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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 International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 82737

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

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Keywords

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

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Published Papers (14 papers)

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Research

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16 pages, 1892 KiB  
Article
Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders
by Jan H. Döring, Julian Schröter, Jerome Jüngling, Saskia Biskup, Kerstin A. Klotz, Thomas Bast, Tobias Dietel, G. Christoph Korenke, Sophie Christoph, Heiko Brennenstuhl, Guido Rubboli, Rikke S. Møller, Gaetan Lesca, Yves Chaix, Stefan Kölker, Georg F. Hoffmann, Johannes R. Lemke and Steffen Syrbe
Int. J. Mol. Sci. 2021, 22(6), 2824; https://doi.org/10.3390/ijms22062824 - 10 Mar 2021
Cited by 24 | Viewed by 5283
Abstract
Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar [...] Read more.
Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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14 pages, 1904 KiB  
Article
A Common Kinetic Property of Mutations Linked to Episodic Ataxia Type 1 Studied in the Shaker Kv Channel
by Juan Zhao, Dimitri Petitjean, Georges A. Haddad, Zarah Batulan and Rikard Blunck
Int. J. Mol. Sci. 2020, 21(20), 7602; https://doi.org/10.3390/ijms21207602 - 14 Oct 2020
Cited by 5 | Viewed by 2832
Abstract
(1) Background: Episodic ataxia type 1 is caused by mutations in the KCNA1 gene encoding for the voltage-gated potassium channel Kv1.1. There have been many mutations in Kv1.1 linked to episodic ataxia reported and typically investigated by themselves or in small groups. The [...] Read more.
(1) Background: Episodic ataxia type 1 is caused by mutations in the KCNA1 gene encoding for the voltage-gated potassium channel Kv1.1. There have been many mutations in Kv1.1 linked to episodic ataxia reported and typically investigated by themselves or in small groups. The aim of this article is to determine whether we can define a functional parameter common to all Kv1.1 mutants that have been linked to episodic ataxia. (2) Methods: We introduced the disease mutations linked to episodic ataxia in the drosophila analog of Kv1.1, the Shaker Kv channel, and expressed the channels in Xenopus oocytes. Using the cut-open oocyte technique, we characterized the gating and ionic currents. (3) Results: We found that the episodic ataxia mutations variably altered the different gating mechanisms described for Kv channels. The common characteristic was a conductance voltage relationship and inactivation shifted to less polarized potentials. (4) Conclusions: We suggest that a combination of a prolonged action potential and slowed and incomplete inactivation leads to development of ataxia when Kv channels cannot follow or adapt to high firing rates. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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13 pages, 2534 KiB  
Article
Association of A Novel Splice Site Mutation in P/Q-Type Calcium Channels with Childhood Epilepsy and Late-Onset Slowly Progressive Non-Episodic Cerebellar Ataxia
by Claudia Stendel, Maria Cristina D’Adamo, Manuela Wiessner, Marina Dusl, Marta Cenciarini, Silvia Belia, Ehsan Nematian-Ardestani, Peter Bauer, Jan Senderek, Thomas Klopstock and Mauro Pessia
Int. J. Mol. Sci. 2020, 21(11), 3810; https://doi.org/10.3390/ijms21113810 - 27 May 2020
Cited by 16 | Viewed by 3654
Abstract
Episodic ataxia type 2 (EA2) is characterized by paroxysmal attacks of ataxia with typical onset in childhood or early adolescence. The disease is associated with mutations in the voltage-gated calcium channel alpha 1A subunit (Cav2.1) that is encoded by the CACNA1A gene. However, [...] Read more.
