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Biomedicines
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Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia
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Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 23391

Special Issue Editor

Dr. Paola Imbrici

E-Mail Website1 Website2
Guest Editor
Dipartimento di Farmacia, Università degli Studi di Bari, Bari, Italy
Interests: Ion channels physiology; Ion channels pharmacology; Ion channel diseases: channelopathies; Autism; Intellectual disability; Epilepsy; Movement disorders, Ataxia; Neurophysiology; Electrophysiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ataxias are rare heterogeneous neurological disorders that affect balance, coordination, and speech. Ataxia syndromes include hereditary forms such as episodic, spinocerebellar, Friedreich’s, X-linked, and mitochondrial ataxia as well as sporadic conditions. The clinical spectrum of these syndromes is wide, and phenotypic variability is recurrent between individuals suffering from the same ataxia subtype. Ataxia can also be a symptom of other diseases, such as multiple sclerosis and cerebral palsy. Episodic ataxias (EAs) are a group of dominantly inherited disorders characterized by transient recurrent incoordination and imbalance, often triggered by physical and emotional stress and mostly with early onset. The number of EAs is expanding and, to date, eight subtypes have been defined, principally on a genetic basis. EA1 and EA2, the most common and better characterized forms, are considered neurologic channelopathies. EA1 is caused by heterozygous mutations in KCNA1, which encodes the voltage-gated potassium channel Kv1.1, predominantly expressed in the cerebellum. EA2 is caused by heterozygous mutations in CACNA1A, which encodes the voltage-gated calcium channel Cav2.1, or P/Q‐type that is abundantly expressed in the cerebellum and the neuromuscular junction. EA2 is allelic with two other neurologic conditions: familial hemiplegic migraine type 1 and spinocerebellar ataxia type 6. The functional characterization of mutant channels in heterologous systems and studies from animal models has helped to shed light on the molecular and cellular mechanisms underlying both EA1 and EA2. EA6 is caused by heterozygous mutations in SLC1A3, which encodes for a subunit of the glial glutamate transporter, EAAT1. The other EA subtypes were defined in single families and are awaiting gene identification and confirmation. Antiepileptic drugs, acetazolamide and 4-aminopyridine are among the symptomatic treatments available for EA syndromes.

This Special Issue “Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia” will comprise a selection of research papers and reviews covering various aspects of EA syndromes, including clinical and genetic diagnosis, genotype–phenotype correlation, disease mechanisms, animal models, and therapeutic management. Manuscripts focusing on other types of rare ataxias will also be considered. We hope that this Special Issue will be a meeting place for scientists working on ataxia, as well as an opportunity to establish collaborations.

This Special Issue is jointly organized between IJMS and Biomedicines journals. According to the Aims and Scope of these journals, articles showing basic studies in biochemistry, molecular biology, and molecular medicine can be submitted to IJMS, while articles presenting more clinical content can be submitted to Biomedicines.

Dr. Paola Imbrici
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • episodic ataxia
  • channelopathies
  • ion channels and transporters
  • cerebellum
  • acetazolamide
  • 4-aminopiridine

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Related Special Issue

Published Papers (6 papers)

