Functional consequences of
            <i>SLC1A3</i>
            mutations associated with episodic ataxia 6

Chivukula, Aparna S.; Suslova, Mariia; Kortzak, Daniel; Kovermann, Peter; Fahlke, Christoph

doi:10.1002/humu.24089

Cited by 31 publications

(37 citation statements)

References 45 publications

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“…Pathogenic variants in SLC1A3 can cause both reduced and enhanced glutamate transport and thus alters channel activity. The cerebellum is sensitive to slight alterations in EAAT1 activity (145).…”

Section: Predominant Episodic Ataxia Genesmentioning

confidence: 99%

Paroxysmal Movement Disorders

2021

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Paroxysmal movement disorders (PxMDs) are a clinical and genetically heterogeneous group of movement disorders characterized by episodic involuntary movements (dystonia, dyskinesia, chorea and/or ataxia). Historically, PxMDs were classified clinically (triggers and characteristics of the movements) and this directed single-gene testing. With the advent of next-generation sequencing (NGS), how we classify and investigate PxMDs has been transformed. Next-generation sequencing has enabled new gene discovery (RHOBTB2, TBC1D24), expansion of phenotypes in known PxMDs genes and a better understanding of disease mechanisms. However, PxMDs exhibit phenotypic pleiotropy and genetic heterogeneity, making it challenging to predict genotype based on the clinical phenotype. For example, paroxysmal kinesigenic dyskinesia is most commonly associated with variants in PRRT2 but also variants identified in PNKD, SCN8A, and SCL2A1. There are no radiological or biochemical biomarkers to differentiate genetic causes. Even with NGS, diagnosis rates are variable, ranging from 11 to 51% depending on the cohort studied and technology employed. Thus, a large proportion of patients remain undiagnosed compared to other neurological disorders such as epilepsy, highlighting the need for further genomic research in PxMDs. Whole-genome sequencing, deep-sequencing, copy number variant analysis, detection of deep-intronic variants, mosaicism and repeat expansions, will improve diagnostic rates. Identifying the underlying genetic cause has a significant impact on patient care, modification of treatment, long-term prognostication and genetic counseling. This paper provides an update on the genetics of PxMDs, description of PxMDs classified according to causative gene rather than clinical phenotype, highlighting key clinical features and providing an algorithm for genetic testing of PxMDs.

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Section: Predominant Episodic Ataxia Genesmentioning

confidence: 99%

Paroxysmal Movement Disorders

2021

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“…In humans, a heterozygous mutation in EAAT1 phenocopies with reductions in glutamate uptake that likely contributes to neuronal hyperexcitability resulting in episodic ataxia and, depending upon the extent of the reduction, seizures. 200,220,221 In mice, loss of EAAT1 does not result in spontaneous seizure generation, but the duration of seizures elicited by electrical stimulation of the amygdala is significantly prolonged, whereas the latency to seizure induced via systemic administration of PTZ is shortened and the seizures themselves more severe. 222 EAAT1 null mice also show locomotor hyperactivity when placed in a novel open field.…”

Section: Introductionmentioning

confidence: 99%

Influence of glutamate and GABA transport on brain excitatory/inhibitory balance

Sears

Hewett

2021

Exp Biol Med (Maywood)

112

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An optimally functional brain requires both excitatory and inhibitory inputs that are regulated and balanced. A perturbation in the excitatory/inhibitory balance—as is the case in some neurological disorders/diseases (e.g. traumatic brain injury Alzheimer’s disease, stroke, epilepsy and substance abuse) and disorders of development (e.g. schizophrenia, Rhett syndrome and autism spectrum disorder)—leads to dysfunctional signaling, which can result in impaired cognitive and motor function, if not frank neuronal injury. At the cellular level, transmission of glutamate and GABA, the principle excitatory and inhibitory neurotransmitters in the central nervous system control excitatory/inhibitory balance. Herein, we review the synthesis, release, and signaling of GABA and glutamate followed by a focused discussion on the importance of their transport systems to the maintenance of excitatory/inhibitory balance.

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“…From the original description of a young boy with episodic ataxia, seizures, migraine, and alternating hemiplegia (31), the phenotype soon expanded to include individuals with EA2-like phenotypes or late-onset episodic ataxia, without epilepsy (173)(174)(175). Experimentally, distinct consequences at the functional and/or expressional level of EAAT1 have been found with different mutations (176), rendering genotype-phenotype correlations unconfirmed in this rare condition.…”

Section: Episodic Ataxia Type 6 and Epilepsymentioning

confidence: 99%

Paroxysmal Genetic Movement Disorders and Epilepsy

et al. 2021

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Paroxysmal movement disorders include paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, paroxysmal exercise-induced dyskinesia, and episodic ataxias. In recent years, there has been renewed interest and recognition of these disorders and their intersection with epilepsy, at the molecular and pathophysiological levels. In this review, we discuss how these distinct phenotypes were constructed from a historical perspective and discuss how they are currently coalescing into established genetic etiologies with extensive pleiotropy, emphasizing clinical phenotyping important for diagnosis and for interpreting results from genetic testing. We discuss insights on the pathophysiology of select disorders and describe shared mechanisms that overlap treatment principles in some of these disorders. In the near future, it is likely that a growing number of genes will be described associating movement disorders and epilepsy, in parallel with improved understanding of disease mechanisms leading to more effective treatments.

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Functional consequences of SLC1A3 mutations associated with episodic ataxia 6

Cited by 31 publications

References 45 publications

Paroxysmal Movement Disorders

Paroxysmal Movement Disorders

Influence of glutamate and GABA transport on brain excitatory/inhibitory balance

Paroxysmal Genetic Movement Disorders and Epilepsy

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