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Handbook of Clinical Neurology 2023Paroxysmal movement disorders have traditionally been classified into paroxysmal dyskinesia (PxD), which consists in attacks of involuntary movements (mainly dystonia... (Review)
Review
Paroxysmal movement disorders have traditionally been classified into paroxysmal dyskinesia (PxD), which consists in attacks of involuntary movements (mainly dystonia and/or chorea) without loss of consciousness, and episodic ataxia (EA), which features spells of cerebellar dysfunction with or without interictal neurological manifestations. In this chapter, PxD will be discussed first according to the trigger-based classification, thus reviewing clinical, genetic, and molecular features of paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia, and paroxysmal exercise-induced dyskinesia. EA will be presented thereafter according to their designated gene or genetic locus. Clinicogenetic similarities among paroxysmal movement disorders have progressively emerged, which are herein highlighted along with growing evidence that their pathomechanisms overlap those of epilepsy and migraine. Advances in our comprehension of the biological pathways underlying paroxysmal movement disorders, which involve ion channels as well as proteins associated with the vesical synaptic cycle or implicated in neuronal energy metabolism, may represent the cornerstone for defining a shared pathophysiologic framework and developing target-specific therapies.
Topics: Humans; Chorea; Movement Disorders; Dystonia; Dystonic Disorders
PubMed: 37620078
DOI: 10.1016/B978-0-323-98817-9.00033-8 -
European Journal of Neurology Oct 2023Most episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non-paroxysmal features. EA is... (Review)
Review
BACKGROUND
Most episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non-paroxysmal features. EA is often caused by pathogenic variants in the CACNA1A, KCNA1, PDHA1, and SLC1A3 genes, listed as paroxysmal movement disorders (PxMD) by the MDS Task Force on the Nomenclature of Genetic Movement Disorders. Little is known about the genotype-phenotype correlation of the different genetic EA forms.
METHODS
We performed a systematic review of the literature to identify individuals affected by an episodic movement disorder harboring pathogenic variants in one of the four genes. We applied the standardized MDSGene literature search and data extraction protocol to summarize the clinical and genetic features. All data are available via the MDSGene protocol and platform on the MDSGene website (https://www.mdsgene.org/).
RESULTS
Information on 717 patients (CACNA1A: 491, KCNA1: 125, PDHA1: 90, and SLC1A3: 11) carrying 287 different pathogenic variants from 229 papers was identified and summarized. We show the profound phenotypic variability and overlap leading to the absence of frank genotype-phenotype correlation aside from a few key 'red flags'.
CONCLUSION
Given this overlap, a broad approach to genetic testing using a panel or whole exome or genome approach is most practical in most circumstances.
Topics: Humans; Ataxia; Movement Disorders; Genotype; Phenotype
PubMed: 37422902
DOI: 10.1111/ene.15969 -
The Primary Care Companion For CNS... Apr 2021
Topics: Anxiety Disorders; Ataxia; Diagnostic Errors; Humans
PubMed: 34000127
DOI: 10.4088/PCC.20l02730 -
Journal of Neurology Nov 2021Episodic ataxia type 2 (EA2) is a hereditary disorder characterized by paroxysmal attacks of ataxia, vertigo and nausea, due to mutations in the CACNA1A gene, which... (Review)
Review
Episodic ataxia type 2 (EA2) is a hereditary disorder characterized by paroxysmal attacks of ataxia, vertigo and nausea, due to mutations in the CACNA1A gene, which encodes for α1 subunit of the P/Q-type voltage-gated Ca channel (CaV2.1). Other manifestations may be associated to CACNA1A mutations, such as migraine and epilepsy. The correlation between episodic ataxia and epilepsy is often underestimated and misdiagnosed. Clinical presentation of EA2 varies among patients and within the same family, and the same genetic mutation can lead to different clinical phenotypes. We herewith describe an Italian family presenting with typical EA2 and, in two of the family members (patients II.3 and III.1), epileptic seizures. The sequencing revealed a heterozygous deletion of 6 nucleotides in exon 28 of CACNA1A gene, present in all affected patients. Evidence suggests that mutations of CACNA1A, conferring a loss/reduction of CaV2.1 function, lead to an increase of thalamocortical excitation that contributes to epileptiform discharges. Our description highlights intra-family variability of EA2 phenotype and suggests that mutations in the CACNA1A gene should be suspected in individuals with focal or generalized epilepsy, associated with a family history of episodic ataxia.