Episodic ataxia type 2 (EA2) is characterized by paroxysmal attacks of ataxia with typical onset in childhood or early adolescence. The disease is associated with mutations in the voltage-gated calcium channel alpha 1A subunit (Cav2.1) that is encoded by the CACNA1A gene. However, previously unrecognized atypical symptoms and the genetic overlap existing between EA2, spinocerebellar ataxia type 6, familial hemiplegic migraine type 1, and other neurological diseases blur the genotype/phenotype correlations, making a differential diagnosis difficult to formulate correctly and delaying early therapeutic intervention. Here we report a new clinical phenotype of a CACNA1A-associated disease characterized by absence epilepsy occurring during childhood. However, much later in life the patient displayed non-episodic, slowly progressive gait ataxia. Gene panel sequencing for hereditary ataxias led to the identification of a novel heterozygous CACNA1A mutation (c.1913 + 2T > G), altering the donor splice site of intron 14. This genetic defect was predicted to result in an in-frame deletion removing 44 amino acids from the voltage-gated calcium channel Cav2.1. An RT-PCR analysis of cDNA derived from patient skin fibroblasts confirmed the skipping of the entire exon 14. Furthermore, two-electrode voltage-clamp recordings performed from Xenopus laevis oocytes expressing a wild-type versus mutant channel showed that the genetic defect caused a complete loss of channel function. This represents the first description of distinct clinical manifestations that remarkably expand the genetic and phenotypic spectrum of CACNA1A-related diseases and should be considered for an early diagnosis and effective therapeutic intervention. 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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21 pages, 5353 KiB  
Review
Dysmetria and Errors in Predictions: The Role of Internal Forward Model
by Pierre Cabaraux, Jordi Gandini, Shinji Kakei, Mario Manto, Hiroshi Mitoma and Hirokazu Tanaka
Int. J. Mol. Sci. 2020, 21(18), 6900; https://doi.org/10.3390/ijms21186900 - 20 Sep 2020
Cited by 22 | Viewed by 9509
Abstract
The terminology of cerebellar dysmetria embraces a ubiquitous symptom in motor deficits, oculomotor symptoms, and cognitive/emotional symptoms occurring in cerebellar ataxias. Patients with episodic ataxia exhibit recurrent episodes of ataxia, including motor dysmetria. Despite the consensus that cerebellar dysmetria is a cardinal symptom, [...] Read more.
The terminology of cerebellar dysmetria embraces a ubiquitous symptom in motor deficits, oculomotor symptoms, and cognitive/emotional symptoms occurring in cerebellar ataxias. Patients with episodic ataxia exhibit recurrent episodes of ataxia, including motor dysmetria. Despite the consensus that cerebellar dysmetria is a cardinal symptom, there is still no agreement on its pathophysiological mechanisms to date since its first clinical description by Babinski. We argue that impairment in the predictive computation for voluntary movements explains a range of characteristics accompanied by dysmetria. Within this framework, the cerebellum acquires and maintains an internal forward model, which predicts current and future states of the body by integrating an estimate of the previous state and a given efference copy of motor commands. Two of our recent studies experimentally support the internal-forward-model hypothesis of the cerebellar circuitry. First, the cerebellar outputs (firing rates of dentate nucleus cells) contain predictive information for the future cerebellar inputs (firing rates of mossy fibers). Second, a component of movement kinematics is predictive for target motions in control subjects. In cerebellar patients, the predictive component lags behind a target motion and is compensated with a feedback component. Furthermore, a clinical analysis has examined kinematic and electromyography (EMG) features using a task of elbow flexion goal-directed movements, which mimics the finger-to-nose test. Consistent with the hypothesis of the internal forward model, the predictive activations in the triceps muscles are impaired, and the impaired predictive activations result in hypermetria (overshoot). Dysmetria stems from deficits in the predictive computation of the internal forward model in the cerebellum. Errors in this fundamental mechanism result in undershoot (hypometria) and overshoot during voluntary motor actions. The predictive computation of the forward model affords error-based motor learning, coordination of multiple degrees of freedom, and adequate timing of muscle activities. Both the timing and synergy theory fit with the internal forward model, microzones being the elemental computational unit, and the anatomical organization of converging inputs to the Purkinje neurons providing them the unique property of a perceptron in the brain. We propose that motor dysmetria observed in attacks of ataxia occurs as a result of impaired predictive computation of the internal forward model in the cerebellum. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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16 pages, 253 KiB  
Review
Episodic Ataxias: Faux or Real?
by Paola Giunti, Elide Mantuano and Marina Frontali
Int. J. Mol. Sci. 2020, 21(18), 6472; https://doi.org/10.3390/ijms21186472 - 5 Sep 2020
Cited by 11 | Viewed by 3600
Abstract
The term Episodic Ataxias (EA) was originally used for a few autosomal dominant diseases, characterized by attacks of cerebellar dysfunction of variable duration and frequency, often accompanied by other ictal and interictal signs. The original group subsequently grew to include other very rare [...] Read more.
