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Open accessJournal ArticleDOI: 10.3389/FNEUR.2021.639994

From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing.

02 Mar 2021-Frontiers in Neurology (Frontiers Media SA)-Vol. 12, pp 639994-639994
Abstract: Ion channel dysfunction is a key pathological substrate of episodic neurological disorders. A classical gene associated to paroxysmal movement disorders is CACNA1A, which codes for the pore-forming subunit of the neuronal calcium channel P/Q. Non-polyglutamine CACNA1A variants underlie familial hemiplegic ataxia type 1 (FHM1) and episodic ataxia type 2 (EA2). Classical paroxysmal manifestations of FHM1 are migraine attacks preceded by motor aura consisting of hemiparesis, aphasia, and disturbances of consciousness until coma. Patients with EA2 suffer of recurrent episodes of vertigo, unbalance, diplopia, and vomiting. Beyond these typical presentations, several reports highlighted manifold clinical features associated with P/Q channelopathies, from chronic progressive cerebellar ataxia to epilepsy and psychiatric disturbances. These manifestations may often outlast the burden of classical episodic symptoms leading to pitfalls in the diagnostic work-up. Lately, the spreading of next generation sequencing techniques linked de novo CACNA1A variants to an even broader phenotypic spectrum including early developmental delay, autism spectrum disorders, epileptic encephalopathy, and early onset paroxysmal dystonia. The age-dependency represents a striking new aspect of these phenotypes und highlights a pivotal role for P/Q channels in the development of the central nervous system in a defined time window. While several reviews addressed the clinical presentation and treatment of FHM1 and EA2, an overview of the newly described age-dependent manifestations is lacking. In this Mini-Review we present a clinical update, delineate genotype-phenotype correlations as well as summarize evidence on the pathophysiological mechanisms underlying the expanded phenotype associated with CACNA1A variants.

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Topics: Ataxia (56.99%), Paroxysmal dystonia (51%), Movement disorders (51%)
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8 results found


Open accessJournal ArticleDOI: 10.3390/BIOMEDICINES9111499
Craig S. McIntosh1, Craig S. McIntosh2, Dunhui Li2, Dunhui Li1  +4 moreInstitutions (2)
20 Oct 2021-Biomedicines
Abstract: Polyglutamine (polyQ) ataxias are a heterogenous group of neurological disorders all caused by an expanded CAG trinucleotide repeat located in the coding region of each unique causative gene. To date, polyQ ataxias encompass six disorders: spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17 and account for a larger group of disorders simply known as polyglutamine disorders, which also includes Huntington’s disease. These diseases are typically characterised by progressive ataxia, speech and swallowing difficulties, lack of coordination and gait, and are unfortunately fatal in nature, with the exception of SCA6. All the polyQ spinocerebellar ataxias have a hallmark feature of neuronal aggregations and share many common pathogenic mechanisms, such as mitochondrial dysfunction, impaired proteasomal function, and autophagy impairment. Currently, therapeutic options are limited, with no available treatments that slow or halt disease progression. Here, we discuss the common molecular and clinical presentations of polyQ spinocerebellar ataxias. We will also discuss the promising antisense oligonucleotide therapeutics being developed as treatments for these devastating diseases. With recent advancements and therapeutic approvals of various antisense therapies, it is envisioned that some of the studies reviewed may progress into clinical trials and beyond.

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Topics: Spinocerebellar ataxia (60%)

4 Citations


Open accessJournal ArticleDOI: 10.3390/NEUROLINT13040055
Abstract: Epileptic encephalopathies often have a genetic etiology. The epileptic activity itself exerts a direct detrimental effect on neurodevelopment, which may add to the cognitive impairment induced by the underlying mutation (“developmental and epileptic encephalopathy”). The focus of this review is on inherited syndromes. The phenotypes of genetic disorders affecting ion channels, metabolic signalling, membrane trafficking and exocytosis, cell adhesion, cell growth and proliferation are discussed. Red flags suggesting family of genes or even specific genes are highlighted. The knowledge of the phenotypical spectrum can indeed prompt the clinician to suspect specific etiologies, expediting the diagnosis.

