CACNA1A-Related Channelopathies: Clinical Manifestations and Treatment Options

Indelicato, Elisabetta; Boesch, Sylvia

doi:10.1007/164_2022_625

Cited by 6 publications

(5 citation statements)

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“…7,8 Emerging evidence also points to CACNA1A-related PTU and paroxysmal torticollis as infantile phenotypic expressions that predate the development classical motor phenotypes such as hemiplegic migraine and episodic ataxia. 9 Treatments have been proposed for PTU regardless of etiology including levodopa 4 and acetazolamide with variable efficacy. 3 In this case, the patient had a novel de novo missense variant in CACNA1A, which has been implicated in the pathogenesis of PTU.…”

Section: Discussionmentioning

confidence: 99%

“…3,9,14 Carbonic anhydrase inhibitors are believed to increase the pH level of the CSF, which stabilizes ion channels of the neuronal membrane through a complex interaction of potassium currents and voltage-gated calcium channels. 9,14 Of interest, there may be therapeutic benefit of acetazolamide across both GOF and LOF variants and their classically related syndromes of hemiplegic migraine and episodic ataxia, respectively. 9 In conclusion, we presented a case of an infant with a novel pathogenic variant in CACNA1A leading to PTU with ataxia that was symptomatically treated with a course of acetazolamide.…”

Section: Discussionmentioning

confidence: 99%

“…9,14 Of interest, there may be therapeutic benefit of acetazolamide across both GOF and LOF variants and their classically related syndromes of hemiplegic migraine and episodic ataxia, respectively. 9…”

Section: Discussionmentioning

confidence: 99%

“…LOF variants may be responsive to carbonic anhydrase inhibitors while GOF variants may be responsive to calcium channel blocking agents. 3,9,14 Carbonic anhydrase inhibitors are believed to increase the pH level of the CSF, which stabilizes ion channels of the neuronal membrane through a complex interaction of potassium currents and voltage-gated calcium channels. 9,14 Of interest, there may be therapeutic benefit of acetazolamide across both GOF and LOF variants and their classically related syndromes of hemiplegic migraine and episodic ataxia, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Pearls & Oy-sters: CACNA1A -Related Paroxysmal Tonic Upgaze With Ataxia Responsive to Acetazolamide

Lazar,

Abid

2024

Neurology

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A 9-month-old male infant was evaluated for sudden onset of paroxysmal episodes of forced, conjugate upward eye deviation. Extensive in-hospital evaluation including electrophysiology and neuroimaging studies were reassuring against seizures or a structural abnormality. Given the clinical presentation of sudden onset intermittent upward eye deviations, downbeating saccades, associated ataxia, and typical development, a clinical diagnosis of paroxysmal tonic upgaze (PTU) with ataxia was made. Targeted genetic testing of CACNA1A was performed, which revealed a variant of undetermined significance, which was later classified as a de novo pathogenic variant after protein modeling and parental testing performed. Off-label use of oral acetazolamide was prescribed, which led to dose-responsive decrease in the frequency and intensity of eye movement episodes. After 6 months of episode freedom at 2 years of age, acetazolamide was discontinued without return of episodes. Neurodevelopmental assessments revealed continued typical development. This case is presented to describe the diagnostic formulation, etiologic evaluation, and symptomatic treatment of CACNA1A-related PTU with ataxia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Pearls & Oy-sters: CACNA1A -Related Paroxysmal Tonic Upgaze With Ataxia Responsive to Acetazolamide

Lazar,

Abid

2024

Neurology

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“…The classical phenotypes include episodic ataxia 2 (EA2) which is mostly caused by nonsense mutations ( Strupp et al, 2007 ), familial hemiplegic migraine type 1 (FHM1) which is frequently caused by missense mutations (mainly gain-of-function (GOF) variants) ( Ducros et al, 2001 ), and spinocerebellar ataxia type 6 (SCA6) which usually occurs because of the expanded CAG repeats ( Klockgether, 2008 ). However, with advanced next-generation sequencing techniques, CACNA1A variants have been linked to more wider phenotypic spectrum including global developmental delay (GDD)/intellectual disability (ID), epileptic encephalopathy (EE), and autism spectrum disorder (ASD) ( Kessi et al, 2021 ; Indelicato and Boesch, 2023 ). Currently, genotype–phenotype correlations of the CACNA1A – related neurodevelopmental disorders such as GDD/ID, ASD, and epilepsy are unknown.…”

