Episodic Ataxia Secondary to <i>CEP290</i> Compound Heterozygous Mutations: A Case Report

Hamed, Moath; Shetty, Aakash; Dzwiniel, Tara; Buller, M.; Koskinen, Lotta; Suchowersky, Oksana

doi:10.1002/mdc3.12872

Cited by 5 publications

(2 citation statements)

References 9 publications

(23 reference statements)

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“…In contrast to the aforementioned types of episodic ataxia the following genes are associated with episodic ataxia, but not OMIM listed as distinct groups: ATP1A3 ( 55 ), PRRT2 ( 56 ), SLC2A1 ( 57 ), TBC1D24 ( 58 ), KCNA2 ( 59 ), CEP290 ( 60 ), FGF14 ( 61 ), and NALCN ( 62 ).…”

Section: Resultsmentioning

confidence: 99%

Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature

et al. 2021

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Introduction: Among genetic paroxysmal movement disorders, variants in ion channel coding genes constitute a major subgroup. Loss-of-function (LOF) variants in KCNA1, the gene coding for KV1.1 channels, are associated with episodic ataxia type 1 (EA1), characterized by seconds to minutes-lasting attacks including gait incoordination, limb ataxia, truncal instability, dysarthria, nystagmus, tremor, and occasionally seizures, but also persistent neuromuscular symptoms like myokymia or neuromyotonia. Standard treatment has not yet been developed, and different treatment efforts need to be systematically evaluated.Objective and Methods: Personalized therapeutic regimens tailored to disease-causing pathophysiological mechanisms may offer the specificity required to overcome limitations in therapy. Toward this aim, we (i) reviewed all available clinical reports on treatment response and functional consequences of KCNA1 variants causing EA1, (ii) examined the potential effects on neuronal excitability of all variants using a single compartment conductance-based model and set out to assess the potential of two sodium channel blockers (SCBs: carbamazepine and riluzole) to restore the identified underlying pathophysiological effects of KV1.1 channels, and (iii) provide a comprehensive review of the literature considering all types of episodic ataxia.Results: Reviewing the treatment efforts of EA1 patients revealed moderate response to acetazolamide and exhibited the strength of SCBs, especially carbamazepine, in the treatment of EA1 patients. Biophysical dysfunction of KV1.1 channels is typically based on depolarizing shifts of steady-state activation, leading to an LOF of KCNA1 variant channels. Our model predicts a lowered rheobase and an increase of the firing rate on a neuronal level. The estimated concentration dependent effects of carbamazepine and riluzole could partially restore the altered gating properties of dysfunctional variant channels.Conclusion: These data strengthen the potential of SCBs to contribute to functional compensation of dysfunctional KV1.1 channels. We propose riluzole as a new drug repurposing candidate and highlight the role of personalized approaches to develop standard care for EA1 patients. These results could have implications for clinical practice in future and highlight the need for the development of individualized and targeted therapies for episodic ataxia and genetic paroxysmal disorders in general.

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Section: Resultsmentioning

confidence: 99%

Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature

et al. 2021

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“…Episodes of ataxia started around the age of 50 years and were characterized by ataxia, fatigue, diplopia, and dysarthria; no triggering factors were identified. Mild cerebral and cerebellar atrophy is described on brain MRI [321].…”

Section: Metabolic Disorders With Eamentioning

confidence: 99%

Clinical and Genetic Overview of Paroxysmal Movement Disorders and Episodic Ataxias

Garone

Capuano

Travaglini

et al. 2020

IJMS

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Paroxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements. Two main categories of PMDs are recognized based on the phenomenology: Paroxysmal dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement disorders, while attacks of cerebellar dysfunction are the hallmark of episodic ataxias (EAs). From an etiological point of view, both primary (genetic) and secondary (acquired) causes of PMDs are known. Recognition and diagnosis of PMDs is based on personal and familial medical history, physical examination, detailed reconstruction of ictal phenomenology, neuroimaging, and genetic analysis. Neurophysiological or laboratory tests are reserved for selected cases. Genetic knowledge of PMDs has been largely incremented by the advent of next generation sequencing (NGS) methodologies. The wide number of genes involved in the pathogenesis of PMDs reflects a high complexity of molecular bases of neurotransmission in cerebellar and basal ganglia circuits. In consideration of the broad genetic and phenotypic heterogeneity, a NGS approach by targeted panel for movement disorders, clinical or whole exome sequencing should be preferred, whenever possible, to a single gene approach, in order to increase diagnostic rate. This review is focused on clinical and genetic features of PMDs with the aim to (1) help clinicians to recognize, diagnose and treat patients with PMDs as well as to (2) provide an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders.

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Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4

Wang¹,

Li²,

Jiang

et al. 2023

American Journal of Ophthalmology

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Episodic Ataxia Secondary to CEP290 Compound Heterozygous Mutations: A Case Report

Abstract: View Supplementary Video 1

Cited by 5 publications

References 9 publications

Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature

Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature

Clinical and Genetic Overview of Paroxysmal Movement Disorders and Episodic Ataxias

Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4

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