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1 Citations


Open accessJournal ArticleDOI: 10.1186/S10194-021-01309-4
Yingji Li1, Wenjing Tang1, Li Kang1, Li Kang2  +5 moreInstitutions (2)
Abstract: Background Mutations in ATP1A2, the gene encoding the α2 subunit of Na+/K+-ATPase, are the main cause of familial hemiplegic migraine type 2 (FHM2). The clinical presentation of FHM2 with mutations in the same gene varies from pure FHM to severe forms with epilepsy and intellectual disability, but the correlation of these symptoms with different ATP1A2 mutations is still unclear. Methods Ten ATP1A2 missense mutations were selected according to different phenotypes of FHM patients. They caused pure FHM (FHM: R65W, R202Q, R593W, G762S), FHM with epilepsy (FHME: R548C, E825K, R938P), or FHM with epilepsy and intellectual disability (FHMEI: T378N, G615R, D718N). After ouabain resistance and fluorescence modification, plasmids carrying those mutations were transiently transfected into HEK293T and HeLa cells. The biochemical functions were studied including cell survival assays, membrane protein extraction, western blotting, and Na+/K+-ATPase activity tests. The electrophysiological functions of G762S, R938P, and G615R mutations were investigated in HEK293T cells using whole-cell patch-clamp. Homology modeling was performed to determine the locational distribution of ATP1A2 mutations. Results Compared with wild-type pumps, all mutations showed a similar level of protein expression and decreased cell viability in the presence of 1 µM ouabain, and there was no significant difference among the mutant groups. The changes in Na+/K+-ATPase activity were correlated with the severity of FHM phenotypes. In the presence of 100 µM ouabain, the Na+/K+-ATPase activity was FHM > FHME > FHMEI. The ouabain-sensitive Na+/K+-ATPase activity of each mutant was significantly lower than that of the wild-type protein, and there was no significant difference among all mutant groups. Whole-cell voltage-clamp recordings in HEK293T cells showed that the ouabain-sensitive pump currents of G615R were significantly reduced, while those of G762S and R938P were comparable to those of the wild-type strain. Conclusions ATP1A2 mutations cause phenotypes ranging from pure FHM to FHM with epilepsy and intellectual disability due to varying degrees of deficits in biochemical and electrophysiological properties of Na+/K+-ATPase. Mutations associated with intellectual disability presented with severe impairment of Na+/K+-ATPase. Whether epilepsy is accompanied, or the type of epilepsy did not seem to affect the degree of impairment of pump function.

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Topics: Familial hemiplegic migraine (69%), ATP1A2 (57.99%), Na+/K+-ATPase (54%)

Open accessJournal ArticleDOI: 10.1007/S00415-021-10878-Y
Abstract: Gait disturbances are a frequent symptom in CACNA1A disorders. Even though, data about their severity and progression are lacking and no CACNA1A-specific scale or assessment for gait is available. We applied a gait assessment protocol in 20 ambulatory patients with genetically confirmed CACNA1A disorders and 39 matched healthy controls. An instrumented gait analysis (IGA) was performed by means of wearable sensors in basal condition and after a treadmill/cycloergometer challenge in selected cases. CACNA1A patients displayed lower gait speed, shorter steps with increased step length variability, a reduced landing acceleration as well as a reduced range of ankle motion compared to controls. Furthermore, gait-width in patients with episodic CACNA1A disorders was narrower as compared to controls. In one patient experiencing mild episodic symptoms after the treadmill challenge, the IGA was able to detect a deterioration over all gait parameters. In CACNA1A patients, the IGA with wearable sensors unravels specific gait signatures which are not detectable at naked eye. These features (narrow-based gait, lower landing acceleration) distinguish these patients from other ataxic disorders and may be target of focused rehabilitative interventions. IGA can potentially be applied to monitor the neurological fluctuations associated with CACNA1A disorders.

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Topics: Gait Disturbance (67%), Gait (human) (61%), Gait analysis (60%)

Open accessJournal ArticleDOI: 10.1007/S00415-021-10897-9
Abstract: Variants in CACNA1A are classically related to episodic ataxia type 2, familial hemiplegic migraine type 1, and spinocerebellar ataxia type 6. Over the years, CACNA1A has been associated with a broader spectrum of phenotypes. Targeted analysis and unbiased sequencing of CACNA1A result not only in clear molecular diagnoses, but also in large numbers of variants of uncertain significance (VUS), or likely pathogenic variants with a phenotype that does not directly match the CACNA1A spectrum. Over the last years, targeted and clinical exome sequencing in our center has identified 41 CACNA1A variants. Ultimately, variants were considered pathogenic or likely pathogenic in 23 cases, with most phenotypes ranging from episodic or progressive ataxia to more complex ataxia syndromes, as well as intellectual disability and epilepsy. In two cases, the causality of the variant was discarded based on non-segregation or an alternative diagnosis. In the remaining 16 cases, the variant was classified as uncertain, due to lack of opportunities for segregation analysis or uncertain association with a non-classic phenotype. Phenotypic variability and the large number of VUS make CACNA1A a challenging gene for neurogenetic diagnostics. Accessible functional read-outs are clearly needed, especially in cases with a non-classic phenotype.

