Longitudinal MRI brain findings in the R1349Q pathogenic variant of CACNA1A

Ho, Chang Yueh; Love, Harrison; Sokol, Deborah K.; Walsh, Laurence E.

doi:10.1016/j.radcr.2021.02.052

Cited by 3 publications

(6 citation statements)

References 13 publications

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“…She presented with significant ischemic injury after a head trauma at the age of 3.5 years. This same variant was later seen in children with strokes as reported by Ho et al 11 and Le Roux et al 10 The next patient described in literature was a 4-year-old girl who was found to have a heterozygous, de novo variant, c.5075T>A (p.L1692Q) in the CACNA1A gene. 8 She presented with ischemic injury secondary to fever as young as 6 weeks old.…”

Section: Discussionsupporting

confidence: 65%

“…It is primarily used in the pediatric population for the treatment of supraventricular tachycardia, but in adult populations it is primarily used as an anti-hypertensive agent, and as a class, calcium channel blockers have been shown to reduce the risk of stroke in hypertensive populations. 11 Verapamil can also be used off-label for prevention of migraines, cluster headaches, and hemiplegic migraines, and is often used by neurointerventionalists for the treatment of cerebral vasospasm. [17][18][19][20] Verapamil was successfully used in an episode of stroke after head trauma and seizures in the patient described by Knierim et al 9 In fact, many of the reported cases of ischemic injury associated with this gene mutation have been treated with verapamil with either unchanged or improved clinical outcomes (including our own, whom were treated with 0.2-0.3mg/kg/day divided into three doses daily).…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19][20] Verapamil was successfully used in an episode of stroke after head trauma and seizures in the patient described by Knierim et al 9 In fact, many of the reported cases of ischemic injury associated with this gene mutation have been treated with verapamil with either unchanged or improved clinical outcomes (including our own, whom were treated with 0.2-0.3mg/kg/day divided into three doses daily). 9,11 Looking at the functional aberration of the Ca v 2.1 channel in Patient 1 specifically, it logically follows that treating a hyperpolarized channel that exhibits facilitated current activation with an agent that attenuates calcium influx would improve clinical response. Additional studies are needed to further characterize the effects of Verapamil in these patients' clinical courses.…”

Section: Discussionmentioning

confidence: 99%

“…7 To date, only six cases of a pathogenic CACNA1A variant associated with strokes in pediatric populations have been described in the literature. 8,9–11 We report the cases of two young girls with pathogenic CACNA1A gene variants that have not been previously associated with strokes in literature. The first patient we describe presented with seizures in the setting of an acute cerebral infarction.…”

Section: Introductionmentioning

confidence: 97%

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Two Children with Early-Onset Strokes and Intractable Epilepsy, Both with CACNA1A Mutations

Bolte

Assaf

Zach

et al. 2022

Child Neurology Open

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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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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Two Children with Early-Onset Strokes and Intractable Epilepsy, Both with CACNA1A Mutations

Bolte

Assaf

Zach

et al. 2022

Child Neurology Open

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“…There were 83 variants reported to relate to epilepsy ( Imbrici et al, 2004 ; Kors et al, 2004 ; Rajakulendran et al, 2010 ; Zangaladze et al, 2010 ; Yamazaki et al, 2011 ; Damaj et al, 2015 ; Byers et al, 2016 ; Reinson et al, 2016 ; Du et al, 2017 ; Lv et al, 2017 ; Epperson et al, 2018 ; Hayashida et al, 2018 ; Kothur et al, 2018 ; Lee et al, 2018 ; Angelini et al, 2019 ; Jiang et al, 2019 ; Yamamoto et al, 2019 ; Gauquelin et al, 2020 ; Gudenkauf et al, 2020 ; Mitta et al, 2020 ; Stendel et al, 2020 ; Zhang et al, 2020 ; Ho et al, 2021 ; Le Roux et al, 2021 ; Stubberud et al, 2021 ; Verriello et al, 2021 ; Alehabib et al, 2022 ; Bolte et al, 2022 ; Hommersom et al, 2022 ; Krygier et al, 2022 ; Li et al, 2022 ; Lipman et al, 2022 ; Niu X. et al, 2022 ; Niu Y. et al, 2022 ) as shown in Supplementary Table 2 . The majority of the variants were missense (77.20%) followed by nonsense (8.80%) as shown in Figure 1A .…”

Section: Resultsmentioning

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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Developing a pathway to clinical trials for CACNA1A-related epilepsies: A patient organization perspective

Fox,

Malepati,

Manaster

et al. 2024

Therapeutic Advances in Rare Disease

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CACNA1A-related disorders are rare neurodevelopmental disorders linked to variants in the CACNA1A gene. This gene encodes the α1 subunit of the P/Q-type calcium channel Cav2.1, which is globally expressed in the brain and crucial for fast synaptic neurotransmission. The broad spectrum of CACNA1A-related neurological disorders includes developmental and epileptic encephalopathies, familial hemiplegic migraine type 1, episodic ataxia type 2, spinocerebellar ataxia type 6, together with unclassified presentations with developmental delay, ataxia, intellectual disability, autism spectrum disorder, and language impairment. The severity of each disorder is also highly variable. The spectrum of CACNA1A-related seizures is broad across both loss-of-function and gain-of-function variants and includes absence seizures, focal seizures with altered consciousness, generalized tonic-clonic seizures, tonic seizures, status epilepticus, and infantile spasms. Furthermore, over half of CACNA1A-related epilepsies are refractory to current therapies. To date, almost 1700 CACNA1A variants have been reported in ClinVar, with over 400 listed as Pathogenic or Likely Pathogenic, but with limited-to-no clinical or functional data. Robust genotype–phenotype studies and impacts of variants on protein structure and function have also yet to be established. As a result, there are few definitive treatment options for CACNA1A-related epilepsies. The CACNA1A Foundation has set out to change the landscape of available and effective treatments and improve the quality of life for those living with CACNA1A-related disorders, including epilepsy. Established in March 2020, the Foundation has built a robust preclinical toolbox that includes patient-derived induced pluripotent stem cells and novel disease models, launched clinical trial readiness initiatives, and organized a global CACNA1A Research Network. This Research Network is currently composed of over 60 scientists and clinicians committed to collaborating to accelerate the path to CACNA1A-specific treatments and one day, a cure.

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Longitudinal MRI brain findings in the R1349Q pathogenic variant of CACNA1A

Cited by 3 publications

References 13 publications

Two Children with Early-Onset Strokes and Intractable Epilepsy, Both with CACNA1A Mutations

Two Children with Early-Onset Strokes and Intractable Epilepsy, Both with CACNA1A Mutations

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

Developing a pathway to clinical trials for CACNA1A-related epilepsies: A patient organization perspective

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