De novo <i>GABRA1</i> mutations in Ohtahara and West syndromes

Kodera, Hirofumi; Ohba, Chihiro; Kato, Mitsuhiro; Maeda, Toshiyuki; Araki, Kazukuni; Tajima, Daisuke; Matsuo, Muneaki; Hino‐Fukuyo, Naomi; Kohashi, Kosuke; Ishiyama, Akihiko; Takeshita, Saoko; Motoi, Hirotaka; Kitamura, Taro; Kikuchi, Atsuo; Tsurusaki, Yoshinori; Nakashima, Mitsuko; Miyake, Noriko; Sasaki, Masayuki; Kure, Shigeo; Haginoya, Kazuhiro; Saitsu, Hirotomo; Matsumoto, Naomichi

doi:10.1111/epi.13344

Cited by 86 publications

(102 citation statements)

References 40 publications

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“…Mutations of this gene are known to be associated with Dravet syndrome 10 and with early infantile epileptic encephalopathy. 12 However, while his phenotype combines some of the key features of the syndrome, there are important aberrations, regarding the age at onset, type of seizures, EEG findings, and response to therapy. Therefore, he can be considered as an atypical Dravet syndrome phenotype.…”

Section: Discussionmentioning

confidence: 99%

Novel SCN1A and GABRA1 Gene Mutations With Diverse Phenotypic Features and the Question on the Existence of a Broader Spectrum of Dravet Syndrome

Gontika

Konialis²,

Pangalos³

et al. 2017

Child Neurology Open

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In the light of modern molecular technologies, the understanding of the complexity of the numerous genotype–phenotype correlations regarding Dravet syndrome is mandatory. Motivated by 2 patients, whose whole-exome sequencing revealed novel mutations that exemplify the phenotypic and genetic heterogeneities associated with typical and atypical Dravet syndrome presentations, the authors discuss the existence of a broader spectrum of Dravet syndrome. The first patient is a 4-year-old boy with fairly typical Dravet syndrome and a novel sodium channel α1 subunit gene mutation of high-predicted combined pathogenicity likelihood. The second patient is a 15-year-old boy with some atypical features of Dravet syndrome, harboring a novel mutation of the γ-aminobutyric acid receptor α1 subunit gene, whose role in this syndrome pathogenesis has recently been highlighted. A brief review of the literature reveals that none of the current diagnostic criteria is thoroughly predictive of the disease, and phenotypic discrepancies are common among patients carrying atypical Dravet syndrome mutations. The authors conclude that the discussion of a Dravet syndrome spectrum is relevant.

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Section: Discussionmentioning

confidence: 99%

Novel SCN1A and GABRA1 Gene Mutations With Diverse Phenotypic Features and the Question on the Existence of a Broader Spectrum of Dravet Syndrome

Gontika

Konialis²,

Pangalos³

et al. 2017

Child Neurology Open

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“…49 Gamma-aminobutyric acid-related genes Mutations in genes encoding subunits of the gammaaminobutyric acid (GABA) type A receptor are increasingly recognized in the epilepsy-dyskinesia spectrum. 50 Recently a de novo GABRA2 mutation was found in a patient with DEE, who also had severe hypotonia, and continuous choreiform movements. Reported Figure 1: Pathophysiology of genetic epilepsy-dyskinesia phenotypes.…”

Section: Sodium Channel Genesmentioning

confidence: 99%

The expanding spectrum of movement disorders in genetic epilepsies

Papandreou

Danti

Spaull

et al. 2019

Develop Med Child Neuro

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An ever‐increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the ‘genetic epilepsy‐dyskinesia’ spectrum are clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease‐specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control. What this paper adds Implicated genes encode proteins with very diverse functions. Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear. Early diagnosis of treatable disorders is essential and next generation sequencing may be required.

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“…The -aminobutyric acid (type A) receptor (GABA A R) is emerging as a major causal agent in some forms of genetic epilepsy. Heritable mutations to the GABA A R , ,  and  subunits have been identified in family pedigrees of epilepsy (6) and new mutations continue to be identified (7,8). Studies of thalamo-cortical connections of the brain have demonstrated that epileptic states are preceded by the synchronisation of excitatory activity in neuronal populations.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory synapse deficits caused by familial α1 GABAA receptor mutations in epilepsy

Chen

Durisic

Lynch

et al. 2017

Neurobiology of Disease

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Epilepsy is a spectrum of neurological disorders with many causal factors. The GABA type-A receptor (GABA A R) is a major genetic target for heritable human epilepsies. Here we examine the functional effects of three epilepsy-causing mutations to the 1 subunit (1 A295D22L receptors also exhibited a heightened temperature sensitivity. In addition, the 1 T10'I22L GABA A Rs were refractory to modulation by carbamazepine or midazolam. In agreement with previous studies, we found that22L GABA A Rs were retained intracellularly in HEK293 cells and neurons. However, preincubation with 100 nM suberanilohydroxamic acid (SAHA) induced 1 A295D22L GABA A Rs to mediate IPSCs that were indistinguishable in magnitude and waveform from those mediated by 122L receptors. Finally, mutation-specific changes to synaptic bouton size, synapse number and neurite branching were also observed. These results provide new insights into the mechanisms of epileptogenesis of 1 epilepsy mutations and suggest possible leads for improving treatments for patients harbouring these mutations.

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De novo GABRA1 mutations in Ohtahara and West syndromes

Cited by 86 publications

References 40 publications

Novel SCN1A and GABRA1 Gene Mutations With Diverse Phenotypic Features and the Question on the Existence of a Broader Spectrum of Dravet Syndrome

Novel SCN1A and GABRA1 Gene Mutations With Diverse Phenotypic Features and the Question on the Existence of a Broader Spectrum of Dravet Syndrome

The expanding spectrum of movement disorders in genetic epilepsies

Inhibitory synapse deficits caused by familial α1 GABAA receptor mutations in epilepsy

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