Biallelic <scp><i>CACNA1A</i></scp> variants: Review of literature and report of a child with drug‐resistant epilepsy and developmental delay

Wong-Spracklen, Vivien; Kolesnik-Taylor, Anna; Eck, Josefine; Sabanathan, Saras; Spasić-Bošković, Olivera; Maw, Anna; Baker, Kate

doi:10.1002/ajmg.a.62960

Cited by 5 publications

(1 citation statement)

References 28 publications

(30 reference statements)

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“…HMOX2 is a constitutive gene that plays a role in heme catabolism, leading to antioxidant and anti-inflammatory effects [117]. CACNA1A encodes the alpha-1a subunit of the voltage-dependent P/Q calcium channel, and has been linked repeatedly to familial hemiplegic migraine (FHM), a subtype of MA [118]. Finally, MPPED2 is a metallophosphoesterase domain-containing protein which has been linked to various functions, including tumor suppression [119].…”

Section: Genome-wide Association Studiesmentioning

confidence: 99%

The Dawn and Advancement of the Knowledge of the Genetics of Migraine

Zalaquett,

Salameh,

Kim

et al. 2024

JCM

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Background: Migraine is a prevalent episodic brain disorder known for recurrent attacks of unilateral headaches, accompanied by complaints of photophobia, phonophobia, nausea, and vomiting. Two main categories of migraine are migraine with aura (MA) and migraine without aura (MO). Main body: Early twin and population studies have shown a genetic basis for these disorders, and efforts have been invested since to discern the genes involved. Many techniques, including candidate-gene association studies, loci linkage studies, genome-wide association, and transcription studies, have been used for this goal. As a result, several genes were pinned with concurrent and conflicting data among studies. It is important to understand the evolution of techniques and their findings. Conclusions: This review provides a chronological understanding of the different techniques used from the dawn of migraine genetic investigations and the genes linked with the migraine subtypes.

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Section: Genome-wide Association Studiesmentioning

confidence: 99%

The Dawn and Advancement of the Knowledge of the Genetics of Migraine

Zalaquett,

Salameh,

Kim

et al. 2024

JCM

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

Cited by 5 publications

References 28 publications

The Dawn and Advancement of the Knowledge of the Genetics of Migraine

The Dawn and Advancement of the Knowledge of the Genetics of Migraine

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

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

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