CACNA1A Mutations Research Articles

Neurological and Systemic Pitfalls in the Diagnosis of Cluster Headaches: A Case-Based Review.

To describe different pitfalls in the diagnosis of primary cluster headaches (CHs) with the guidance of seven case vignettes. The question of whether primary CHs and migraines are totally different entities has been long debated. Autonomic features can be detected in as many as 60% of migraine patients. Although some genetic similarities have been found, CACNA1A mutations have not been detected among CH patients with hemimotor aura in contrast to hemiplegic migraine. Recently, functional MRI studies have shown that the left thalamic network was the most discriminative MRI feature in distinguishing migraine from CH patients. Compared to migraine, CH patients showed decreased functional interaction between the left thalamus and cortical areas mediating interception and sensory integration. However, clinically the most significant feature had been the restlessness and agitation seen during headache attacks patients with CHs. This feature is also important in distinguishing cluster patients from other patients having other trigeminal autonomic cephalalgias except for a subset of patients with hemicrania continua. CH is an important member of the group of headache disorders characterized by their association with one or more autonomic features in the trigeminal nerve distribution and termed Trigeminal Autonomic Cephalalgias (TACs). Although CH is a relatively rare condition, judged by the distress it generally causes to the affected individual, early diagnosis and institution of appropriate therapy seem mandatory. Correct diagnosis of CHs needs avoidance of pitfalls. Such pitfalls generally include differentiation from migraine, differentiation from other side locked headache disorders, from other trigeminal autonomic cephalalgias (TACs), and lastly, recognition of rare presentations of cluster-like manifestations with hemiplegic aura and simulating trigeminal and glossopharyngeal neuralgias. Differentiation between primary and symptomatic CHs related to sellar pathologies and systemic medical conditions is of equal importance. In the present review such issues are discussed with the assistance of seven case vignettes.

Treatment of CACNA1A Encephalopathy and Cerebral Edema with Magnesium and Dexamethasone.

Pathogenic CACNA1A mutations can result in paroxysmal attacks of encephalopathy, hemiplegia and cerebral edema. We report two patients with CACNA1A-associated encephalopathy, hemiplegia and contralateral hemispheric cerebral edema treated successfully with intravenous magnesium sulfate and dexamethasone. One patient met the clinical criteria for familial hemiplegic migraine. There is a paucity of guidance in the literature on how to manage these patients. Despite some discrepancies in the treatment protocols in our two cases, they indicate that magnesium and dexamethasone could be part of the treatment algorithm for these patients. Further research to delineate appropriate dosing and duration of therapy is needed.

Lack of evidence for GWAS signals of exfoliation glaucoma working via monogenic loss-of-function mutation in the nearest gene.

Exfoliation syndrome (XFS) is a systemic disease of elastin-rich tissues involving a deposition of fibrillar exfoliative material (XFM) in the anterior chamber of the eye, which can promote glaucoma. The purpose of this study was to create mice with CRISPR/Cas9-induced variations in candidate genes identified from human genome-wide association studies (GWAS) and screen them for indices of XFS. Variants predicted to be deleterious were sought in the Agpat1, Cacna1a, Loxl1, Pomp, Rbms3, Sema6a, and Tlcd5 genes of C57BL/6J mice using CRISPR/Cas9-based gene editing. Strains were phenotyped by slit-lamp, SD-OCT imaging, and fundus exams at 1-5 mos of age. Smaller cohorts of 12-mos-old mice were also studied. Deleterious variants were identified in six targets; Pomp was recalcitrant to targeting. Multiple alleles of some targets were isolated, yielding 12 strains. Across all genotypes and ages, 277 mice were assessed by 902 slit-lamp exams, 928 SD-OCT exams, and 358 fundus exams. Homozygosity for Agpat1 or Cacna1a mutations led to early lethality; homozygosity for Loxl1 mutations led to pelvic organ prolapse, preventing aging. Loxl1 homozygotes exhibited a conjunctival phenotype of potential relevance to XFS. Multiple other genotype-specific phenotypes were variously identified. XFM was not observed in any mice. This study did not detect XFM in any of the strains. This may have been due to species-specific differences, background dependence, or insufficient aging. Alternatively, it is possible that the current candidates, selected based on proximity to GWAS signals, are not effectors acting via monogenic loss-of-function mechanisms.

