Two Missense CACNA1A Variants in a Single Family with Variable Neurobehavioral, Cerebellar, Epileptic, and Oculomotor Features

Ko, Pin-Yi; Glass, Ian A.; Crandall, Suzanne; Weiss, Avery H.; Dorschner, Michael O.; Kelly, John P.; Phillips, James O.; Lopez, Jonathan

doi:10.1055/s-0040-1721686

Cited by 4 publications

(4 citation statements)

References 26 publications

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“…Family members with heterozygous variants manifested ID and ataxia. A similar patient has since been reported (Ko et al, 2021 ). Recently, a CACNA1A homozygous truncating variant (p.Arg932*) was reported in a consanguineous family.…”

Section: Introductionsupporting

confidence: 77%

Biallelic CACNA1A variants: Review of literature and report of a child with drug‐resistant epilepsy and developmental delay

Wong-Spracklen

Kolesnik-Taylor

Eck

et al. 2022

American J of Med Genetics Pt A

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Biallelic variants in CACNA1A have previously been reported in nine individuals (four families) presenting with epilepsy and cognitive impairments of variable severity and age-of-onset. Here, we describe a child who presented at 6 months of age with drugresistant epilepsy and developmental delay. At 10 years of age, she has profound impairments in motor function and communication. MRI was initially unremarkable, but progressed to severe cerebellar atrophy by age 3 years. Next Generation Sequencing and panel analysis identified a maternally inherited truncating variant c.2042_2043delAG, p.(Gln681ArgfsTer100) and paternally inherited missense variant c.1693G>A, p.(Glu565Lys). In contrast to previously reported biallelic cases, parents carrying these monoallelic variants did not display clear signs of a CACNA1Aassociated syndrome. In conclusion, we provide further evidence that biallelic CAC-NA1A variants can cause a severe epileptic and developmental encephalopathy with progressive cerebellar atrophy, and highlight complexities of genetic counseling in such situations.

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Section: Introductionsupporting

confidence: 77%

Biallelic CACNA1A variants: Review of literature and report of a child with drug‐resistant epilepsy and developmental delay

Wong-Spracklen

Kolesnik-Taylor

Eck

et al. 2022

American J of Med Genetics Pt A

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“…On review of the latest literature in the EA, published since the closing date of our initial systematic literature review (April 2021–June 2022), we identified a total of nine related articles (Table S4). These reported on 10 patients with novel variants in the CACNA1A [19–29]. In a case report of CACNA1A ‐related EA, dalfampridine 0.3 mg/kg was shown to resolve falls that had been unresponsive to acetazolamide (treatment was delayed due to insufficient literature on the topic) [30].…”

Section: Resultsmentioning

confidence: 99%

“…Our review of the latest literature (April 2021–June 2022) revealed a total of two related articles (Table S4). These were reported on two patients with novel variants in the PDHA1 gene [19–29].…”

Section: Resultsmentioning

confidence: 99%

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Genotype–phenotype relations for episodic ataxia genes: MDSGene systematic review

Olszewska,

Shetty,

Rajalingam

et al. 2023

Euro J of Neurology

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BackgroundMost episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non‐paroxysmal features. EA is often caused by pathogenic variants in the CACNA1A, KCNA1, PDHA1, and SLC1A3 genes, listed as paroxysmal movement disorders (PxMD) by the MDS Task Force on the Nomenclature of Genetic Movement Disorders. Little is known about the genotype–phenotype correlation of the different genetic EA forms.MethodsWe performed a systematic review of the literature to identify individuals affected by an episodic movement disorder harboring pathogenic variants in one of the four genes. We applied the standardized MDSGene literature search and data extraction protocol to summarize the clinical and genetic features. All data are available via the MDSGene protocol and platform on the MDSGene website (https://www.mdsgene.org/).ResultsInformation on 717 patients (CACNA1A: 491, KCNA1: 125, PDHA1: 90, and SLC1A3: 11) carrying 287 different pathogenic variants from 229 papers was identified and summarized. We show the profound phenotypic variability and overlap leading to the absence of frank genotype–phenotype correlation aside from a few key ‘red flags’.ConclusionGiven this overlap, a broad approach to genetic testing using a panel or whole exome or genome approach is most practical in most circumstances.

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CACNA1A-Related Channelopathies: Clinical Manifestations and Treatment Options

Indelicato

Boesch

2023

Handbook of Experimental Pharmacology

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Two Missense CACNA1A Variants in a Single Family with Variable Neurobehavioral, Cerebellar, Epileptic, and Oculomotor Features

Cited by 4 publications

References 26 publications

Biallelic CACNA1A variants: Review of literature and report of a child with drug‐resistant epilepsy and developmental delay

Biallelic CACNA1A variants: Review of literature and report of a child with drug‐resistant epilepsy and developmental delay

Genotype–phenotype relations for episodic ataxia genes: MDSGene systematic review

CACNA1A-Related Channelopathies: Clinical Manifestations and Treatment Options

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