibiting intractable epilepsy, ischemic stroke, and developmental delays. Results: Whole exome sequencing demonstrated de novo pathogenic mutations in the CACNA1A gene, which both caused similar phenotypes in unrelated patients. Conclusion: Pediatric patients who present with ischemic stroke and a history of seizures should be evaluated for CACNA1A mutations, as prompt recognition can help providers facilitate appropriate medical management.

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Maksemous, Neven, Heidi G. Sutherland, Robert A. Smith, Larisa M. Haupt i Lyn R. Griffiths. "Comprehensive Exonic Sequencing of Known Ataxia Genes in Episodic Ataxia". Biomedicines 8, nr 5 (25.05.2020): 134. http://dx.doi.org/10.3390/biomedicines8050134.

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Episodic Ataxias (EAs) are a small group (EA1–EA8) of complex neurological conditions that manifest as incidents of poor balance and coordination. Diagnostic testing cannot always find causative variants for the phenotype, however, and this along with the recently proposed EA type 9 (EA9), suggest that more EA genes are yet to be discovered. We previously identified disease-causing mutations in the CACNA1A gene in 48% (n = 15) of 31 patients with a suspected clinical diagnosis of EA2, and referred to our laboratory for CACNA1A gene testing, leaving 52% of these cases (n = 16) with no molecular diagnosis. In this study, whole exome sequencing (WES) was performed on 16 patients who tested negative for CACNA1A mutations. Tiered analysis of WES data was performed to first explore (Tier-1) the ataxia and ataxia-associated genes (n = 170) available in the literature and databases for comprehensive EA molecular genetic testing; we then investigated 353 ion channel genes (Tier-2). Known and potential causal variants were identified in n = 8/16 (50%) patients in 8 genes (SCN2A, p.Val1325Phe; ATP1A3, p.Arg756His; PEX7, p.Tyr40Ter; and KCNA1, p.Arg167Met; CLCN1, p.Gly945ArgfsX39; CACNA1E, p.Ile614Val; SCN1B, p.Cys121Trp; and SCN9A, p.Tyr1217Ter). These results suggest that mutations in these genes might cause an ataxia phenotype or that combinations of more than one mutation contribute to ataxia disorders.

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Isaacs, David Alan, Michael J. Bradshaw, Kelly Brown i Peter Hedera. "Case report of novel CACNA1A gene mutation causing episodic ataxia type 2". SAGE Open Medical Case Reports 5 (1.01.2017): 2050313X1770604. http://dx.doi.org/10.1177/2050313x17706044.

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Background: Episodic ataxia type 2 (OMIM 108500) is an autosomal dominant channelopathy characterized by paroxysms of ataxia, vertigo, nausea, and other neurologic symptoms. More than 50 mutations of the CACNA1A gene have been discovered in families with episodic ataxia type 2, although 30%–50% of all patients with typical episodic ataxia type 2 phenotype have no detectable mutation of the CACNA1A gene. Case: A 46-year-old Caucasian man, with a long history of bouts of imbalance, vertigo, and nausea, presented to our hospital with 2 weeks of ataxia and headache. Subsequent evaluation revealed a novel mutation in the CACNA1A gene: c.1364 G > A Arg455Gln. Acetazolamide was initiated with symptomatic improvement. Conclusion: This case report expands the list of known CACNA1A mutations associated with episodic ataxia type 2.

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Mannerak, Mari Aaroe, Aslan Lashkarivand i Per Kristian Eide. "Trigeminal neuralgia and genetics: A systematic review". Molecular Pain 17 (styczeń 2021): 174480692110161. http://dx.doi.org/10.1177/17448069211016139.

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Trigeminal neuralgia (TN) is a severe facial pain disease of unknown cause and unclear genetic background. To examine the existing knowledge about genetics in TN, we performed a systematic study asking about the prevalence of familial trigeminal neuralgia, and which genes that have been identified in human TN studies and in animal models of trigeminal pain. MedLine, Embase, Cochrane Library and Web of Science were searched from inception to January 2021. 71 studies were included in the systematic review. Currently, few studies provide information about the prevalence of familial TN; the available evidence indicates that about 1–2% of TN cases have the familial form. The available human studies propose the following genes to be possible contributors to development of TN: CACNA1A, CACNA1H, CACNA1F, KCNK1, TRAK1, SCN9A, SCN8A, SCN3A, SCN10A, SCN5A, NTRK1, GABRG1, MPZ gene, MAOA gene and SLC6A4. Their role in familial TN still needs to be addressed. The experimental animal studies suggest an emerging role of genetics in trigeminal pain, though the animal models may be more relevant for trigeminal neuropathic pain than TN per se. In summary, this systematic review suggests a more important role of genetic factors in TN pathogenesis than previously assumed.

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Sjöstrand, C., V. Giedratis, K. Ekbom, E. Waldenlind i J. Hillert. "CACNA1A Gene Polymorphisms in Cluster Headache". Cephalalgia 21, nr 10 (grudzień 2001): 953–58. http://dx.doi.org/10.1046/j.1468-2982.2001.00281.x.

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Cluster headache (CH) is a primary headache disorder where the aetiological and pathophysiological mechanisms still are largely unknown. An increased risk of CH in first- and second-degree relatives suggests the importance of genetic factors. Mutations of the P/Q type calcium channel alpha 1 subunit (CACNA1A) gene on chromosome 19p13 have been shown to cause several neurological disorders with a wide clinical spectrum, mainly episodic diseases. Missence mutations of the gene cause familial hemiplegic migraine (FHM) and it is also likely to be involved in the more common forms of migraine. The CACNA1A gene is thus a promising candidate gene for CH. In this study we performed an association analysis of an intragenic polymorphic (CA)n-repeat with marker D19S1150 and a (CAG)n-repeat in the 3′UTR region, in 75 patients with CH according to IHS criteria and 108 matched controls. Genotypes and allele frequencies were similarly distributed in patients and controls. Linkage disequilibrium between the two markers was similar in patients and controls. We conclude that an importance of the CACNA1A gene in sporadic CH is unlikely.

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Thomsen, LL, E. Oestergaard, A. Bjornsson, H. Stefansson, AC Fasquel, J. Gulcher, K. Stefansson i J. Olesen. "Screen for CACNA1A and ATP1A2 Mutations in Sporadic Hemiplegic Migraine Patients". Cephalalgia 28, nr 9 (wrzesień 2008): 914–21. http://dx.doi.org/10.1111/j.1468-2982.2008.01599.x.

