A novel mutation in &lt;i&gt;CACNA1A&lt;/i&gt; gene in a Saudi female with episodic ataxia type 2 with no response to acetazolamide or 4-aminopyridine

Algahtani, Hussein; Shirah, Bader; Algahtani, Raghad; Al-Qahtani, Mohammad H.; Abdulkareem, Angham Abdulrahman; Naseer, Muhammad Imran

doi:10.5582/irdr.2018.01133

Cited by 6 publications

(6 citation statements)

References 23 publications

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“…Verapamil and acetazolamide are good for migraine [ 205 ]. Acetazolamide has been reported to be effective for ataxia to some cases [ 206 ] and ineffective for others [ 207 ]. Ethosuximide and valproic acid are effective for absence epilepsy [ 208 ].…”

Section: Summary Of the Clinical Featuresmentioning

confidence: 99%

Calcium channelopathies and intellectual disability: a systematic review

Kessi

Chen

Peng

et al. 2021

Orphanet J Rare Dis

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Background Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. Main body A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. Conclusion Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

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Section: Summary Of the Clinical Featuresmentioning

confidence: 99%

Calcium channelopathies and intellectual disability: a systematic review

Kessi

Chen

Peng

et al. 2021

Orphanet J Rare Dis

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“…Using whole-exome sequencing, Khaiboullina et al identified an R583Q missense mutation in patients with FHM (5). Algahtani et al summarized that there are more than 170 disease-causing variants of CACNA1A, including mutations with small deletions, gross deletions, missense variants, nonsense variants, splice variants, small insertions, complex rearrangements and repeat variations (19).…”

Section: Discussionmentioning

confidence: 99%

An elongated tract of polyQ in the carboxyl‑terminus of human α1A calcium channel induces cell apoptosis by nuclear translocation

Sun

et al. 2020

Oncol Rep

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An aberrant elongated tract of glutamine residues (polyQ) in proteins induces multiple diseases treated in the clinic. In our previous study of progressive myoclonic epilepsy (PME), using whole-exome sequencing, a mutant Cav2.1 protein with an aberrant elongated polyQ tract was identified in PME patients. To investigate the molecular mechanism and cell biology of this aberrant elongated polyQ tract, wild-type Cav2.1 with 13 polyQ repeats (Cav2.1 wt-Q13) and mutant-type Cav2.1 with 26 polyQ repeats (Cav2.1 mt-Q26) were prepared and introduced into human SH-SY5Y neuroblastoma cells. Using a WST-1 assay, it was revealed that Cav2.1 mt-Q26 markedly suppressed the proliferation of the SH-SY5Y cells, a result not observed for the Cav2.1 wt-Q13-transfected cells. It was also revealed that Cav2.1 mt and its truncated molecules suppressed cell proliferation by inducing apoptosis rather than arresting the cell cycle. Further investigations indicated a nuclear translocation phenomenon associated with the Cav2.1 mt molecules. Mechanistically, it was revealed that the Cav2.1 mt molecules activated the Bcl-2/Bax, caspase-3 and poly ADP-ribose polymerase (PARP) apoptotic pathways. The present study may provide new insights for interpreting the pathogenesis of PME and the relationship among polyQ, CACNA1A gene mutations and PME.

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“…In a case series published in Neurology, 6 out of 13 families with EA2 patients complain of generalized fluctuating weakness [ 57 ]. Also, single case reports described EA2 patients with generalized weakness during attacks, occasionally accompanied by areflexia, dysarthria, and dysphagia [ 58 , 59 , 60 ]. Moreover, within a four-generation Chinese family, some of the affected members presented with myokymia and limb weakness [ 61 ].…”

Section: Episodic Ataxia Typementioning

confidence: 99%

“…Moreover, within a four-generation Chinese family, some of the affected members presented with myokymia and limb weakness [ 61 ]. Additionally, there is a report about an EA2 patient in whom a 24-h Holter monitoring showed sinus bradycardia with marked sinus arrhythmia [ 60 ].…”

Section: Episodic Ataxia Typementioning

confidence: 99%

“…The NCS performed in the mentioned female patient with sinus arrhythmia revealed axonal sensory neuropathy with the reduced sensory action potential (SNAP) amplitude in the median and ulnar nerves bilaterally and unrecordable responses from the sural and superficial peroneal nerves bilaterally. In addition, low-compound muscle action potential (CMAP) amplitude in both peroneal nerves was observed [ 60 ].…”

Section: Episodic Ataxia Typementioning

confidence: 99%

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Involvement of the Peripheral Nervous System in Episodic Ataxias

Koźmiński¹,

Pera

2020

Biomedicines

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Episodic ataxias comprise a group of inherited disorders, which have a common hallmark—transient attacks of ataxia. The genetic background is heterogeneous and the causative genes are not always identified. Furthermore, the clinical presentation, including intraictal and interictal symptoms, as well as the retention and progression of neurological deficits, is heterogeneous. Spells of ataxia can be accompanied by other symptoms—mostly from the central nervous system. However, in some of episodic ataxias involvement of peripheral nervous system is a part of typical clinical picture. This review intends to provide an insight into involvement of peripheral nervous system in episodic ataxias.

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A novel mutation in <i>CACNA1A</i> gene in a Saudi female with episodic ataxia type 2 with no response to acetazolamide or 4-aminopyridine

Cited by 6 publications

References 23 publications

Calcium channelopathies and intellectual disability: a systematic review

Calcium channelopathies and intellectual disability: a systematic review

An elongated tract of polyQ in the carboxyl‑terminus of human α1A calcium channel induces cell apoptosis by nuclear translocation

Involvement of the Peripheral Nervous System in Episodic Ataxias

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