A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia

Battistini, Stefania; Stenirri, Stefania; Piatti, M.; Gelfi, Cecilia; Righetti, P. G.; Rocchi, Raniero; Giannini, Flavio; Battistini, N.; Guazzi, Gianni; Ferrari, Marco; Carrera, Paola

doi:10.1212/wnl.53.1.38

Cited by 170 publications

(117 citation statements)

References 40 publications

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“…All fulfilled minimal diagnostic criteria, including episodes of ataxia or vertigo of variable duration, interictal nystagmus, and absence of mutations in SCA1, 2,3,6,7,8,10,12,14,17, and DRPLA genes. The response to acetazolamide was not included among the criteria, since in some cases the burden of the disease was so mild that the side effects of treatment would not compensate its advantages.…”

Section: Subjectsmentioning

confidence: 99%

Clusters of non-truncating mutations of P/Q type Ca2+ channel subunit Cav2.1 causing episodic ataxia 2

Mantuano

2004

Journal of Medical Genetics

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N Episodic ataxia type 2 (EA2) is mostly due to loss of function mutations that truncate or severely disrupt the pore forming (Cav2.1) subunit of P/Q type Ca2+ channels, coded by the CACNA1A gene. Gain of function missense mutations of the same gene are responsible for familial hemiplegic migraine. In a few cases, EA2 is due to mutations that do not truncate or disrupt the Cav2.1 subunit. N Screening for CACNA1A gene mutations was carried out for 27 patients with either typical EA2 or cerebellar ataxia of no known genetic type. N Five new Cav2.1 non-truncating/disrupting mutations were detected. From almost doubling the number of these mutations, it clearly emerges that they have a preferential location in specific protein regions, namely S5–S6 linkers and their borders. Their associated clinical phenotype is comparable with that reported for carriers of truncating/disrupting mutations, but data suggest a possible difference in age at onset and frequency of mental retardation. N The results show that EA2 mutations that do not truncate or disrupt the Cav2.1 subunit are not as rare as previously thought. Their associated phenotype might be less severe than that of truncating/disrupting mutations. They are clustered in highly conserved protein regions which may be particularly vulnerable to amino acid changes and are likely to have a critical role in the channel gating activity

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Section: Subjectsmentioning

confidence: 99%

Clusters of non-truncating mutations of P/Q type Ca2+ channel subunit Cav2.1 causing episodic ataxia 2

Mantuano

2004

Journal of Medical Genetics

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“…Individuals with episodic ataxia type 2 (EA2) and familial hemiplegic migraine (FHM) experience paroxysmal attacks of migraine, ataxia, and other neurological signs that are triggered by emotional stress, exercise, caffeine, or ethanol (Griggs and Nutt, 1995;Gordon, 1998;Battistini et al, 1999;Denier et al, 1999;Jen, 1999;Bhatia et al, 2000;Subramony et al, 2003). EA2 and FHM are both caused by mutations in the CACNA1A gene, which encodes the pore-forming ␣ 1 2.1 subunit of Ca v 2.1 (P/Qtype) voltage-gated calcium channels (Ophoff et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Potassium Channel Blockers Inhibit the Triggers of Attacks in the Calcium Channel Mouse Mutanttottering

Weisz¹,

Raike²,

Soria-Jasso³

et al. 2005

J. Neurosci.

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Humans with the disorder episodic ataxia type 2 (EA2) and the tottering mouse mutant exhibit episodic attacks induced by emotional and chemical stress. Both the human and mouse disorders result from mutations in CACNA1A, the gene encoding the ␣ 1 2.1 subunit of Ca v 2.1 voltage-gated calcium channels. These mutations predict reduced calcium currents, particularly in cerebellar Purkinje cells, where these channels are most abundant. 4-Aminopyridine (4-AP), a nonselective blocker of K v voltage-gated potassium channels, alleviates attacks of ataxia in EA2 patients. To test the specificity of the effect for K v channels, aminopyridine analogs were assessed for their ability to ameliorate attacks of dyskinesia in tottering mice. 4-AP and 3,4-diaminopyridine (3,4-DiAP), which have relatively high affinities for K v channels, reduced the frequency of restraint-and caffeine-induced attacks. Furthermore, microinjection of 3,4-DiAP into the cerebellum completely blocked attacks in tottering mice. Other aminopyridine analogs reduced attack frequency but, consistent with their lower affinities for K v channels, required comparatively higher doses. These results suggest that aminopyridines block tottering mouse attacks via cerebellar K v channels. That both stress-and caffeine-induced attacks were blocked by aminopyridines suggests that these triggers act via similar mechanisms. Although 4-AP and 3,4-DiAP were effective in preventing attacks in tottering mice, these compounds did not affect the severity of "breakthrough" attacks that occurred in the presence of a drug. These results suggest that the aminopyridines increase the threshold for attack initiation without mitigating the character of the attack, indicating that attack initiation is mediated by mechanisms that are independent of the neurological phenotype.

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“…2014) p.Arg583Gln (rs121908217) (Battistini et al. 1999; Cleves et al. 2010) and; the two nonsense mutations found in exon 27 and 37, p.Trp1448Ter (Jen et al.…”

Section: Resultsmentioning

confidence: 99%

“…In more detail, Battistini et al. (1999) reported two sisters with p.Arg583Gln mutation who have typical hemiplegic migraine attacks associated with confusion and fever, accompanied with progressive cerebellar ataxia. In 2010, the same mutation was reported by Cleves et al.…”

Section: Discussionmentioning

confidence: 99%

Next‐generation sequencing identifies novel CACNA1A gene mutations in episodic ataxia type 2

Maksemous

Roy

Smith

et al. 2016

Molec Gen & Gen Med

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Episodic Ataxia type 2 (EA2) is a rare autosomal dominantly inherited neurological disorder characterized by recurrent disabling imbalance, vertigo, and episodes of ataxia lasting minutes to hours. EA2 is caused most often by loss of function mutations of the calcium channel gene CACNA1A. In addition to EA2, mutations in CACNA1A are responsible for two other allelic disorders: familial hemiplegic migraine type 1 (FHM1) and spinocerebellar ataxia type 6 (SCA6). Herein, we have utilized next‐generation sequencing (NGS) to screen the coding sequence, exon‐intron boundaries, and Untranslated Regions (UTRs) of five genes where mutation is known to produce symptoms related to EA2, including CACNA1A. We performed this screening in a group of 31 unrelated patients with EA2 symptoms. Both novel and known mutations were detected through NGS technology, and confirmed through Sanger sequencing. Genetic testing showed in total 15 mutation bearing patients (48%), of which nine were novel mutations (6 missense and 3 small frameshift deletion mutations) and six known mutations (4 missense and 2 nonsense).These results demonstrate the efficiency of our NGS‐panel for detecting known and novel mutations for EA2 in the CACNA1A gene, also identifying a novel missense mutation in ATP1A2 which is not a normal target for EA2 screening.

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A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia

Abstract: The combination of episodic dysfunction and permanent deficit could depend on the variety of functions of calcium channels and their distribution in the nervous system.

Cited by 170 publications

References 40 publications

Clusters of non-truncating mutations of P/Q type Ca2+ channel subunit Cav2.1 causing episodic ataxia 2

Clusters of non-truncating mutations of P/Q type Ca2+ channel subunit Cav2.1 causing episodic ataxia 2

Potassium Channel Blockers Inhibit the Triggers of Attacks in the Calcium Channel Mouse Mutanttottering

Next‐generation sequencing identifies novel CACNA1A gene mutations in episodic ataxia type 2

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