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The aim of this study was to investigate the involvement of the CACNA1A and ATP1A2 gene in a population-based sample of sporadic hemiplegic migraine (SHM). Patients with SHM ( n = 105) were identified in a nationwide search in the Danish population. We sequenced all exons and promoter regions of the CACNA1A and ATP1A2 genes in 100 patients with SHM to search for possible SHM mutations. Novel DNA variants were discovered in eight SHM patients, four in exons of the CACNA1A gene and four in exons of the ATP1A2 gene. Six of the variants were considered non-pathogenic. The causal role of the two remaining DNA variants is unknown until functional studies have been made or independent genetic evidence is discovered. Only very few DNA variants were identified in 100 SHM patients, and regardless of whether the identified variants are causal the CACNA1A and ATP1A2 genes are not major genes in SHM.

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Haan, J., JA van Vliet, EE Kors, GM Terwindt, FLMG Vermeulen, AMJM van den Maagdenberg, RR Frants i MD Ferrari. "No Involvement of the Calcium Channel Gene (CACNA1A) in a Family with Cluster Headache". Cephalalgia 21, nr 10 (grudzień 2001): 959–62. http://dx.doi.org/10.1046/j.1468-2982.2001.00283.x.

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It is very likely that genetic factors play a role in the pathophysiology of cluster headache (CH). As CH shares its paroxysmal character with migraine, and migraine has been described in coexistence with CH in some families, we hypothesized that both diseases might share a genetic aetiology. In this study, we tested whether the migraine CACNA1A gene on chromosome 19 is involved in CH in an extended pedigree. Haplotype analysis did not reveal an obvious disease haplotype, and SSCP analysis of all 47 exons of the CACNA1A gene did not reveal a causative mutation. CH in this family is not caused by mutations in the CACNA1A gene.

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Cleves, C., S. Parikh, AD Rothner i SJ Tepper. "Link between confusional migraine, hemiplegic migraine and episodic ataxia type 2: Hypothesis, family genealogy, gene typing and classification". Cephalalgia 30, nr 6 (1.08.2009): 740–43. http://dx.doi.org/10.1111/j.1468-2982.2009.01958.x.

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An association between hemiplegic migraine (HM) and episodic ataxia type 2 (EA2) has been described; both disorders are linked to mutations in the CACNA1A gene. Although confusion occurs in 21% of patients with HM, we found only one case in the literature of confusional episodes associated with ataxia without hemiplegia. These findings raise the possibility of confusional episodes being part of both the HM and EA2 phenotype. However, a patient with episodic ataxia, confusional spells and CACNA1A gene mutations has not been identified. We describe four individuals, spanning three generations of a family, with episodic ataxia without hemiplegia and confusion, in association with a CACNA1A mutation. We follow with a description of the relationship between the CACNA1A mutations and the three syndromes, suggesting a potential need for a new classification in which the conditions can be subsumed.

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de Vries, B., AH Stam, F. Beker, AMJM van den Maagdenberg, KRJ Vanmolkot, LAEM Laan, IB Ginjaar i in. "CACNA1A Mutation Linking Hemiplegic Migraine and Alternating Hemiplegia of Childhood". Cephalalgia 28, nr 8 (sierpień 2008): 887–91. http://dx.doi.org/10.1111/j.1468-2982.2008.01596.x.

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Familial hemiplegic migraine (FHM) and alternating hemiplegia of childhood (AHC) are severe neurological disorders that share clinical features. Therefore, FHM genes are candidates for AHC. We performed mutation analysis in the CACNA1A gene in a monozygotic twin pair with clinical features overlapping with both AHC and FHM and identified a novel de novo CACNA1A mutation. We provide the first evidence that a CACNA1A mutation can cause atypical AHC, indicating an overlap of molecular mechanisms causing AHC and FHM. These results also suggest that CACNA1A mutation scanning is indicated in patients with a severe neurological phenotype that includes paroxysmal (alternating) hemiplegia.

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van den Maagdenberg, Arn M. J. M., Joerg Striessnig, Michel D. Ferrari i Rune R. Frants. "CACNA1A gene mutations in familial hemiplegic migraine". Journal of Headache and Pain 1, S2 (grudzień 2000): S121—S128. http://dx.doi.org/10.1007/s101940070005.

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Prontera, P., P. Sarchielli, S. Caproni, C. Bedetti, LM Cupini, P. Calabresi i C. Costa. "Epilepsy in hemiplegic migraine: Genetic mutations and clinical implications". Cephalalgia 38, nr 2 (6.01.2017): 361–73. http://dx.doi.org/10.1177/0333102416686347.

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Objective We performed a systematic review on the comorbidities of familial/sporadic hemiplegic migraine (F/SHM) with seizure/epilepsy in patients with CACNA1A, ATP1A2 or SCN1A mutations, to identify the genotypes associated and investigate for the presence of mutational hot spots. Methods We performed a search in MEDLINE and in the Human Gene Mutation and Leiden Open Variation Databases for mutations in the CACNA1A, ATP1A2 and SCN1A genes. After having examined the clinical characteristics of the patients, we selected those having HM and seizures, febrile seizures or epilepsy. For each gene, we determined both the frequency and the positions at protein levels of these mutations, as well as the penetrance of epilepsy within families. Results Concerning F/SHM-Epilepsy1 (F/SHME1) and F/SHME2 endophenotypes, we observed a prevalent involvement of the transmembrane domains, and a strong correlation in F/SHME1 when the positively charged amino acids were involved. The penetrance of epilepsy within the families was highest for patients carrying mutation in the CACNA1A gene (60%), and lower in those having SCN1A (33.3%) and ATP1A2 (30.9%) mutations. Conclusion Among the HM cases with seizure/epilepsy, we observed mutational hot spots in the transmembrane domains of CACNA1A and ATP1A2 proteins. These findings could lead to a better understanding of the pathological mechanisms underlying migraine and epilepsy, therein guaranteeing the most appropriate therapeutic approach.

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Geerlings, Rianne PJ, Peter J. Koehler, Danielle YP Haane, Anine H. Stam, Boukje de Vries, Elles MJ Boon i Joost Haan. "Head tremor related to CACNA1A mutations". Cephalalgia 31, nr 12 (18.07.2011): 1315–19. http://dx.doi.org/10.1177/0333102411414442.

