The electrophysiological footprint of CACNA1A disorders

Indelicato, Elisabetta; Unterberger, Iris; Nachbauer, Wolfgang; Eigentler, Andreas; Amprosi, Matthias; Zeiner, F.; Haberlandt, Edda; Kaml, Manuela; Gizewski, Elke R.; Boesch, Sylvia

doi:10.1007/s00415-021-10415-x

Cited by 7 publications

(3 citation statements)

References 62 publications

(101 reference statements)

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“…An association between epilepsy and CACNA1A disorders has been postulated early (12) and then corroborated by several independent reports describing co-occurrence of epileptic features in CACNA1A pedigrees [reviewed in (63)]. Epileptic features display some genotype-specificity.…”

Section: Clinical Presentation and Genotype-phenotype Correlationmentioning

confidence: 68%

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

Indelicato

Boesch

2021

Front. Neurol.

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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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Section: Clinical Presentation and Genotype-phenotype Correlationmentioning

confidence: 68%

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

Indelicato

Boesch

2021

Front. Neurol.

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“…Neurophysiological studies may show abnormal signatures for EA2. EEG abnormalities are highly prevalent between attacks, especially in younger patients or with earlyonset attacks [46]. Amongst CACNA1Apositive adult cases with EA, instrumented gait analysis can detect a specific gait signature of narrowbased gait and lower landing acceleration [47].…”

Section: Expanded Descriptionmentioning

confidence: 99%

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

Hassan¹

2023

Tremor and Other Hyperkinetic Movements

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Background: Episodic ataxia (EA), characterized by recurrent attacks of cerebellar dysfunc tion, 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.Methods: 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.Results: EA1 and EA2 phenotypes have further broadened. In particular, EA2 may be accom panied by other paroxysmal disorders of childhood with chronic neuropsychiatric features. New treatments for EA2 include dalfampridine and fampridine, in addition to 4aminopyridine 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), GLUT1, 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, toxicmetabolic). 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.Discussion: EA may be overlooked or misdiagnosed for a variety of reasons, including phenotypegenotype 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.

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“…Chronic neurological symptoms consist of various degree of cerebellar ataxia, developmental delay, cognitive and psychiatric symptoms [1]. Based on the mutation type, prevalent phenotype and clinical course, four clinical entities are currently defined: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) spinocerebellar ataxia type 6 (SCA6) and the early infantile epileptic encephalopathy type 42 (EIEE42) [1,2].…”

Section: Introductionmentioning

confidence: 99%

Instrumented gait analysis defines the walking signature of CACNA1A disorders

et al. 2021

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Background 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. Methods 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. Results 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. Conclusions 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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The electrophysiological footprint of CACNA1A disorders

Cited by 7 publications

References 62 publications

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

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

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

Instrumented gait analysis defines the walking signature of CACNA1A disorders

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