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117 results found


Open accessJournal ArticleDOI: 10.1177/0333102413485658
01 Jul 2013-Cephalalgia
Abstract: The International Classification of Headache Disorders, 3 edition (beta version), may be reproduced freely for scientific, educational or clinical uses by institutions, societies or individuals. Otherwise, copyright belongs exclusively to the International Headache Society. Reproduction of any part or parts in any manner for commercial uses requires the Society’s permission, which will be granted on payment of a fee. Please contact the publisher at the address below. International Headache Society 2013. Applications for copyright permissions should be submitted to Sage Publications Ltd, 1 Oliver’s Yard, 55 City Road, London EC1Y 1SP, United Kingdom (tel: þ44 (0) 20 7324 8500; fax: þ44 (0) 207 324 8600) (www.sagepub.co.uk). Translations

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5,925 Citations


Open accessJournal ArticleDOI: 10.1016/S0092-8674(00)81373-2
01 Nov 1996-Cell
Abstract: Genes for familial hemiplegic migraine (FHM) and episodic ataxia type-2 (EA-2) have been mapped to chromosome 19p13. We characterized a brain- specific P/Q-type Ca2+ channel α1-subunit gene, CACNLIA4, covering 300 kb with 47 exons. Sequencing of all exons and their surroundings revealed polymorphic variations, including a (CA)(n)-repeat (D19S1150), a (CAG)(n)- repeat in the 3'-UTR, and different types of deleterious mutations in FHM and EA-2. In FHM, we found four different missense mutations in conserved functional domains. One mutation has occurred on two different haplotypes in unrelated FHM families. In EA-2, we found two mutations disrupting the reading frame. Thus, FHM and EA-2 can be considered as allelic channelopathies. A similar etiology may be involved in common types of migraine.

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Topics: Familial hemiplegic migraine (76%), Spinocerebellar ataxia type 6 (62%), Episodic ataxia (61%) ... show more

2,190 Citations


Journal ArticleDOI: 10.1038/NG0197-62
Olga Zhuchenko1, Jennifer Bailey1, Penelope E. Bonnen1, T. Ashizawa1  +7 moreInstitutions (5)
01 Jan 1997-Nature Genetics
Abstract: A polymorphic CAG repeat was identified in the human α1A voltage-dependent calcium channel subunit. To test the hypothesis that expansion of this CAG repeat could be the cause of an inherited progressive ataxia, we genotyped a large number of unrelated controls and ataxia patients. Eight unrelated patients with late onset ataxia had alleles with larger repeat numbers (21‐27) compared to the number of repeats (4‐16) in 475 non‐ataxia individuals. Analysis of the repeat length in families of the affected individuals revealed that the expansion segregated with the phenotype in every patient. We identified six isoforms of the human α1A calcium channel subunit. The CAG repeat is within the open reading frame and is predicted to encode glutamine in three of the isoforms. We conclude that a small polyglutamine expansion in the human α1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.

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1,517 Citations


Open accessJournal ArticleDOI: 10.1038/NATURE12439
12 Sep 2013-Nature
Abstract: Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.

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Topics: Mutation rate (52%), Ohtahara syndrome (52%), Mutation (51%) ... show more

1,109 Citations


Open accessJournal ArticleDOI: 10.1101/CSHPERSPECT.A003947
William A. Catterall1Institutions (1)
Abstract: Voltage-gated calcium (Ca(2+)) channels are key transducers of membrane potential changes into intracellular Ca(2+) transients that initiate many physiological events. There are ten members of the voltage-gated Ca(2+) channel family in mammals, and they serve distinct roles in cellular signal transduction. The Ca(V)1 subfamily initiates contraction, secretion, regulation of gene expression, integration of synaptic input in neurons, and synaptic transmission at ribbon synapses in specialized sensory cells. The Ca(V)2 subfamily is primarily responsible for initiation of synaptic transmission at fast synapses. The Ca(V)3 subfamily is important for repetitive firing of action potentials in rhythmically firing cells such as cardiac myocytes and thalamic neurons. This article presents the molecular relationships and physiological functions of these Ca(2+) channel proteins and provides information on their molecular, genetic, physiological, and pharmacological properties.

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Topics: SK channel (59%), T-type calcium channel (57.99%), Calcium signaling (56%) ... show more

1,082 Citations


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