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Introduction: Familial hemiplegic migraine (FHM) is characterized by the familial occurrence of migraine attacks with fully reversible transient hemiplegia. Mutations in three different genes have been identified; CACNA1A (FHM1), ATP1A2 (FHM2) and SCN1A (FHM3). Besides hemiplegia, several other symptoms have been described in FHM 1–3 mutation carriers, including epilepsy and cerebellar symptoms. Case report: We describe two patients in whom hemiplegic attacks were not the presenting symptom, but in whom an otherwise unexplained head tremor led us to search for FHM mutations. Both patients carried a mutation in the CACNA1A gene. Discussion: CACNA1A mutations can give significant symptoms other than (hemiplegic) migraine as reason for presentation.

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Maksemous, Neven, Robert A. Smith, Heidi G. Sutherland, Bridget H. Maher, Omar Ibrahim, Garth A. Nicholson, Elisabeth P. Carpenter, Rod A. Lea, M. Zameel Cader i Lyn R. Griffiths. "Targeted next generation sequencing identifies a genetic spectrum of DNA variants in patients with hemiplegic migraine". Cephalalgia Reports 2 (1.01.2019): 251581631988163. http://dx.doi.org/10.1177/2515816319881630.

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Objective: Hemiplegic migraine in both familial (FHM) and sporadic (SHM) forms is a rare subtype of migraine with aura that can be traced to mutations in the CACNA1A, ATP1A2 and SCN1A genes. It is characterised by severe attacks of typical migraine accompanied by hemiparesis, as well as episodes of complex aura that vary significantly between individuals. Methods: Using a targeted next generation sequencing (NGS) multigene panel, we have sequenced the genomic DNA of 172 suspected hemiplegic migraine cases, in whom no mutation had previously been found by Sanger sequencing (SS) of a limited number of exons with high mutation frequency in FHM genes. Results: Genetic screening identified 29 variants, 10 of which were novel, in 35 cases in the three FHM genes ( CACNA1A, ATP1A2 and SCN1A). Interestingly, in this suspected HM cohort, the ATP1A2 gene harboured the highest number of variants with 24/35 cases (68.6%), while CACNA1A ranked the second gene, with 5 variants identified in 7/35 cases (20%). All detected variants were confirmed by SS and were absent in 100 non-migraine healthy control individuals. Assessment of variants with the American College of Medical Genetics and Genomics guidelines classified 8 variants as pathogenic, 3 as likely pathogenic and 18 as variants of unknown significance. Targeted NGS gene panel increased the diagnostic yield by fourfold over iterative SS in our diagnostics facility. Conclusion: We have identified 29 potentially causative variants in an Australian and New Zealand cohort of suspected HM cases and found that the ATP1A2 gene was the most commonly mutated gene. Our results suggest that screening using NGS multigene panels to investigate ATP1A2 alongside CACNA1A and SCN1A is a clinically useful and efficient method.

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Stubberud, Anker, Emer O’Connor, Erling Tronvik, Henry Houlden i Manjit Matharu. "R1352Q CACNA1A Variant in a Patient with Sporadic Hemiplegic Migraine, Ataxia, Seizures and Cerebral Oedema: A Case Report". Case Reports in Neurology 13, nr 1 (16.02.2021): 123–30. http://dx.doi.org/10.1159/000512275.

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Mutations in the CACNA1A gene show a wide range of neurological phenotypes including hemiplegic migraine, ataxia, mental retardation and epilepsy. In some cases, hemiplegic migraine attacks can be triggered by minor head trauma and culminate in encephalopathy and cerebral oedema. A 37-year-old male without a family history of complex migraine experienced hemiplegic migraine attacks from childhood. The attacks were usually triggered by minor head trauma, and on several occasions complicated with encephalopathy and cerebral oedema. Genetic testing of the proband and unaffected parents revealed a de novo heterozygous nucleotide missense mutation in exon 25 of the CACNA1A gene (c.4055G>A, p.R1352Q). The R1352Q CACNA1A variant shares the phenotype with other described CACNA1A mutations and highlights the interesting association of trauma as a precipitant for hemiplegic migraine. Subjects with early-onset sporadic hemiplegic migraine triggered by minor head injury or associated with seizures, ataxia or episodes of encephalopathy should be screened for mutations. These patients should also be advised to avoid activities that may result in head trauma, and anticonvulsants should be considered as prophylactic migraine therapy.

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Maksemous, Neven, Robert Smith, Heidi Sutherland, Hugo Sampaio i Lyn Griffiths. "Whole-Exome Sequencing Implicates SCN2A in Episodic Ataxia, but Multiple Ion Channel Variants May Contribute to Phenotypic Complexity". International Journal of Molecular Sciences 19, nr 10 (11.10.2018): 3113. http://dx.doi.org/10.3390/ijms19103113.

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Although the clinical use of targeted gene sequencing-based diagnostics is valuable, whole-exome sequencing has also emerged as a successful diagnostic tool in molecular genetics laboratories worldwide. Molecular genetic tests for episodic ataxia type 2 (EA2) usually target only the specific calcium channel gene (CACNA1A) that is known to cause EA2. In cases where no mutations are identified in the CACNA1A gene, it is important to identify the causal gene so that more effective treatment can be prioritized for patients. Here we present a case of a proband with a complex episodic ataxias (EA)/seizure phenotype with an EA-affected father; and an unaffected mother, all negative for CACNA1A gene mutations. The trio was studied by whole-exome sequencing to identify candidate genes responsible for causing the complex EA/seizure phenotype. Three rare or novel variants in Sodium channel α2-subunit; SCN2A (c.3973G>T: p.Val1325Phe), Potassium channel, Kv3.2; KCNC2 (c.1006T>C: p.Ser336Pro) and Sodium channel Nav1.6; SCN8A (c.3421C>A: p.Pro1141Thr) genes were found in the proband. While the SCN2A variant is likely to be causal for episodic ataxia, each variant may potentially contribute to the phenotypes observed in this family. This study highlights that a major challenge of using whole-exome/genome sequencing is the identification of the unique causative mutation that is associated with complex disease.