A de novo mutation in CACNA1A is associated with autosomal dominant bovine familial convulsions and ataxia in Angus cattle.

Bovine familial convulsions and ataxia (BFCA) is considered an autosomal dominant syndrome with incomplete penetrance. Nine Angus calves from the same herd were diagnosed with BFCA within days of birth. Necropsy revealed cerebellar and spinal cord lesions associated with the condition. Parentage testing confirmed that all affected calves had a common sire. The sire was then bred to 36 cows across two herds using artificial insemination, producing an additional 14 affected calves. The objective of this investigation was to identify hypothesized dominant genetic variation underlying the condition. Whole-genome sequencing was performed on the sire, six affected and seven unaffected paternal half-sibling calves and combined with data from 135 unrelated controls. The sire and five of the six affected calves were heterozygous for a nonsense variant (Chr7 g.12367906C>T, c.5073C>T, p.Arg1681*) in CACNA1A. The other affected calves (N = 8) were heterozygous for the variant but it was absent in the other unaffected calves (N = 7) and parents of the sire. This variant was also absent in sequence data from over 6500 other cattle obtained via public repositories and collaborator projects. The variant in CACNA1A is expressed in the cerebellum of the ataxic calves as detected in the transcriptome and was not differentially expressed compared with controls. The CACNA1A protein is part of a highly expressed cerebellar calcium voltage gated channel. The nonsense variant is proposed to cause haploinsufficiency, preventing proper transmission of neuronal signals through the channel and resulting in BFCA.

Chapter 8 - The episodic ataxias

The primary episodic ataxias (EAs) are a group of autosomal-dominant disorders characterized by transient recurrent incoordination and truncal instability, often triggered by physical exertion or emotional stress and variably associated with progressive baseline ataxia. There are now nine designated subtypes EA1-9 (OMIM) and late onset cerebellar ataxia with episodic features as newly designated SCA27B, based largely on genetic loci. Mutations have been identified in multiple individuals and families in 4 of the 9 EA subtypes, mostly with the onset before adulthood. This chapter focuses on the clinical assessment and management of EA, genetic diagnosis, and neurophysiologic consequences of the causative mutations in the best characterized EA syndromes: EA1 caused by mutations in KCNA1 encoding a neuronal voltage-gated potassium channel, EA2 caused by mutations in CACNA1A encoding a neuronal voltage-gated calcium channel, EA6 caused by mutations in SLC1A3 encoding a glutamate transporter that is also an anion channel, and SCA27B with late onset episodic ataxia caused by an intronic trinucleotide repeat in FGF14 encoding fibroblast growth factor 14 important in regulating the distribution of voltage-gated sodium channels in the cerebellar Purkinje and granule cells. The study of EA has illuminated previously unrecognized but important roles of ion channels and transporters in brain function with shared mechanisms underlying cerebellar ataxia, migraine, and epilepsy.

Intellectual Disability in Episodic Ataxia Type 2: Beyond Paroxysmal Vertigo and Ataxia.

Episodic ataxia type 2 (EA2) is characterized by recurrent vertigo and ataxia due to mutations in CACNA1A that encodes the α1A-subunit of the P/Q-type voltage-gated calcium channel. This study aimed to determine intellectual function in EA2. During 2019-2023, 13 patients (6 males, age range=10-52 years, median age=29 years) with a genetically confirmed diagnosis of EA2 had their intellectual function evaluated using the Korean versions of the Wechsler Intelligence Scales (version IV) for adults or children in 3 referral-based university hospitals in South Korea. The full-scale intelligence quotients (FSIQs) among the 13 patients were below the average (90-109) in 11, low average (80-89) in 5 (38.5%), borderline (70-79) in 1 (7.7%), and indicated intellectual disability (≤69) in 5 (38.5%). These patterns of cognitive impairments were observed in all four of the following subtests: verbal comprehension, perceptual reasoning, working memory, and processing speed. The FSIQ was not correlated with the ages at onset for vertigo and ataxia (Pearson correlation: p=0.40). Patients with EA2 may have hidden intellectual disabilities even without a history of epilepsy or administration of antiepileptic drugs, and should be considered for genetic counseling and therapeutic interventions. Given the availability of medication to control episodic vertigo and ataxia, early diagnosis and management are important in preventing irreversible brain dysfunction in EA2.