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Research

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14 pages, 1981 KiB  
Article
Musculoskeletal Features without Ataxia Associated with a Novel de novo Mutation in KCNA1 Impairing the Voltage Sensitivity of Kv1.1 Channel
by Paola Imbrici, Andrea Accogli, Rikard Blunck, Concetta Altamura, Michele Iacomino, Maria Cristina D’Adamo, Anna Allegri, Marina Pedemonte, Noemi Brolatti, Stella Vari, Matteo Cataldi, Valeria Capra, Stefano Gustincich, Federico Zara, Jean-Francois Desaphy and Chiara Fiorillo
Biomedicines 2021, 9(1), 75; https://doi.org/10.3390/biomedicines9010075 - 14 Jan 2021
Cited by 5 | Viewed by 3234
Abstract
The KCNA1 gene encodes the α subunit of the voltage-gated Kv1.1 potassium channel that critically regulates neuronal excitability in the central and peripheral nervous systems. Mutations in KCNA1 have been classically associated with episodic ataxia type 1 (EA1), a movement disorder triggered by [...] Read more.
The KCNA1 gene encodes the α subunit of the voltage-gated Kv1.1 potassium channel that critically regulates neuronal excitability in the central and peripheral nervous systems. Mutations in KCNA1 have been classically associated with episodic ataxia type 1 (EA1), a movement disorder triggered by physical and emotional stress. Additional features variably reported in recent years include epilepsy, myokymia, migraine, paroxysmal dyskinesia, hyperthermia, hypomagnesemia, and cataplexy. Interestingly, a few individuals with neuromyotonia, either isolated or associated with skeletal deformities, have been reported carrying variants in the S2–S3 transmembrane segments of Kv1.1 channels in the absence of any other symptoms. Here, we have identified by whole-exome sequencing a novel de novo variant, T268K, in KCNA1 in a boy displaying recurrent episodes of neuromyotonia, muscle hypertrophy, and skeletal deformities. Through functional analysis in heterologous cells and structural modeling, we show that the mutation, located at the extracellular end of the S3 helix, causes deleterious effects, disrupting Kv1.1 function by altering the voltage dependence of activation and kinetics of deactivation, likely due to abnormal interactions with the voltage sensor in the S4 segment. Our study supports previous evidence suggesting that specific residues within the S2 and S3 segments of Kv1.1 result in a distinctive phenotype with predominant musculoskeletal presentation. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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14 pages, 1286 KiB  
Article
The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood
by Jan Henje Döring, Afshin Saffari, Thomas Bast, Knut Brockmann, Laura Ehrhardt, Walid Fazeli, Wibke G. Janzarik, Gerhard Kluger, Hiltrud Muhle, Rikke S. Møller, Konrad Platzer, Joana Larupa Santos, Iben Bache, Astrid Bertsche, Michaela Bonfert, Ingo Borggräfe, Philip J. Broser, Alexandre N. Datta, Trine Bjørg Hammer, Hans Hartmann, Anette Hasse-Wittmer, Marco Henneke, Hermann Kühne, Johannes R. Lemke, Oliver Maier, Eva Matzker, Andreas Merkenschlager, Joachim Opp, Steffi Patzer, Kevin Rostasy, Birgit Stark, Adam Strzelczyk, Celina von Stülpnagel, Yvonne Weber, Markus Wolff, Birgit Zirn, Georg Friedrich Hoffmann, Stefan Kölker and Steffen Syrbeadd Show full author list remove Hide full author list
Biomedicines 2020, 8(11), 456; https://doi.org/10.3390/biomedicines8110456 - 28 Oct 2020
Cited by 28 | Viewed by 4626
Abstract
Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated [...] Read more.
Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated phenotypes in these children and their relatives. Only a few recent larger cohort studies are on record and findings from single reports were not confirmed so far. We collected detailed genetic and phenotypic data of 40 previously unreported patients from 36 families. All patients had benign infantile epilepsy and harbored pathogenic variants in PRRT2 (core cohort). Clinical data of 62 family members were included, comprising a cohort of 102 individuals (extended cohort) with PRRT2-associated neurological disease. Additional phenotypes in the cohort of patients with benign sporadic and familial infantile epilepsy consist of movement disorders with paroxysmal kinesigenic dyskinesia in six patients, infantile-onset movement disorders in 2 of 40 individuals, and episodic ataxia after mild head trauma in one girl with bi-allelic variants in PRRT2. The same girl displayed a focal cortical dysplasia upon brain imaging. Familial hemiplegic migraine and migraine with aura were reported in nine families. A single individual developed epilepsy with continuous spikes and waves during sleep. In addition to known variants, we report the novel variant c.843G>T, p.(Trp281Cys) that co-segregated with benign infantile epilepsy and migraine in one family. Our study highlights the variability of clinical presentations of patients harboring pathogenic PRRT2 variants and expands the associated phenotypic spectrum. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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13 pages, 442 KiB  
Article
Comprehensive Exonic Sequencing of Known Ataxia Genes in Episodic Ataxia
by Neven Maksemous, Heidi G. Sutherland, Robert A. Smith, Larisa M. Haupt and Lyn R. Griffiths
Biomedicines 2020, 8(5), 134; https://doi.org/10.3390/biomedicines8050134 - 25 May 2020
Cited by 8 | Viewed by 3611
Abstract
Episodic Ataxias (EAs) are a small group (EA1–EA8) of complex neurological conditions that manifest as incidents of poor balance and coordination. Diagnostic testing cannot always find causative variants for the phenotype, however, and this along with the recently proposed EA type 9 (EA9), [...] Read more.
Episodic Ataxias (EAs) are a small group (EA1–EA8) of complex neurological conditions that manifest as incidents of poor balance and coordination. Diagnostic testing cannot always find causative variants for the phenotype, however, and this along with the recently proposed EA type 9 (EA9), suggest that more EA genes are yet to be discovered. We previously identified disease-causing mutations in the CACNA1A gene in 48% (n = 15) of 31 patients with a suspected clinical diagnosis of EA2, and referred to our laboratory for CACNA1A gene testing, leaving 52% of these cases (n = 16) with no molecular diagnosis. In this study, whole exome sequencing (WES) was performed on 16 patients who tested negative for CACNA1A mutations. Tiered analysis of WES data was performed to first explore (Tier-1) the ataxia and ataxia-associated genes (n = 170) available in the literature and databases for comprehensive EA molecular genetic testing; we then investigated 353 ion channel genes (Tier-2). Known and potential causal variants were identified in n = 8/16 (50%) patients in 8 genes (SCN2A, p.Val1325Phe; ATP1A3, p.Arg756His; PEX7, p.Tyr40Ter; and KCNA1, p.Arg167Met; CLCN1, p.Gly945ArgfsX39; CACNA1E, p.Ile614Val; SCN1B, p.Cys121Trp; and SCN9A, p.Tyr1217Ter). These results suggest that mutations in these genes might cause an ataxia phenotype or that combinations of more than one mutation contribute to ataxia disorders. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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Review