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Jaudon, Fanny, Simona Baldassari, Ilaria Musante, Agnes Thalhammer, Federico Zara i Lorenzo A. Cingolani. "Targeting Alternative Splicing as a Potential Therapy for Episodic Ataxia Type 2". Biomedicines 8, nr 9 (5.09.2020): 332. http://dx.doi.org/10.3390/biomedicines8090332.

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Episodic ataxia type 2 (EA2) is an autosomal dominant neurological disorder characterized by paroxysmal attacks of ataxia, vertigo, and nausea that usually last hours to days. It is caused by loss-of-function mutations in CACNA1A, the gene encoding the pore-forming α1 subunit of P/Q-type voltage-gated Ca2+ channels. Although pharmacological treatments, such as acetazolamide and 4-aminopyridine, exist for EA2, they do not reduce or control the symptoms in all patients. CACNA1A is heavily spliced and some of the identified EA2 mutations are predicted to disrupt selective isoforms of this gene. Modulating splicing of CACNA1A may therefore represent a promising new strategy to develop improved EA2 therapies. Because RNA splicing is dysregulated in many other genetic diseases, several tools, such as antisense oligonucleotides, trans-splicing, and CRISPR-based strategies, have been developed for medical purposes. Here, we review splicing-based strategies used for genetic disorders, including those for Duchenne muscular dystrophy, spinal muscular dystrophy, and frontotemporal dementia with Parkinsonism linked to chromosome 17, and discuss their potential applicability to EA2.

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Debiais, S., C. Hommet, I. Bonnaud, MA Barthez, S. Rimbaux, F. Riant i A. Autret. "The FHM1 Mutation S218L: A Severe Clinical Phenotype? A Case Report and Review of the Literature". Cephalalgia 29, nr 12 (grudzień 2009): 1337–39. http://dx.doi.org/10.1111/j.1468-2982.2009.01884.x.

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Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura that is characterized by motor weakness during attacks. FHM1 is associated with mutations in the CACNA1A gene located on chromosome 19. We report a severe, prolonged HM attack in a young pregnant patient who had the S218L FHM1. This CACNA1A mutation has been associated with HM, delayed cerebral oedema and coma following minor head trauma. The case history we report suggests a specific, severe phenotype and the co-occurrence of HM and epilepsy related to the S218L FHM1 mutation.

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Bruun, Marie, Lena Elisabeth Hjermind, Carsten Thomsen, Else Danielsen, Lise Lykke Thomsen, Lars Hageman Pinborg, Nastaran Khabbazbavani i Joergen Erik Nielsen. "Familial Hemiplegic Migraine Type 1 Associated with Parkinsonism: A Case Report". Case Reports in Neurology 7, nr 1 (14.04.2015): 84–89. http://dx.doi.org/10.1159/000381827.

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Familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) are allelic disorders caused by mutations in the CACNA1A gene on chromosome 19p13. It is well described that FHM1 can present with cerebellar signs, but parkinsonism has not previously been reported in FHM1 or EA2 even though parkinsonism has been described in SCA6. We report a 63-year-old woman with FHM1 caused by an R583Q mutation in the CACNA1A gene, clinically presenting with migraine and permanent cerebellar ataxia. Since the age of 60 years, the patient also developed parkinsonism with rigidity, bradykinesia and a resting tremor. An MRI showed a normal substantia nigra, but a bilateral loss of substance in the basal ganglia, which is in contrast to the typically normal MRI in idiopathic Parkinson's disease. Dopamine transporter (DAT) imaging with single-photon emission computed tomography demonstrated a decreased DAT-binding potential in the putamen. We wish to draw attention to FHM1 associated with parkinsonism; however, whether the reported case is a consequence of FHM1 being allelic to SCA6, unknown modifiers to the specific R583Q CACNA1A mutation or idiopathic Parkinson's disease remains unanswered.

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Pelzer, Nadine, Joost Haan, Anine H. Stam, Lisanne S. Vijfhuizen, Stephany C. Koelewijn, Amber Smagge, Boukje de Vries, Michel D. Ferrari, Arn M. J. M. van den Maagdenberg i Gisela M. Terwindt. "Clinical spectrum of hemiplegic migraine and chances of finding a pathogenic mutation". Neurology 90, nr 7 (17.01.2018): e575-e582. http://dx.doi.org/10.1212/wnl.0000000000004966.

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ObjectiveTo investigate whether the clinical characteristics of patients with hemiplegic migraine with and without autosomal dominant mutations in CACNA1A, ATP1A2, or SCN1A differ, and whether the disease may be caused by mutations in other genes.MethodsWe compared the clinical characteristics of 208 patients with familial (n = 199) or sporadic (n = 9) hemiplegic migraine due to a mutation in CACNA1A, ATP1A2, or SCN1A with those of 73 patients with familial (n = 49) or sporadic (n = 24) hemiplegic migraine without a mutation in these genes. In addition, 47 patients (familial: n = 33; sporadic: n = 14) without mutations in CACNA1A, ATP1A2, or SCN1A were scanned for mutations in novel genes using whole exome sequencing.ResultsPatients with mutations in CACNA1A, ATP1A2, or SCN1A had a lower age at disease onset, larger numbers of affected family members, and more often attacks (1) triggered by mild head trauma, (2) with extensive motor weakness, and (3) with brainstem features, confusion, and brain edema. Mental retardation and progressive ataxia were exclusively found in patients with a mutation. Whole exome sequencing failed to identify pathogenic mutations in new genes.ConclusionsMost patients with hemiplegic migraine without a mutation in CACNA1A, ATP1A2, or SCN1A display a mild phenotype that is more akin to that of common (nonhemiplegic) migraine. A major fourth autosomal dominant gene for hemiplegic migraine remains to be identified. Our observations might guide physicians in selecting patients for mutation screening and in providing adequate genetic counseling.

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Lopes, Luciana R., Mario Fernando Prieto Peres, Kaate R. J. Vanmolkot, Patrícia R. Tobo, Eliova Zukerman, Rune R. Frants, Arn M. J. M. van den Maagdenberg i Carlos Alberto Moreira-Filho. "Mutation analysis of CACNA1A and ATP1A2 genes in Brazilian FHM families". Arquivos de Neuro-Psiquiatria 64, nr 3a (wrzesień 2006): 549–52. http://dx.doi.org/10.1590/s0004-282x2006000400001.