Chapter 9 - Familial hemiplegic migraine

Hemiplegic migraine consists of attacks of migraine with aura that includes reversible motor weakness. It is classified as familial or sporadic depending on the involvement or not of a first or second degree relative. The most described subtypes of familial hemiplegic migraine include FHM1, FHM2, and FHM3. These have been demonstrated to have a mutation in either CACNA1A, ATP1A2 or SCN1A, which encode different subunits of channels, involving P/Q-type calcium channel, Na/K pump and Na channel, respectively, located in neurons and glial cells. Mutations localized in different genes are defined as "other loci." Patients with a known mutation can have different genetic penetrance, and may present a more complex and disabling phenotype that develops earlier in life. The clinical manifestations can be similar in the three mutations, including neurologic comorbidities other than muscular weakness, such as episodes of loss of consciousness, epilepsy, gait or limb ataxia or movement disorders, among others. Treatment includes antiepileptics such as lamotrigine, valproate or topiramate, calcium blockers such as flunarizine or verapamil and acetazolamide.

CACNA1A mutations in essential tremor lead to dysregulation of neuron exocytosis machinery

CACNA1A mutations in essential tremor lead to dysregulation of neuron exocytosis machinery

Two pediatric patients with hemiplegic migraine presenting as acute encephalopathy: case reports and a literature review.

Hemiplegic migraine (HM) is a rare subtype of migraine. HM in children may be atypical in the initial stage of the disease, which could easily lead to misdiagnosis. We report two cases of atypical hemiplegic migraine that onset as an acute encephalopathy. And a comprehensive search was performed using PubMed, Web of Science, and Scopus. We selected only papers that reported complete clinical information about the patients with CACNA1A or ATP1A2 gene mutation. Patient #1 showed a de novo mutation, c.674C>A (p. Pro225His), in exon 5 of the CACNA1A gene. And patient #2 showed a missense mutation (c.2143G>A, p. Gly715Arg) in exon 16 of the ATP1A2. Together with our two cases, a total of 160 patients (73 CACNA1A and 87 ATP1A2) were collected and summarized finally. Acute encephalopathy is the main manifestation of severe attacks of HM in children, which adds to the difficulty of diagnosis. Physicians should consider HM in the differential diagnosis of patients presenting with somnolence, coma, or convulsion without structural, epileptic, infectious, or inflammatory explanation. When similar clinical cases appear, gene detection is particularly important, which is conducive to early diagnosis and treatment. Early recognition and treatment of the disease can help improve the prognosis.

A neurodevelopmental disorder caused by a dysfunctional CACNA1A allele.

P/Q-type Ca2+ flux into nerve terminals via CaV2.1 channels is essential for neurotransmitter release at neuromuscular junctions and nearly all central synapses. Mutations in CACNA1A, the gene encoding CaV2.1, cause a spectrum of pediatric neurological disorders. We have identified a patient harboring an autosomal-dominant de novo frameshift-causing nucleotide duplication in CACNA1A (c.5018dupG). The duplicated guanine precipitated 43 residues of altered amino acid sequence beginning with a glutamine to serine substitution in CaV2.1 at position 1674 ending with a premature stop codon (CaV2.1 p.Gln1674Serfs*43). The patient presented with episodic downbeat vertical nystagmus, hypotonia, ataxia, developmental delay and febrile seizures. In patch-clamp experiments, no Ba2+ current was observed in tsA-201 cells expressing CaV2.1 p.Gln1674Serfs*43 with β4 and α2δ-1 auxiliary subunits. The ablation of divalent flux in response to depolarization was likely attributable to the inability of CaV2.1 p.Gln1674Serfs*43 to form a complete channel pore. Our results suggest that the pathology resulting from this frameshift-inducing nucleotide duplication is a consequence of an effective haploinsufficiency.