Section: Introductionmentioning

confidence: 99%

The genotype–phenotype correlations of the CACNA1A-related neurodevelopmental disorders: a small case series and literature reviews

Kessi¹,

Chen²,

Pang³

et al. 2023

Front. Mol. Neurosci.

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BackgroundGenotype–phenotype correlations of the CACNA1A-related neurodevelopmental disorders such as global developmental delay (GDD)/intellectual disability (ID), epileptic encephalopathy (EE), and autism spectrum disorder (ASD) are unknown. We aimed to summarize genotype–phenotype correlations and potential treatment for CACNA1A-related neurodevelopmental disorders.MethodsSix children diagnosed with CACNA1A-related neurodevelopmental disorders at Xiangya Hospital, Central South University from April 2018 to July 2021 were enrolled. The PubMed database was systematically searched for all reported patients with CACNA1A-related neurodevelopmental disorders until February 2023. Thereafter, we divided patients into several groups for comparison.ResultsSix patients were recruited from our hospital. Three cases presented with epilepsy, five with GDD/ID, five with ataxia, and two with ASD. The variants included p.G701R, p.R279C, p.D1644N, p.Y62C, p.L1422Sfs*8, and p. R1664Q [two gain-of-function (GOF) and four loss-of-function (LOF) variants]. About 187 individuals with GDD/ID harboring 123 variants were found (case series plus data from literature). Of those 123 variants, p.A713T and p.R1664* were recurrent, 37 were LOF, and 7 were GOF. GOF variants were linked with severe-profound GDD/ID while LOF variants were associated with mild–moderate GDD/ID (p = 0.001). The p.A713T variant correlated with severe-profound GDD/ID (p = 0.003). A total of 130 epileptic patients harboring 83 variants were identified. The epileptic manifestations included status epilepticus (n = 64), provoked seizures (n = 49), focal seizures (n = 37), EE (n = 29), absence seizures (n = 26), and myoclonic seizures (n = 10). About 49 (42.20%) patients had controlled seizures while 67 (57.80%) individuals remained with refractory seizures. Status epilepticus correlated with variants located on S4, S5, and S6 (p = 0.000). Among the 83 epilepsy-related variants, 23 were recurrent, 32 were LOF, and 11 were GOF. Status epilepticus was linked with GOF variants (p = 0.000). LOF variants were associated with absence seizures (p = 0.000). Six patients died at an early age (3 months to ≤5 years). We found 18 children with ASD. Thirteen variants including recurrent ones were identified in those 18 cases. GOF changes were more linked to ASD.ConclusionThe p.A713T variant is linked with severe-profound GDD/ID. More than half of CACNA1A-related epilepsy is refractory. The most common epileptic manifestation is status epilepticus, which correlates with variants located on S4, S5, and S6.

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Movement disorders and seizures: Overlapping phenomenology, shared etiologies and diagnostic challenges

Gaber,

Shalash

2024

International Review of Movement Disorders

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CACNA1A-Related Channelopathies: Clinical Manifestations and Treatment Options

Cited by 6 publications

References 146 publications

Pearls & Oy-sters: CACNA1A -Related Paroxysmal Tonic Upgaze With Ataxia Responsive to Acetazolamide

Pearls & Oy-sters: CACNA1A -Related Paroxysmal Tonic Upgaze With Ataxia Responsive to Acetazolamide

The genotype–phenotype correlations of the CACNA1A-related neurodevelopmental disorders: a small case series and literature reviews

Movement disorders and seizures: Overlapping phenomenology, shared etiologies and diagnostic challenges

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