The term Episodic Ataxias (EA) was originally used for a few autosomal dominant diseases, characterized by attacks of cerebellar dysfunction of variable duration and frequency, often accompanied by other ictal and interictal signs. The original group subsequently grew to include other very rare EAs, frequently reported in single families, for some of which no responsible gene was found. The clinical spectrum of these diseases has been enormously amplified over time. In addition, episodes of ataxia have been described as phenotypic variants in the context of several different disorders. The whole group is somewhat confused, since a strong evidence linking the mutation to a given phenotype has not always been established. In this review we will collect and examine all instances of ataxia episodes reported so far, emphasizing those for which the pathophysiology and the clinical spectrum is best defined. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
15 pages, 1039 KiB  
Review
KCND3-Related Neurological Disorders: From Old to Emerging Clinical Phenotypes
by Luca Pollini, Serena Galosi, Manuela Tolve, Caterina Caputi, Carla Carducci, Antonio Angeloni and Vincenzo Leuzzi
Int. J. Mol. Sci. 2020, 21(16), 5802; https://doi.org/10.3390/ijms21165802 - 13 Aug 2020
Cited by 17 | Viewed by 3712
Abstract
KCND3 encodes the voltage-gated potassium ion channel subfamily D member 3, a six trans-membrane protein (Kv4.3), involved in the transient outward K+ current. KCND3 defect causes both cardiological and neurological syndromes. From a neurological perspective, Kv4.3 defect has been associated to SCA [...] Read more.
KCND3 encodes the voltage-gated potassium ion channel subfamily D member 3, a six trans-membrane protein (Kv4.3), involved in the transient outward K+ current. KCND3 defect causes both cardiological and neurological syndromes. From a neurological perspective, Kv4.3 defect has been associated to SCA type 19/22, a complex neurological disorder encompassing a wide spectrum of clinical features beside ataxia. To better define the phenotypic spectrum and course of KCND3-related neurological disorder, we review the clinical presentation and evolution in 68 reported cases. We delineated two main clinical phenotypes according to the age of onset. Neurodevelopmental disorder with epilepsy and/or movement disorders with ataxia later in the disease course characterized the early onset forms, while a prominent ataxic syndrome with possible cognitive decline, movement disorders, and peripheral neuropathy were observed in the late onset forms. Furthermore, we described a 37-year-old patient with a de novo KCND3 variant [c.901T>C (p.Ser301Pro)], previously reported in dbSNP as rs79821338, and a clinical phenotype paradigmatic of the early onset forms with neurodevelopmental disorder, epilepsy, parkinsonism-dystonia, and ataxia in adulthood, further expanding the clinical spectrum of this condition. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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18 pages, 459 KiB  
Review
Inherited Metabolic Disorders Presenting with Ataxia
by Grace Silver and Saadet Mercimek-Andrews
Int. J. Mol. Sci. 2020, 21(15), 5519; https://doi.org/10.3390/ijms21155519 - 1 Aug 2020
Cited by 12 | Viewed by 5503
Abstract
Ataxia is a common clinical feature in inherited metabolic disorders. There are more than 150 inherited metabolic disorders in patients presenting with ataxia in addition to global developmental delay, encephalopathy episodes, a history of developmental regression, coarse facial features, seizures, and other types [...] Read more.
Ataxia is a common clinical feature in inherited metabolic disorders. There are more than 150 inherited metabolic disorders in patients presenting with ataxia in addition to global developmental delay, encephalopathy episodes, a history of developmental regression, coarse facial features, seizures, and other types of movement disorders. Seizures and a history of developmental regression especially are important clinical denominators to consider an underlying inherited metabolic disorder in a patient with ataxia. Some of the inherited metabolic disorders have disease specific treatments to improve outcomes or prevent early death. Early diagnosis and treatment affect positive neurodevelopmental outcomes, so it is important to think of inherited metabolic disorders in the differential diagnosis of ataxia. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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31 pages, 1041 KiB  
Review
Fundamental Mechanisms of Autoantibody-Induced Impairments on Ion Channels and Synapses in Immune-Mediated Cerebellar Ataxias
by Hiroshi Mitoma, Jerome Honnorat, Kazuhiko Yamaguchi and Mario Manto
Int. J. Mol. Sci. 2020, 21(14), 4936; https://doi.org/10.3390/ijms21144936 - 13 Jul 2020
Cited by 19 | Viewed by 4991
Abstract
In the last years, different kinds of limbic encephalitis associated with autoantibodies against ion channels and synaptic receptors have been described. Many studies have demonstrated that such autoantibodies induce channel or receptor dysfunction. The same mechanism is discussed in immune-mediated cerebellar ataxias (IMCAs), [...] Read more.