Skew deviation and ocular tilt reaction as presenting feature of CACNA1A mutation

We report the case of a 9-year-old girl with aggravation of childhood left head tilt without diplopia. She had right hypertropia and right incyclotorsion, which was compatible with skew deviation and ocular tilt reaction (OTR). She had ataxia, epilepsy, and cerebellar atrophy. Her OTR and neurologic dysfunctions were secondary to a channelopathy caused by CACNA1A mutation.

A novel CACNA1A variant causing Developmental and Epileptic Encephalopathy 42: Report of the first case in Colombia (P3-1.010)

<h3>Objective:</h3> To report a CACNA1A Novel variant causing Developmental and Epileptic Encephalopathy 42. <h3>Background:</h3> CACNA1A encodes the α1A subunit (pore-forming subunit) of a neuronal P/Q type calcium channel. Mutations within this gene lead to clinically significant neurological abnormalities with multiple phenotypic presentations, including Familial Hemiplegic Migraine (FHM), episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6 (SCA6), and Developmental and Epileptic Encephalopathy 42 (DEE42). DEE42 is a disorder characterized by the developmental delay with cognitive impairment and multiple types of seizures in the neonatal period. <h3>Design/Methods:</h3> A karyotype was performed using peripheral blood lymphocytes. A Microarray-based Comparative Genomic Hybridization (aCGH) using CytoScan 750K Array (Affymetrix, Santa Clara, CA, USA) and whole exome sequencing (WES). <h3>Results:</h3> Our patient is a female born to non-consanguineous parents with a family history of speech and psychomotor developmental delay in her mother. She was born at term with uneventful antenatal and perinatal history. At 12 months, she presented to the Neurology and Genetics department with macrocephaly, frontal bossing, severe hypotonia, psychomotor delay, and repeated episodes of seizures requiring therapy with valproic acid and levetiracetam. EEG evidenced generalized spike waves. Her course was complicated by a traumatic brain injury that precipitated repeated episodes of status epilepticus. At 28 months old, she had cognitive and communication deficits with severe speech delay. The aCGH showed a 4q21.21 deletion. The final result was given as 46, XX arr[GRCh37/hg19] chr4:79766081-80327420. In this study, we describe a patient with DEE42 due to a novel mutation in CACNA1A identified using WES. WES revealed a novel heterozygous variant in the CACNA1A gene: c.4174G&gt;A (p.Val1392Met). Parent analysis was negative for the mutation. This novel variant was predicted as a disease-causing mutation. <h3>Conclusions:</h3> These findings widen the mutation and phenotypic spectrum of CACNA1A-associated disease. The potential genotype-phenotype correlation would facilitate early identification and help guide future pharmacologic treatment research. <b>Disclosure:</b> Dr. Orellana Zambrano has nothing to disclose. Dr. Candelo has nothing to disclose. Mrs. Diaz has nothing to disclose. Dr. Pacheco has nothing to disclose. Mr. Giraldo-Ocampo has nothing to disclose. Dr. Gomez-Pineda has nothing to disclose. Dr. Pachajoa has nothing to disclose.

Episodic Ataxias: Primary and Secondary Etiologies, Treatment, and Classification Approaches.

Episodic ataxia (EA), characterized by recurrent attacks of cerebellar dysfunction, is the manifestation of a group of rare autosomal dominant inherited disorders. EA1 and EA2 are most frequently encountered, caused by mutations in KCNA1 and CACNA1A. EA3-8 are reported in rare families. Advances in genetic testing have broadened the KCNA1 and CACNA1A phenotypes, and detected EA as an unusual presentation of several other genetic disorders. Additionally, there are various secondary causes of EA and mimicking disorders. Together, these can pose diagnostic challenges for neurologists. A systematic literature review was performed in October 2022 for 'episodic ataxia' and 'paroxysmal ataxia', restricted to publications in the last 10 years to focus on recent clinical advances. Clinical, genetic, and treatment characteristics were summarized. EA1 and EA2 phenotypes have further broadened. In particular, EA2 may be accompanied by other paroxysmal disorders of childhood with chronic neuropsychiatric features. New treatments for EA2 include dalfampridine and fampridine, in addition to 4-aminopyridine and acetazolamide. There are recent proposals for EA9-10. EA may also be caused by gene mutations associated with chronic ataxias (SCA-14, SCA-27, SCA-42, AOA2, CAPOS), epilepsy syndromes (KCNA2, SCN2A, PRRT2), GLUT-1, mitochondrial disorders (PDHA1, PDHX, ACO2), metabolic disorders (Maple syrup urine disease, Hartnup disease, type I citrullinemia, thiamine and biotin metabolism defects), and others. Secondary causes of EA are more commonly encountered than primary EA (vascular, inflammatory, toxic-metabolic). EA can be misdiagnosed as migraine, peripheral vestibular disorders, anxiety, and functional symptoms. Primary and secondary EA are frequently treatable which should prompt a search for the cause. EA may be overlooked or misdiagnosed for a variety of reasons, including phenotype-genotype variability and clinical overlap between primary and secondary causes. EA is highly treatable, so it is important to consider in the differential diagnosis of paroxysmal disorders. Classical EA1 and EA2 phenotypes prompt single gene test and treatment pathways. For atypical phenotypes, next generation genetic testing can aid diagnosis and guide treatment. Updated classification systems for EA are discussed which may assist diagnosis and management.