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12 pages, 287 KiB  
Review
Involvement of the Peripheral Nervous System in Episodic Ataxias
by Wojciech Koźmiński and Joanna Pera
Biomedicines 2020, 8(11), 448; https://doi.org/10.3390/biomedicines8110448 - 22 Oct 2020
Cited by 4 | Viewed by 2229
Abstract
Episodic ataxias comprise a group of inherited disorders, which have a common hallmark—transient attacks of ataxia. The genetic background is heterogeneous and the causative genes are not always identified. Furthermore, the clinical presentation, including intraictal and interictal symptoms, as well as the retention [...] Read more.
Episodic ataxias comprise a group of inherited disorders, which have a common hallmark—transient attacks of ataxia. The genetic background is heterogeneous and the causative genes are not always identified. Furthermore, the clinical presentation, including intraictal and interictal symptoms, as well as the retention and progression of neurological deficits, is heterogeneous. Spells of ataxia can be accompanied by other symptoms—mostly from the central nervous system. However, in some of episodic ataxias involvement of peripheral nervous system is a part of typical clinical picture. This review intends to provide an insight into involvement of peripheral nervous system in episodic ataxias. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
23 pages, 1625 KiB  
Review
Targeting Alternative Splicing as a Potential Therapy for Episodic Ataxia Type 2
by Fanny Jaudon, Simona Baldassari, Ilaria Musante, Agnes Thalhammer, Federico Zara and Lorenzo A. Cingolani
Biomedicines 2020, 8(9), 332; https://doi.org/10.3390/biomedicines8090332 - 5 Sep 2020
Cited by 13 | Viewed by 5619
Abstract
Episodic ataxia type 2 (EA2) is an autosomal dominant neurological disorder characterized by paroxysmal attacks of ataxia, vertigo, and nausea that usually last hours to days. It is caused by loss-of-function mutations in CACNA1A, the gene encoding the pore-forming α1 subunit [...] Read more.
Episodic ataxia type 2 (EA2) is an autosomal dominant neurological disorder characterized by paroxysmal attacks of ataxia, vertigo, and nausea that usually last hours to days. It is caused by loss-of-function mutations in CACNA1A, the gene encoding the pore-forming α1 subunit of P/Q-type voltage-gated Ca2+ channels. Although pharmacological treatments, such as acetazolamide and 4-aminopyridine, exist for EA2, they do not reduce or control the symptoms in all patients. CACNA1A is heavily spliced and some of the identified EA2 mutations are predicted to disrupt selective isoforms of this gene. Modulating splicing of CACNA1A may therefore represent a promising new strategy to develop improved EA2 therapies. Because RNA splicing is dysregulated in many other genetic diseases, several tools, such as antisense oligonucleotides, trans-splicing, and CRISPR-based strategies, have been developed for medical purposes. Here, we review splicing-based strategies used for genetic disorders, including those for Duchenne muscular dystrophy, spinal muscular dystrophy, and frontotemporal dementia with Parkinsonism linked to chromosome 17, and discuss their potential applicability to EA2. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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Other

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12 pages, 683 KiB  
Case Report
Ataxia as the Major Manifestation of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Case Series
by Maria Jimena Salcedo-Arellano, Ana Maria Cabal-Herrera, Nattaporn Tassanakijpanich, Yingratana A. McLennan and Randi J. Hagerman
Biomedicines 2020, 8(5), 136; https://doi.org/10.3390/biomedicines8050136 - 25 May 2020
Cited by 8 | Viewed by 3450
Abstract
Fragile X-associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disease developed by carriers of a premutation in the fragile X mental retardation 1 (FMR1) gene. The core clinical symptoms usually manifest in the early 60s, typically beginning with intention tremor followed [...] Read more.
Fragile X-associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disease developed by carriers of a premutation in the fragile X mental retardation 1 (FMR1) gene. The core clinical symptoms usually manifest in the early 60s, typically beginning with intention tremor followed by cerebellar ataxia. Ataxia can be the only symptom in approximately 20% of the patients. FXTAS has a slow progression, and patients usually experience advanced deterioration 15 to 25 years after the initial diagnosis. Common findings in brain imaging include substantial brain atrophy and white matter disease (WMD). We report three cases with an atypical clinical presentation, all presenting with gait problems as their initial manifestation and with ataxia as the dominant symptom without significant tremor, as well as a faster than usual clinical progression. Magnetic resonance imaging (MRI) was remarkable for severe brain atrophy, ventriculomegaly, thinning of the corpus callosum, and periventricular WMD. Two cases were diagnosed with definite FXTAS on the basis of clinical and radiological findings, with one individual also developing moderate dementia. Factors such as environmental exposure and general anesthesia could have contributed to their clinical deterioration. FXTAS should be considered in the differential diagnosis of patients presenting with ataxia, even in the absence of tremor, and FMR1 DNA testing should be sought in those with a family history of fragile X syndrome or premutation disorders. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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