In the last years, different kinds of limbic encephalitis associated with autoantibodies against ion channels and synaptic receptors have been described. Many studies have demonstrated that such autoantibodies induce channel or receptor dysfunction. The same mechanism is discussed in immune-mediated cerebellar ataxias (IMCAs), but the pathogenesis has been less investigated. The aim of the present review is to evaluate what kind of cerebellar ion channels, their related proteins, and the synaptic machinery proteins that are preferably impaired by autoantibodies so as to develop cerebellar ataxias (CAs). The cerebellum predictively coordinates motor and cognitive functions through a continuous update of an internal model. These controls are relayed by cerebellum-specific functions such as precise neuronal discharges with potassium channels, synaptic plasticity through calcium signaling pathways coupled with voltage-gated calcium channels (VGCC) and metabotropic glutamate receptors 1 (mGluR1), a synaptic organization with glutamate receptor delta (GluRδ), and output signal formation through chained GABAergic neurons. Consistently, the association of CAs with anti-potassium channel-related proteins, anti-VGCC, anti-mGluR1, and GluRδ, and anti-glutamate decarboxylase 65 antibodies is observed in IMCAs. Despite ample distributions of AMPA and GABA receptors, however, CAs are rare in conditions with autoantibodies against these receptors. Notably, when the autoantibodies impair synaptic transmission, the autoimmune targets are commonly classified into three categories: release machinery proteins, synaptic adhesion molecules, and receptors. This physiopathological categorization impacts on both our understanding of the pathophysiology and clinical prognosis. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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23 pages, 1693 KiB  
Review
Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications
by Ana Maria Cabal-Herrera, Nattaporn Tassanakijpanich, Maria Jimena Salcedo-Arellano and Randi J. Hagerman
Int. J. Mol. Sci. 2020, 21(12), 4391; https://doi.org/10.3390/ijms21124391 - 20 Jun 2020
Cited by 67 | Viewed by 10612
Abstract
The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55–200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 [...] Read more.
The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55–200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then FMR1 DNA testing is essential in patients with these symptoms. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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20 pages, 1328 KiB  
Review
Hereditary Ataxia: A Focus on Heme Metabolism and Fe-S Cluster Biogenesis
by Deborah Chiabrando, Francesca Bertino and Emanuela Tolosano
Int. J. Mol. Sci. 2020, 21(11), 3760; https://doi.org/10.3390/ijms21113760 - 26 May 2020
Cited by 15 | Viewed by 4297
Abstract
Heme and Fe-S clusters regulate a plethora of essential biological processes ranging from cellular respiration and cell metabolism to the maintenance of genome integrity. Mutations in genes involved in heme metabolism and Fe-S cluster biogenesis cause different forms of ataxia, like posterior column [...] Read more.
Heme and Fe-S clusters regulate a plethora of essential biological processes ranging from cellular respiration and cell metabolism to the maintenance of genome integrity. Mutations in genes involved in heme metabolism and Fe-S cluster biogenesis cause different forms of ataxia, like posterior column ataxia and retinitis pigmentosa (PCARP), Friedreich’s ataxia (FRDA) and X-linked sideroblastic anemia with ataxia (XLSA/A). Despite great efforts in the elucidation of the molecular pathogenesis of these disorders several important questions still remain to be addressed. Starting with an overview of the biology of heme metabolism and Fe-S cluster biogenesis, the review discusses recent progress in the understanding of the molecular pathogenesis of PCARP, FRDA and XLSA/A, and highlights future line of research in the field. A better comprehension of the mechanisms leading to the degeneration of neural circuity responsible for balance and coordinated movement will be crucial for the therapeutic management of these patients. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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53 pages, 2935 KiB  
Review
Clinical and Genetic Overview of Paroxysmal Movement Disorders and Episodic Ataxias
by Giacomo Garone, Alessandro Capuano, Lorena Travaglini, Federica Graziola, Fabrizia Stregapede, Ginevra Zanni, Federico Vigevano, Enrico Bertini and Francesco Nicita
Int. J. Mol. Sci. 2020, 21(10), 3603; https://doi.org/10.3390/ijms21103603 - 20 May 2020
Cited by 44 | Viewed by 8638
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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21 pages, 1295 KiB  
Review
Kv1.1 Channelopathies: Pathophysiological Mechanisms and Therapeutic Approaches
by Maria Cristina D’Adamo, Antonella Liantonio, Jean-Francois Rolland, Mauro Pessia and Paola Imbrici
Int. J. Mol. Sci. 2020, 21(8), 2935; https://doi.org/10.3390/ijms21082935 - 22 Apr 2020
Cited by 61 | Viewed by 7014
Abstract
Kv1.1 belongs to the Shaker subfamily of voltage-gated potassium channels and acts as a critical regulator of neuronal excitability in the central and peripheral nervous systems. KCNA1 is the only gene that has been associated with episodic ataxia type 1 (EA1), an autosomal [...] Read more.