Whole Exome Sequencing of Hemiplegic Migraine Patients Shows an Increased Burden of Missense Variants in CACNA1H and CACNA1I Genes

Hemiplegic migraine (HM) is a rare subtype of migraine with aura. Given that causal missense mutations in the voltage-gated calcium channel α1A subunit gene CACNA1A have been identified in a subset of HM patients, we investigated whether HM patients without a mutation have an increased burden of such variants in the “CACNA1x gene family”. Whole exome sequencing data of an Australian cohort of unrelated HM patients (n = 184), along with public data from gnomAD, as controls, was used to assess the burden of missense variants in CACNA1x genes. We performed both a variant and a subject burden test. We found a significant burden for the number of variants in CACNA1E (p = 1.3 × 10−4), CACNA1H (p < 2.2 × 10−16) and CACNA1I (p < 2.2 × 10−16). There was also a significant burden of subjects with missense variants in CACNA1E (p = 6.2 × 10−3), CACNA1H (p < 2.2 × 10−16) and CACNA1I (p < 2.2 × 10−16). Both the number of variants and number of subjects were replicated for CACNA1H (p = 3.5 × 10−8; p = 0.012) and CACNA1I (p = 0.019, p = 0.044), respectively, in a Dutch clinical HM cohort (n = 32), albeit that CACNA1I did not remain significant after multiple testing correction. Our data suggest that HM, in the absence of a single causal mutation, is a complex trait, in which an increased burden of missense variants in CACNA1H and CACNA1I may contribute to the risk of disease.

A Rare Cause of Paroxysmal Movement Disorder Associated with TBC1D24 Gene Mutation in Two Siblings.

A Rare Cause of Paroxysmal Movement Disorder Associated with TBC1D24 Gene Mutation in Two Siblings.

Episodic ataxia type 2: a clinical, genetic and radiological study of 10 patients

To describe a series of patients with episodic ataxia type 2 (EA2), attending to epidemiological, clinical, radiological, and therapeutic variables. Retrospective revision of patients with molecular diagnosis of EA2 (CACNA1A mutations), between 1988 and 2022. Information achieved from the database of our Movement Disorders clinic. A descriptive statistical analysis was made. Ten patients from five families were analyzed (six women). Median age at diagnosis was 37.5 years-old, with a median diagnostic delay of 20 years. 70% reported familial history of CACNA1A associated symptoms, although 50% presented migraine, epilepsy, dystonia, or neuropsychiatric alterations. Two heterozygous consanguineous patients had homozygotic descendance with infant mortality due to early-onset epileptic encephalopathy type 42. Five pathogenic/probably pathogenic CACNA1A variants were detected. 80% of patients had episodic triggers, being stress the most common. Episodes had a weekly frequency before treatment initiation. Six patients developed chronic ataxia (one patient demand gait support). 50% of patients with neuroimaging presented cerebellar atrophy. Acetazolamide were initiated in 80%, and 75% of them showed improvement of episodic symptoms. Nephrolithiasis was the most frequent side effect. EA2 has a great intrafamilial and interfamilial phenotypic variability. The most frequent phenotype were weekly episodes of unsteadiness, several hours of length, stress as the main trigger, chronic ataxia and gaze-evoked nystagmus. Acetazolamide is effective, although complications are usual. Neurologist must be alert as diagnostic delay is constant.