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Familial hemiplegic migraine (FHM) is a rare autosomal dominant form of migraine with aura. This disease has been associated with missense mutations in the CACNA1A and ATP1A2 genes. The aim of this study was to identify whether CACNA1A and ATP1A2 are or not related to Brazilian FHM. Here we screened four Brazilian FHM families (total of 26 individuals - 13 affected and 13 asymptomatic or normal) for mutations in both genes. We found an amino acid change in a member of family FHM-D (Arg2206Gly). However since this alteration is not present in all affected individuals and is present in one asymptomatic individual it should be considered a polymorphism. Further studies with additional families will be necessary to reveal the importance of both CACNA1A and ATP1A2 genes on the pathogeneses of FHM in Brazil and to test the third gene (SCN1A) in these FHM families.

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Camia, Francesca, Livia Pisciotta, Giovanni Morana, Maria Cristina Schiaffino, Salvatore Renna, Paola Carrera, Maurizio Ferrari i in. "Combined early treatment in hemiplegic attacks related to CACNA1A encephalopathy with brain oedema: Blocking the cascade?" Cephalalgia 37, nr 12 (19.09.2016): 1202–6. http://dx.doi.org/10.1177/0333102416668655.

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Introduction Variants in the CACNA1A gene on chromosome 19p13 result in a spectrum of neurological phenotypes ranging from familial or sporadic hemiplegic migraine to congenital or progressive encephalopathies. Patients with CACNA1A variants often show acute attacks with ataxia or hemiplegia till coma, sometimes related to unilateral brain oedema. No guidelines for the medical management of these attacks are available since treatment is empiric, and many cases do not respond to common antimigraine drugs. Case description We report on the emergency personalized treatment protocol used in an 11 year-old girl with CACNA1A-related encephalopathy for the management of acute attacks of headache, hemiconvulsions and hemiplegia with coma. Discussion Combined corticosteroid pulses and hypertonic solution led to a reduction in severity and duration of acute attacks when administered in the early stages, characterized by migraine, seizure, fever, vomiting and impairment of consciousness associated to hemispheric slowing on the EEG.

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Stendel, Claudia, Maria Cristina D’Adamo, Manuela Wiessner, Marina Dusl, Marta Cenciarini, Silvia Belia, Ehsan Nematian-Ardestani i in. "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". International Journal of Molecular Sciences 21, nr 11 (27.05.2020): 3810. http://dx.doi.org/10.3390/ijms21113810.

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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 > 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.

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Stuart, Shani, Bishakha Roy, Gail Davies, Nevene Maksemous, Robert Smith i Lyn R. Griffiths. "Detection of a Novel Mutation in the CACNA1A gene". Twin Research and Human Genetics 15, nr 1 (luty 2012): 120–25. http://dx.doi.org/10.1375/twin.15.1.120.

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Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. It is divided into three subtypes FHM1, FHM2 and FHM3, which are caused by mutations in the CACNA1A, ATP1A2 and SCN1A genes respectively. As part of a regular diagnostic service, we investigated 168 patients with FHM symptoms. Samples were tested for mutations contained within the CACNA1A gene. Some tested samples (4.43%) showed an FHM1 mutation, with five of the mutations found in exon 5, one mutation in exon 16 and one in exon 17. Four polymorphisms were also detected, one of which occurred in a large percentage of samples (14.88%). The exon 16 2094G>A polymorphism, however, has been found to occur in healthy Caucasian control populations up to a frequency of 16% and is not considered to be significantly associated with FHM. A finding of significance, found in a single patient, was the detection of a novel mutation in exon 5 that results in a P225H change. The affected individual was an 8-year-old female. The exact phenotypic effect of this mutation is unknown, and further studies are needed to understand the pathophysiology of this mutation in FHM1. New information will allow for diagnostic procedures to be constantly updated, thus improving accuracy of diagnosis. It is possible that new information will also aid the development of new therapeutic agents for the treatment of FHM.

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Zhang, Yang, Ning Chen, Muke Zhou, Jian Guo, Jiang Guo i Li He. "A novel SCN1A mutation identified in a Chinese family with familial hemiplegic migraine: A case report". Cephalalgia 37, nr 13 (12.11.2016): 1294–98. http://dx.doi.org/10.1177/0333102416677049.

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Background Familial hemiplegic migraine (FHM) is a rare type of migraine with aura that is characterized by transient hemiparesis. Mutations in three genes (CACNA1A, ATP1A2, and SCN1A) have been found to cause FHM. Among these, nine SCN1A gene mutations were reported to cause familial hemiplegic migraine type 3 (FHM3). However, none of them was reported in China. Method The clinical manifestations of a Chinese FHM family were recorded and all coding exons and flanking intronic regions of the CACNA1A, ATP1A2, and SCN1A genes were tested for mutations. Results All FHM patients in the investigated family have typical hemiplegic migraine attacks characteristic of FHM. We identified a novel mutation (p.Leu1670Trp) of the SCN1A gene. The affected amino acid is highly conserved across different species and therefore likely plays an important role in SCN1A gene function. Conclusion The identification of a novel mutation in the SCN1A gene in the Chinese population may further aid in the understanding of FHM genetics.

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Zhang, Lin, Yun Sun, Xiaochao Zhang, Xiyun Shan, Jianmei Li, Yao Yao, Yun Shu i in. "Three Novel Genetic Variants in the FAM110D, CACNA1A, and NLRP12 Genes Are Associated With Susceptibility to Hypertension Among Dai People". American Journal of Hypertension 34, nr 8 (23.02.2021): 874–79. http://dx.doi.org/10.1093/ajh/hpab040.

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Abstract BACKGROUND Although the genetic factors associated with hypertension remain unknown, genetic variations in genes related to ion channels, inflammation, and the cell cycle may affect susceptibility to hypertension. In the present study, the association between hypertension and 10 candidate single-nucleotide polymorphisms (SNPs) was evaluated among Chinese Dai people, who have a smaller gene pool than Han individuals. METHODS A total of 1,193 samples from Dai people were collected, including 488 with hypertension and 705 with normal blood pressure. Based on the preliminary results of whole-genome sequencing among pools of individuals (Pool-seq), 10 candidate SNPs in 6 genes (FAM110D, ADD1, RAG1, CACNA1C, CACNA1A, and NLRP12) were genotyped in the case and control groups by multiplex PCR for SNP genotyping with next-generation sequencing (MultiPCR-NGS). The relationship between hypertension and each candidate SNP was evaluated using the χ 2 test and multiple logistic regression analysis. RESULTS The χ 2 test showed that the allele frequencies of rs3748856 in FAM110D, rs139118504 in CACNA1A, and rs34436714 in NLRP12 were significantly different between the case and control groups (P < 0.005). After adjusting for age, body mass index, total cholesterol, triglyceride, and low-density lipoprotein, logistic regression analyses revealed that the association between the 3 SNPs and hypertension among Dai people remained significant (P = 0.012, 2.71 × 10−4, and 0.017, respectively). CONCLUSIONS These findings indicate that there may be different molecular pathogeneses of hypertension among Dai people, which should be noted in future studies.