Kv1.1 belongs to the Shaker subfamily of voltage-gated potassium channels and acts as a critical regulator of neuronal excitability in the central and peripheral nervous systems. KCNA1 is the only gene that has been associated with episodic ataxia type 1 (EA1), an autosomal dominant disorder characterized by ataxia and myokymia and for which different and variable phenotypes have now been reported. The iterative characterization of channel defects at the molecular, network, and organismal levels contributed to elucidating the functional consequences of KCNA1 mutations and to demonstrate that ataxic attacks and neuromyotonia result from cerebellum and motor nerve alterations. Dysfunctions of the Kv1.1 channel have been also associated with epilepsy and kcna1 knock-out mouse is considered a model of sudden unexpected death in epilepsy. The tissue-specific association of Kv1.1 with other Kv1 members, auxiliary and interacting subunits amplifies Kv1.1 physiological roles and expands the pathogenesis of Kv1.1-associated diseases. In line with the current knowledge, Kv1.1 has been proposed as a novel and promising target for the treatment of brain disorders characterized by hyperexcitability, in the attempt to overcome limited response and side effects of available therapies. This review recounts past and current studies clarifying the roles of Kv1.1 in and beyond the nervous system and its contribution to EA1 and seizure susceptibility as well as its wide pharmacological potential. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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20 pages, 1413 KiB  
Review
Clinical Spectrum of KCNA1 Mutations: New Insights into Episodic Ataxia and Epilepsy Comorbidity
by Kelsey Paulhus, Lauren Ammerman and Edward Glasscock
Int. J. Mol. Sci. 2020, 21(8), 2802; https://doi.org/10.3390/ijms21082802 - 17 Apr 2020
Cited by 60 | Viewed by 6447
Abstract
Mutations in the KCNA1 gene, which encodes voltage-gated Kv1.1 potassium channel α-subunits, cause a variety of human diseases, complicating simple genotype–phenotype correlations in patients. KCNA1 mutations are primarily associated with a rare neurological movement disorder known as episodic ataxia type 1 (EA1). However, [...] Read more.
Mutations in the KCNA1 gene, which encodes voltage-gated Kv1.1 potassium channel α-subunits, cause a variety of human diseases, complicating simple genotype–phenotype correlations in patients. KCNA1 mutations are primarily associated with a rare neurological movement disorder known as episodic ataxia type 1 (EA1). However, some patients have EA1 in combination with epilepsy, whereas others have epilepsy alone. KCNA1 mutations can also cause hypomagnesemia and paroxysmal dyskinesia in rare cases. Why KCNA1 variants are associated with such phenotypic heterogeneity in patients is not yet understood. In this review, literature databases (PubMed) and public genetic archives (dbSNP and ClinVar) were mined for known pathogenic or likely pathogenic mutations in KCNA1 to examine whether patterns exist between mutation type and disease manifestation. Analyses of the 47 deleterious KCNA1 mutations that were identified revealed that epilepsy or seizure-related variants tend to cluster in the S1/S2 transmembrane domains and in the pore region of Kv1.1, whereas EA1-associated variants occur along the whole length of the protein. In addition, insights from animal models of KCNA1 channelopathy were considered, as well as the possible influence of genetic modifiers on disease expressivity and severity. Elucidation of the complex relationship between KCNA1 variants and disease will enable better diagnostic risk assessment and more personalized therapeutic strategies for KCNA1 channelopathy. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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Review
Non-Invasive Cerebellar Stimulation in Neurodegenerative Ataxia: A Literature Review
by Alberto Benussi, Alvaro Pascual-Leone and Barbara Borroni
Int. J. Mol. Sci. 2020, 21(6), 1948; https://doi.org/10.3390/ijms21061948 - 12 Mar 2020
Cited by 43 | Viewed by 5456
Abstract
Cerebellar ataxias are a heterogenous group of degenerative disorders for which we currently lack effective and disease-modifying interventions. The field of non-invasive brain stimulation has made much progress in the development of specific stimulation protocols to modulate cerebellar excitability and try to restore [...] Read more.
Cerebellar ataxias are a heterogenous group of degenerative disorders for which we currently lack effective and disease-modifying interventions. The field of non-invasive brain stimulation has made much progress in the development of specific stimulation protocols to modulate cerebellar excitability and try to restore the physiological activity of the cerebellum in patients with ataxia. In light of limited evidence-based pharmacologic and non-pharmacologic treatment options for patients with ataxia, several different non-invasive brain stimulation protocols have emerged, particularly employing repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) techniques. In this review, we summarize the most relevant rTMS and tDCS therapeutic trials and discuss their implications in the care of patients with degenerative ataxias. Full article
(This article belongs to the Special Issue Molecular Mechanisms, Physiopathology and Therapeutic Management of Episodic Ataxia)
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