Topics: Ataxia; Cerebellar Ataxia; Epilepsy; Humans; Nystagmus, Pathologic
PubMed: 33983550
DOI: 10.1007/s00415-021-10555-0 -
Brain & Development Jan 1998Clinical details are given of different types of episodic ataxia: type 1, with myokymia, and attacks which usually last a few minutes, and may occur several times a day,... (Review)
Review
Clinical details are given of different types of episodic ataxia: type 1, with myokymia, and attacks which usually last a few minutes, and may occur several times a day, and treatment with acetazolamide can reduce the number of attacks; type 2, with interictal nystagmus, and attacks which last for several hours to a day or more, and treatment with acetazolamide is very effective; paroxysmal choreoathetosis with episodic ataxia, with attacks lasting for about 20 min and occurring at varying intervals; and familial hemiplegic migraine, with transient hemiplegia presenting during the aura of a migraine headache, the symptoms improving on treatment with acetazolamide. Their inheritance is of dominant type; and the gene for type 1 is mapped to chromosome 12p near to a cluster of potassium channel genes, and that for type 2 and for familial hemiplegic migraine to chromosome 19p near to calcium channel genes. The differential diagnosis from other conditions with a periodic symptomatology is discussed, especially from a number of metabolic disorders. Treatment is effective for many of these, and the treatment of the episodic ataxias with acetazolamide can sometimes have a dramatic effect. The possible role of the channelopathies in the causation of some periodic neurological disorders is considered; with the expectation that further research will improve the identification of specific diseases, and lead to more effective treatment.
Topics: Acetazolamide; Ataxia; Athetosis; Cerebellar Ataxia; Chorea; Hemiplegia; Humans; Ion Channels; Migraine Disorders; Nervous System Diseases; Time Factors
PubMed: 9533553
DOI: 10.1016/s0387-7604(97)00086-7 -
European Journal of Medical Genetics Apr 2022This review article focuses on clinical and genetic features of paroxysmal neurological disorders featuring episodic ataxia (EA) and epilepsy and help clinicians... (Review)
Review
OBJECTIVE
This review article focuses on clinical and genetic features of paroxysmal neurological disorders featuring episodic ataxia (EA) and epilepsy and help clinicians recognize, diagnose, and treat patients with co-existing EA and epilepsy. It also provides an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders.
METHODS
Based on a literature review on Pubmed database, a list of genes linked to paroxysmal neurological disorders featuring EA and epilepsy were compiled. Online Mendelian Inheritance in Man (OMIM) was used to identify further reports relevant to each gene.
RESULTS
Among the various forms of EAs, only EA1 (KCNA1), EA2 (CACNA1A), EA5 (CACNB4), EA6 (SLC1A3), and EA9 (SCN2A) phenotypes with associated epilepsy have been described. Next-generation sequencing (NGS) has helped in the identification of other genes (e.g.: KCNA2, ATP1A3, SLC2A1, PRRT2) which have shown an overlapping phenotype with EA and epilepsy.
CONCLUSION
Overlapping clinical features between EA and epilepsy may hinder an accurate classification, and complex genotype-phenotype correlation may often lead to misdiagnosis. NGS has increased the awareness of common genetic etiologies for these conditions. In the future, extensive genetic and phenotypic characterizations can help us to elucidate the boundaries of a wide phenotypic spectrum. These insights may help develop new precision therapies in paroxysmal neurological disorders featuring EA and epilepsy.
Topics: Ataxia; Epilepsy; Genetic Association Studies; Humans; Mutation; Phenotype; Sodium-Potassium-Exchanging ATPase
PubMed: 35219921
DOI: 10.1016/j.ejmg.2022.104450 -
Neurologia Sep 2020
Topics: Ataxia; Delayed Diagnosis; Humans; Mutation
PubMed: 31047732
DOI: 10.1016/j.nrl.2019.02.002 -
Revue Neurologique May 2011Episodic ataxia (EA) designates a group of autosomal dominant channelopathies that manifest as paroxysmal attacks of imbalance and incoordination. EA conditions are... (Review)
Review
INTRODUCTION
Episodic ataxia (EA) designates a group of autosomal dominant channelopathies that manifest as paroxysmal attacks of imbalance and incoordination. EA conditions are clinically and genetically heterogeneous. Seven types of EA have been reported so far but the majority of clinical cases result from two recognized entities.