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Malamud, Emily, i Scott I. Otallah. "Use of Dalfampridine in a Young Child with Episodic Ataxia Type 2". Child Neurology Open 9 (styczeń 2022): 2329048X2210754. http://dx.doi.org/10.1177/2329048x221075447.

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Episodic ataxia type 2 (EA2) is a rare autosomal dominant disorder associated with mutations of the CACNA1A gene. 1 Because there is no curative therapy available, EA2 is typically managed symptomatically. First line treatment has typically been with acetazolamide. 2 Dalfampridine has also been noted to decrease the frequency and duration of ataxic attacks in patients ranging in age from adolescence through adulthood. 3 , 4 The efficacy and dosing of dalfampridine has not yet been studied in younger pediatric populations. The lack of published experience in younger children can and has led to these patients going without potentially safe and effective treatment. Thus, we describe an 8-year-old girl with EA2 and a confirmed CACNA1A gene mutation whose symptoms had been previously unrelieved by acetazolamide. She was subsequently trialed on dalfampridine and experienced symptomatic relief at a dose of 0.3 mg/kg.

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Sleigh, Jamie W., Kate Leslie, Andrew J. Davidson, David J. Amor, Peter Diakumis, Vesna Lukic, Paul J. Lockhart i Melanie Bahlo. "Genetic Analysis of Patients Who Experienced Awareness with Recall while under General Anesthesia". Anesthesiology 131, nr 5 (1.11.2019): 974–82. http://dx.doi.org/10.1097/aln.0000000000002877.

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Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Intraoperative awareness with recall while under apparently adequate general anesthesia is a rare, unexplained, and often very distressing phenomenon. It is possible that a relatively small number of genetic variants might underlie the failure of general anesthetic drugs to adequately suppress explicit memory formation and recall in the presence of apparently adequate anesthesia concentrations. Methods The authors recruited 12 adult patients who had experienced an episode of intraoperative awareness with recall (compared with 12 controls), performed whole exome sequencing, and applied filtering to obtain a set of genetic variants that might be associated with intraoperative awareness with recall. The criteria were that the variant (1) had a minor allele frequency less than 0.1% in population databases, (2) was within exonic or splicing regions, (3) caused a nonsynonymous change, (4) was predicted to be functionally damaging, (5) was expressed in the top 50% of genes expressed in the brain, and (6) was within genes in Kyoto Encyclopedia of Genes and Genomes pathways associated with general anesthesia, drug metabolism, arousal, and memory. Results The authors identified 29 rare genetic variants in 27 genes that were absent in controls and could plausibly be associated with this disorder. One variant in CACNA1A was identified in two patients and two different variants were identified in both CACNA1A and CACNA1S. Of interest was the relative overrepresentation of variants in genes encoding calcium channels and purinergic receptors. Conclusions Within the constraints of the filtering process used, the authors did not find any single gene variant or gene that was strongly associated with intraoperative awareness with recall. The authors report 27 candidate genes and associated pathways identified in this pilot project as targets of interest for future larger biologic and epidemiologic studies.

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Wani, IrfanYousuf, Aadil Bashir, Shiekh Saleem, Maqbool Wani, Roohi Rasool, Azhara Gulnar i Sawan Verma. "Association of single nucleotide polymorphisms of CACNA1A gene in migraine". Indian Journal of Human Genetics 20, nr 1 (2014): 59. http://dx.doi.org/10.4103/0971-6866.132757.

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Zangaladze, Andro, Ali A. Asadi-Pooya, Avi Ashkenazi i Michael R. Sperling. "Sporadic hemiplegic migraine and epilepsy associated with CACNA1A gene mutation". Epilepsy & Behavior 17, nr 2 (luty 2010): 293–95. http://dx.doi.org/10.1016/j.yebeh.2009.12.017.

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Brugnoni, R., M. Leone, A. Rigamonti, E. Moranduzzo, F. Cornelio, R. Mantegazza i G. Bussone. "Is the CACNA1A gene involved in familial migraine with aura?" Neurological Sciences 23, nr 1 (kwiecień 2002): 1–5. http://dx.doi.org/10.1007/s100720200015.

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Nikaido, Koki, Nobutada Tachi, Kazuhiro Ohya, Takahito Wada i Hiroyuki Tsutsumi. "New mutation of CACNA1A gene in episodic ataxia type 2". Pediatrics International 53, nr 3 (czerwiec 2011): 415–16. http://dx.doi.org/10.1111/j.1442-200x.2011.03390.x.

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Kors, E. E., J. Haan, N. J. Giffin, L. Pazdera, C. Schnittger, G. G. Lennox, G. M. Terwindt i in. "Expanding the Phenotypic Spectrum of the CACNA1A Gene T666M Mutation". Archives of Neurology 60, nr 5 (1.05.2003): 684. http://dx.doi.org/10.1001/archneur.60.5.684.

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Stahl, John S., i Zachary C. Thumser. "Flocculus Purkinje cell signals in mouse Cacna1a calcium channel mutants of escalating severity: an investigation of the role of firing irregularity in ataxia". Journal of Neurophysiology 112, nr 10 (15.11.2014): 2647–63. http://dx.doi.org/10.1152/jn.00129.2014.