Complex effects on CaV2.1 channel gating caused by a CACNA1A variant associated with a severe neurodevelopmental disorder

P/Q-type Ca2+ currents mediated by CaV2.1 channels are essential for active neurotransmitter release at neuromuscular junctions and many central synapses. Mutations in CACNA1A, the gene encoding the principal CaV2.1 α1A subunit, cause a broad spectrum of neurological disorders. Typically, gain-of-function (GOF) mutations are associated with migraine and epilepsy while loss-of-function (LOF) mutations are causative for episodic and congenital ataxias. However, a cluster of severe CaV2.1 channelopathies have overlapping presentations which suggests that channel dysfunction in these disorders cannot always be defined bimodally as GOF or LOF. In particular, the R1667P mutation causes focal seizures, generalized hypotonia, dysarthria, congenital ataxia and, in one case, cerebral edema leading ultimately to death. Here, we demonstrate that the R1667P mutation causes both channel GOF (hyperpolarizing voltage-dependence of activation, slowed deactivation) and LOF (slowed activation kinetics) when expressed heterologously in tsA-201 cells. We also observed a substantial reduction in Ca2+ current density in this heterologous system. These changes in channel gating and availability/expression manifested in diminished Ca2+ flux during action potential-like stimuli. However, the integrated Ca2+ fluxes were no different when normalized to tail current amplitude measured upon repolarization from the reversal potential. In summary, our findings indicate a complex functional effect of R1667P and support the idea that pathological missense mutations in CaV2.1 may not represent exclusively GOF or LOF.

Hippocampus-related cognitive disorders develop in the absence of epilepsy and ataxia in the heterozygous Cacna1a mutant mice tottering

ABSTRACT CACNA1A-associated epilepsy and ataxia frequently accompany cognitive impairments as devastating co-morbidities. However, it is unclear whether the cognitive deficits are consequences secondary to the neurological symptoms elicited by CACNA1A mutations. To address this issue, Cacna1a mutant mice tottering (tg), and in particular tg/+ heterozygotes, serve as a suitable model system, given that tg/+ heterozygotes fail to display spontaneous absence epilepsy and ataxia typically observed in tg/tg homozygotes. Here, we examined hippocampus-dependent behaviors and hippocampal learning-related synaptic plasticity in tg mice. In behavioral analyses of tg/+ and tg/tg, acquisition and retention of spatial reference memory were characteristically impaired in the Morris water maze task, while working memory was intact in the eight-arm radial maze and T-maze tasks. tg/+ heterozygotes showed normal motor function in contrast to tg/tg homozygotes. In electrophysiological analyses, Schaffer collateral–CA1 synapses showed a deficit in the maintenance of long-term potentiation in tg/+ and tg/tg mice and an increased paired-pulse facilitation induced by paired pulses with 100 ms in tg/tg mice. Our results indicate that the tg mutation causes a dominant disorder of the hippocampus-related memory and synaptic plasticity, raising the possibility that in CACNA1A-associated human diseases, functionally aberrant CaV2.1 Ca2+ channels actively induce the observed cognitive deficits independently of the neurological symptoms.

Sporadic Hemiplegic Migraine with CACNA1A Mutation Masquerading as Acute Meningoencephalitis

Sporadic Hemiplegic Migraine with CACNA1A Mutation Masquerading as Acute Meningoencephalitis

Sporadic Hemiplegic Migraine Presenting ATP1A2 Mutation in Korea

Hemiplegic migraine (HM) is a rare form of migraine, characterized by migraine with reversible motor weakness. HM can be divided into sporadic and familiar HM based on familiarity. Mutations in CACNA1A, ATP1A2 and SCN1A were identified in familiar HM. We present a patient with sporadic HM exhibiting recurrent hemiplegia, mental change and fever along with headache attacks. During the hemiplegia, he showed perfusion delay in left middle cerebral artery territory. Genetic panel test revealed a likely pathogenic varia nt in ATP1A2.