STATE OF ART
Episodic ataxia type 1 (EA1) is characterized by brief episodes of ataxia and dysarthria, and interictal myokymia. Onset occurs during the first two decades of life. Associated epilepsy has been reported in some EA1 patients. EA1 is caused by mutations of the KCNA1 gene coding for the voltage-gated potassium channel Kv1.1. Mutation is mostly missense mutations. Acetazolamide, a carbonic-anhydrase inhibitor, may reduce the frequency and severity of the attacks in some but not all affected individuals. Episodic ataxia type 2 (EA2) is characterized by episodes lasting longer than in EA1, that manifest by ataxia, dysarthria, vertigo, and also, in most of the cases, an interictal nystagmus. Other clinical features as developmental delay or epilepsy can be present in some patients. Brain MRI shows frequently a vermian atrophy. Onset occurs typically in childhood or early adolescence, but can sometimes be in adulthood. EA2 is caused by mutations in CACNA1A, a gene coding for the neuronal voltage-gated calcium channel Cav1.1. For two-thirds of the cases, mutations lead to a stop codon. This type is most often responsive to acetazolamide that reduces the frequency and severity of attacks, but does not appear to prevent the progression of interictal symptoms.
PERSPECTIVES
This article summarizes current knowledge on episodic ataxia type 1 and 2 and describes briefly the other types of EA.
CONCLUSION
Molecular analysis of KCNA1 or CACNA1A provides a confirmation of the diagnosis of EA1 and EA2. Other types remain rare phenotypic variants. Among them, only two genes have been identified: CACNB4 in EA5 and SLC1A3 in EA6 and mutations have been found in a very few cases. No mutation can be detected in some familial cases of episodic ataxia, suggesting further heterogeneity.
Topics: Humans; Spinocerebellar Degenerations
PubMed: 21492892
DOI: 10.1016/j.neurol.2010.10.016 -
Neurotherapeutics : the Journal of the... Apr 2007Episodic ataxia type 2 (EA 2) is a rare neurological disorder of autosomal dominant inheritance resulting from dysfunction of a voltage-gated calcium channel. It... (Review)
Review
Episodic ataxia type 2 (EA 2) is a rare neurological disorder of autosomal dominant inheritance resulting from dysfunction of a voltage-gated calcium channel. It manifests with recurrent disabling attacks of imbalance, vertigo, and ataxia, and can be provoked by physical exertion or emotional stress. In the spell-free interval, patients present with central ocular motor dysfunction, mainly downbeat nystagmus. A slow progression of cerebellar signs accompanied by a slight atrophy of midline cerebellar structures is commonly observed during the course of the disease. EA 2 is caused most often by the loss of function mutations of the calcium channel gene CACNA1A, which encodes the Ca(v)2.1 subunit of the P/Q-type calcium channel and is primarily expressed in Purkinje cells. To date, more than 30 mutations have been described. Two effective treatment options have been established for EA 2: acetazolamide (ACTZ), which probably changes the intracellular pH and thereby the transmembraneous potential, and 4-aminopyridine (4-AP), a potassium channel blocker. Approximately 70% of all patients respond to treatment with ACTZ, but the effect is often only transient. In an open trial, 4-AP prevented attacks in five of six patients with EA 2, most likely by increasing the resting activity and excitability of the Purkinje cells. These findings were confirmed by experiments in animal models of EA 2. Many aspects of the pathophysiology (e.g., induction of the attacks) and treatment of EA 2 (e.g., mode of action of ACTZ and 4-AP) still remain unclear and need to be addressed in further animal and clinical studies.
Topics: 4-Aminopyridine; Acetazolamide; Animals; Calcium Channels; Carbonic Anhydrase Inhibitors; Cerebellar Ataxia; Disease Models, Animal; Humans; Mutation; Potassium Channel Blockers
PubMed: 17395137
DOI: 10.1016/j.nurt.2007.01.014