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Mutation of the Cacna1a gene for the P/Q (CaV2.1) calcium channel invariably leads to cerebellar dysfunction. The dysfunction has been attributed to disrupted rhythmicity of cerebellar Purkinje cells, but the hypothesis remains unproven. If irregular firing rates cause cerebellar dysfunction, then the irregularity and behavioral deficits should covary in a series of mutant strains of escalating severity. We compared firing irregularity in floccular and anterior vermis Purkinje cells in the mildly affected rocker and moderately affected tottering Cacna1a mutants and normal C57BL/6 mice. We also measured the amplitude and timing of modulations of floccular Purkinje cell firing rate during the horizontal vestibuloocular reflex (VOR, 0.25–1 Hz) and the horizontal and vertical optokinetic reflex (OKR, 0.125–1 Hz). We recorded Purkinje cells selective for rotational stimulation about the vertical axis (VAPCs) and a horizontal axis (HAPCs). Irregularity scaled with behavioral deficit severity in the flocculus but failed to do so in the vermis, challenging the irregularity hypothesis. Mutant VAPCs exhibited unusually strong modulation during VOR and OKR, the response augmentation scaling with phenotypic severity. HAPCs exhibited increased OKR modulation but in tottering only. The data contradict prior claims that modulation amplitude is unaffected in tottering but support the idea that attenuated compensatory eye movements in Cacna1a mutants arise from defective transfer of Purkinje cell signals to downstream circuitry, rather than attenuated synaptic transmission within the cerebellar cortex. Shifts in the relative sizes of the VAPC and HAPC populations raise the possibility that Cacna1a mutations influence the development of floccular zone architecture.

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Martínez-Monseny, Antonio F., Albert Edo, Dídac Casas-Alba, Mercè Izquierdo-Serra, Mercè Bolasell, David Conejo, Loreto Martorell i in. "CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings". International Journal of Molecular Sciences 22, nr 10 (13.05.2021): 5180. http://dx.doi.org/10.3390/ijms22105180.

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The CACNA1A gene encodes the pore-forming α1A subunit of the voltage-gated CaV2.1 Ca2+ channel, essential in neurotransmission, especially in Purkinje cells. Mutations in CACNA1A result in great clinical heterogeneity with progressive symptoms, paroxysmal events or both. During infancy, clinical and neuroimaging findings may be unspecific, and no dysmorphic features have been reported. We present the clinical, radiological and evolutionary features of three patients with congenital ataxia, one of them carrying a new variant. We report the structural localization of variants and their expected functional consequences. There was an improvement in cerebellar syndrome over time despite a cerebellar atrophy progression, inconsistent response to acetazolamide and positive response to methylphenidate. The patients shared distinctive facial gestalt: oval face, prominent forehead, hypertelorism, downslanting palpebral fissures and narrow nasal bridge. The two α1A affected residues are fully conserved throughout evolution and among the whole human CaV channel family. They contribute to the channel pore and the voltage sensor segment. According to structural data analysis and available functional characterization, they are expected to exert gain- (F1394L) and loss-of-function (R1664Q/R1669Q) effect, respectively. Among the CACNA1A-related phenotypes, our results suggest that non-progressive congenital ataxia is associated with developmental delay and dysmorphic features, constituting a recognizable syndromic neurodevelopmental disorder.

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Naik, Swati, Keith Pohl, Mohsin Malik, Ata Siddiqui i Dragana Josifova. "Early-Onset Cerebellar Atrophy Associated With Mutation in the CACNA1A Gene". Pediatric Neurology 45, nr 5 (listopad 2011): 328–30. http://dx.doi.org/10.1016/j.pediatrneurol.2011.08.002.

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Li, Weidong, Ying Zhou, Xiaoli Tian, Tae Yeon Kim, Namiko Ito, Kaori Watanabe, Akiko Tsuji i in. "New Ataxic Tottering-6j Mouse Allele Containing a Cacna1a Gene Mutation". PLoS ONE 7, nr 8 (31.08.2012): e44230. http://dx.doi.org/10.1371/journal.pone.0044230.

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Zielman, R., WM Teeuwisse, F. Bakels, J. Van der Grond, A. Webb, MA van Buchem, MD Ferrari, MC Kruit i GM Terwindt. "Biochemical changes in the brain of hemiplegic migraine patients measured with 7 tesla 1H-MRS". Cephalalgia 34, nr 12 (20.03.2014): 959–67. http://dx.doi.org/10.1177/0333102414527016.

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Aim The aim of this study was to assess biochemical changes in the brain of patients with hemiplegic migraine in between attacks. Methods Eighteen patients with hemiplegic migraine (M:F, 7:11; age 38 ± 14 years) of whom eight had a known familial hemiplegic migraine (FHM) mutation (five in the CACNA1A gene (FHM1), three in the ATP1A2 gene (FHM2)) and 19 age- and sex-matched healthy controls (M:F, 7:12; mean age 38 ± 12 years) were studied. We used single-voxel 7 tesla 1H-MRS (STEAM, TR/TM/TE = 2000/19/21 ms) to investigate four brain regions in between attacks: cerebellum, hypothalamus, occipital lobe, and pons. Results Patients with hemiplegic migraine showed a significantly lower total N-acetylaspartate/total creatine ratio (tNAA/tCre) in the cerebellum (median 0.73, range 0.59–1.03) than healthy controls (median 0.79, range (0.67–0.95); p = 0.02). In FHM1 patients with a CACNA1A mutation, the tNAA/tCre was lowest. Discussion We found a decreased cerebellar tNAA/tCre ratio that might serve as an early biomarker for neuronal dysfunction and/or loss. This is the first high-spectral resolution 7 tesla 1H-MRS study of interictal biochemical brain changes in hemiplegic migraine patients.

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Haan, J., EE Kors, GM Terwindt, FLMG Vermeulen, MN Vergouwe, AMJM van den Maagdenberg, DS Gill i in. "Alternating Hemiplegia of Childhood: No Mutations in the Familial Hemiplegic Migraine CACNA1A Gene". Cephalalgia 20, nr 8 (październik 2000): 696–700. http://dx.doi.org/10.1046/j.0333-1024.2000.00095.x.

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Introduction Alternating hemiplegia of childhood (AHC) is a rare disorder mainly characterized by attacks of hemiplegia and mental retardation. It has been often associated with migraine. The CACNA1A gene on chromosome 19 is involved in familial hemiplegic migraine and other episodic cerebral disorders, but also with progressive neuronal damage. Methods We performed mutation analysis in this gene in four AHC patients, using single strand conformation polymorphism analysis. Results We found nine polymorphisms, but no mutations in any of the 47 exons. Conclusions Other cerebral ion channel genes remain candidate genes for AHC.

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Frontali, M., A. Novelletto, G. Annesi i C. Jodice. "CAG repeat instability, cryptic sequence variation and pathogeneticity: evidence from different loci". Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 354, nr 1386 (29.06.1999): 1089–94. http://dx.doi.org/10.1098/rstb.1999.0464.

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Different aspects of expanded polyglutamine tracts and of their pathogenetic role are taken into consideration here. (i) The (CAG) n length of wild-type alleles of the Huntington disease gene was analysed in instability-prone tumour tissue from colon cancer patients to test whether the process leading to the elongation of alleles towards the expansion range involves single-unit stepwise mutations or larger jumps. The analysis showed that length changes of a single unit had a relatively low frequency. (ii) The observation of an expanded spinocerebellar ataxia (SCA)1 allele with an unusual pattern of multiple CAT interruptions showed that cryptic sequence variations are critical not only for sequence length stability but also for the expression of the disease phenotype. (iii) Small expansions of the (CAG) n sequence at the CACNA1A gene have been reported as causing SCA6. The analysis of families with SCA6 and episodic ataxia type 2 showed that these phenotypes are, in fact, expressions of the same disorder caused either by point mutations or by small (CAG) n expansions. A gain of function has been hypothesized for all proteins containing an expanded polyglutamine stretch, including the α 1A subunit of the voltage-gated calcium channel type P/Q coded by the CACNA1A gene. Because point mutations at the same gene with similar phenotypic consequences are highly unlikely to have this effect, an alternative common pathogenetic mechanism for all these mutations, including small expansions, can be hypothesized.

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Chioza, B., H. Wilkie, L. Nashef, J. Blower, D. McCormick, P. Sham, P. Asherson i A. J. Makoff. "Association between the 1a calcium channel gene CACNA1A and idiopathic generalized epilepsy". Neurology 56, nr 9 (8.05.2001): 1245–46. http://dx.doi.org/10.1212/wnl.56.9.1245.

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Vahedi, K., C. Denier, A. Ducros, V. Bousson, C. Levy, H. Chabriat, M. Haguenau, E. Tournier-Lasserve i M. G. Bousser. "CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy". Neurology 55, nr 7 (10.10.2000): 1040–42. http://dx.doi.org/10.1212/wnl.55.7.1040.

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Shimazaki, H., T. Mashiko, Y. Kim, T. Ozawa, R. Koide, T. Matsuura i S. Fujimoto. "Two sporadic cases of episodic ataxia type 2 with CACNA1A gene mutations". Journal of the Neurological Sciences 381 (październik 2017): 660. http://dx.doi.org/10.1016/j.jns.2017.08.1858.

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Chan, Y. C., E. Wilder-Smith, J. M. Burgunder, V. Sharma i B. Ong. "P20.2 Spectrum of electroencephalographic changes in patients with S218L CACNA1A gene mutation". Clinical Neurophysiology 117 (wrzesień 2006): 215–16. http://dx.doi.org/10.1016/j.clinph.2006.06.411.

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Chan, Kayi Y., Alejandro Labastida-Ramírez, Martha B. Ramírez-Rosas, Sieneke Labruijere, Ingrid M. Garrelds, Alexander HJ Danser, Arn MJM van den Maagdenberg i Antoinette MaassenVanDenBrink. "Trigeminovascular calcitonin gene-related peptide function in Cacna1a R192Q-mutated knock-in mice". Journal of Cerebral Blood Flow & Metabolism 39, nr 4 (9.08.2017): 718–29. http://dx.doi.org/10.1177/0271678x17725673.

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Familial hemiplegic migraine type 1 (FHM1) is a rare migraine subtype. Whereas transgenic knock-in mice with the human pathogenic FHM1 R192Q missense mutation in the Cacna1a gene reveal overall neuronal hyperexcitability, the effects on the trigeminovascular system and calcitonin gene-related peptide (CGRP) receptor are largely unknown. This gains relevance as blockade of CGRP and its receptor are therapeutic targets under development. Hence, we set out to test these effects in FHM1 mice. We characterized the trigeminovascular system of wild-type and FHM1 mice through: (i) in vivo capsaicin- and CGRP-induced dural vasodilation in a closed-cranial window; (ii) ex vivo KCl-induced CGRP release from isolated dura mater, trigeminal ganglion and trigeminal nucleus caudalis; and (iii) peripheral vascular function in vitro . In mutant mice, dural vasodilatory responses were significantly decreased compared to controls. The ex vivo release of CGRP was not different in the components of the trigeminovascular system between genotypes; however, sumatriptan diminished the release in the trigeminal ganglion, trigeminal nucleus caudalis and dura mater but only in wild-type mice. Peripheral vascular function was similar between genotypes. These data suggest that the R192Q mutation might be associated with trigeminovascular CGRP receptor desensitization. Novel antimigraine drugs should be able to revert this complex phenomenon.

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Battistini, S., S. Stenirri, M. Piatti, C. Gelfi, P. G. Righetti, R. Rocchi, F. Giannini i in. "A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia". Neurology 53, nr 1 (1.07.1999): 38. http://dx.doi.org/10.1212/wnl.53.1.38.

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Chabriat, H., K. Vahedi, C. A. Clark, C. Poupon, A. Ducros, C. Denier, D. Le Bihan i M. G. Bousser. "Decreased hemispheric water mobility in hemiplegic migraine related to mutation of CACNA1A gene". Neurology 54, nr 2 (25.01.2000): 510. http://dx.doi.org/10.1212/wnl.54.2.510.

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García-Baró-Huarte, María, Ana María Iglesias-Mohedano, María Slöcker-Barrio, María Vázquez-López, Marina García-Morín, María Concepción Miranda-Herrero i Pedro Castro-Castro. "Phenotypic Variability in a Four Generation Family With a p.Thr666Met CACNA1A Gene Mutation". Pediatric Neurology 51, nr 4 (październik 2014): 557–59. http://dx.doi.org/10.1016/j.pediatrneurol.2014.07.008.

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Trettel, Flavia, Elide Mantuano, Valentina Calabresi, Liana Veneziano, Anne S. Olsen, Anca Georgescu, Laurie Gordon, Guglielmo Sabbadini, Marina Frontali i Carla Jodice. "A fine physical map of the CACNA1A gene region on 19p13.1–p13.2 chromosome". Gene 241, nr 1 (styczeń 2000): 45–50. http://dx.doi.org/10.1016/s0378-1119(99)00470-9.

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