A two-hit story: Seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies

Salgueiro-Pereira, Ana Rita; Duprat, Fabrice; Pousinha, Paula A.; Loucif, Alexandre; Douchamps, Vincent; Regondi, Maria Cristina; Ayrault, Marion; Eugie, Martine; Stunault, Marion I.; Escayg, Andrew; Goutagny, Romain; Gnatkovsky, Vadym; Frassoni, Carolina; Marie, Hélène; Bethus, Ingrid; Mantegazza, Massimo

doi:10.1016/j.nbd.2019.01.006

Cited by 56 publications

(73 citation statements)

References 67 publications

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“…A similar increase in seizure frequency and severity was observed in rats long after postnatal hypoxia–ischemia . Finally, inducing several brief seizures in an asymptomatic mouse carrying a mutation of SCN1A identified in humans with Dravet syndrome causes severe epilepsy and cognitive decline; remarkably, inducing similar brief seizures in WT mice has no overt deleterious consequences …”

Section: Discussionsupporting

confidence: 55%

“…30,31 Finally, inducing several brief seizures in an asymptomatic mouse carrying a mutation of SCN1A identified in humans with Dravet syndrome causes severe epilepsy and cognitive decline; remarkably, inducing similar brief seizures in WT mice has no overt deleterious consequences. 16 Collectively, these findings imply that some molecular consequences of a seizure promote the worsening of epilepsy. Our findings implicate TrkB-PLCγ1 signaling as one such consequence.…”

Section: Discussionmentioning

confidence: 99%

“…Evoking many (eg, 70–80) such seizures culminated in recurrent seizures occurring without stimulation, often associated with fatality . Furthermore, the frequency and severity of seizures progressively increases long after the onset of epilepsy in diverse models including hypoxia–ischemia, status epilepticus (SE), and genetic channelopathies; the occurrence of seizures in all of these models is thought to contribute to the progression …”

mentioning

confidence: 99%

“…12,13 Furthermore, the frequency and severity of seizures progressively increases long after the onset of epilepsy in diverse models including hypoxia-ischemia, status epilepticus (SE), and genetic channelopathies; the occurrence of seizures in all of these models is thought to contribute to the progression. [14][15][16] Understanding the molecular consequences by which a seizure promotes progression of epilepsy could provide novel targets and strategies to limit subsequent worsening of disease. One molecular consequence of an isolated seizure is the increased activation of the brain-derived neurotrophic factor receptor, tropomyosin kinase B (TrkB), and its signaling effector, phospholipase-C-gamma-1 (PLCγ1), spanning a couple of days as evident in biochemical and histochemical measures.…”

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confidence: 99%

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Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure

Krishnamurthy

Huang

Harward

et al. 2019

Annals of Neurology

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Objective Temporal lobe epilepsy (TLE) is a devastating disease in which seizures persist in 35% of patients despite optimal use of antiseizure drugs. Clinical and preclinical evidence implicates seizures themselves as one factor promoting epilepsy progression. What is the molecular consequence of a seizure that promotes progression? Evidence from preclinical studies led us to hypothesize that activation of tropomyosin kinase B (TrkB)–phospholipase‐C‐gamma‐1 (PLCγ1) signaling induced by a seizure promotes epileptogenesis. Methods To examine the effects of inhibiting TrkB signaling on epileptogenesis following an isolated seizure, we implemented a modified kindling model in which we induced a seizure through amygdala stimulation and then used either a chemical–genetic strategy or pharmacologic methods to disrupt signaling for 2 days following the seizure. The severity of a subsequent seizure was assessed by behavioral and electrographic measures. Results Transient inhibition of TrkB‐PLCγ1 signaling initiated after an isolated seizure limited progression of epileptogenesis, evidenced by the reduced severity and duration of subsequent seizures. Unexpectedly, transient inhibition of TrkB‐PLCγ1 signaling initiated following a seizure also reverted a subset of animals to an earlier state of epileptogenesis. Remarkably, inhibition of TrkB‐PLCγ1 signaling in the absence of a recent seizure did not reduce severity of subsequent seizures. Interpretation These results suggest a novel strategy for limiting progression or potentially ameliorating severity of TLE whereby transient inhibition of TrkB‐PLCγ1 signaling is initiated following a seizure. ANN NEUROL 2019;86:939–950

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure

Krishnamurthy

Huang

Harward

et al. 2019

Annals of Neurology

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“…The reason for this discrepancy is not yet clear. A recent study performed with Scn1a R1648H/+ mice in a 50%‐50% 129‐C57Bl/6F1 strain, which are asymptomatic and do not have spontaneous seizures, has shown that seizures induced in the period of seizure onset for Scn1a models can cause remodeling that leads to a severe DS‐like phenotype, including cognitive deficits . The remodeling is dependent on the presence of the mutation (the same induced seizures have no effect in wild‐type littermates) and can involve hyperexcitability of selective populations of excitatory neurons (e.g., hippocampal granular dentate gyrus neurons become hyperexcitable, but CA1 pyramidal neurons do not).…”

Section: Cellular/network Mechanisms and Phenotypes Studied With Animmentioning

confidence: 99%

SCN1A/Na_V1.1 channelopathies: Mechanisms in expression systems, animal models, and human iPSC models

Mantegazza

Broccoli

2019

Epilepsia

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Summary Pathogenic SCN1A/NaV1.1 mutations cause well‐defined epilepsies, including genetic epilepsy with febrile seizures plus (GEFS+) and the severe epileptic encephalopathy Dravet syndrome. In addition, they cause a severe form of migraine with aura, familial hemiplegic migraine. Moreover, SCN1A/NaV1.1 variants have been inferred as risk factors in other types of epilepsy. We review here the advancements obtained studying pathologic mechanisms of SCN1A/NaV1.1 mutations with experimental systems. We present results gained with in vitro expression systems, gene‐targeted animal models, and the induced pluripotent stem cell (iPSC) technology, highlighting advantages, limits, and pitfalls for each of these systems. Overall, the results obtained in the last two decades confirm that the initial pathologic mechanism of epileptogenic SCN1A/NaV1.1 mutations is loss‐of‐function of NaV1.1 leading to hypoexcitability of at least some types of γ‐aminobutyric acid (GABA)ergic neurons (including cortical and hippocampal parvalbumin‐positive and somatostatin‐positive ones). Conversely, more limited results point to NaV1.1 gain‐of‐function for familial hemiplegic migraine (FHM) mutations. Behind these relatively simple pathologic mechanisms, an unexpected complexity has been observed, in part generated by technical issues in experimental studies and in part related to intrinsically complex pathophysiologic responses and remodeling, which yet remain to be fully disentangled.

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Pathogenic variants in KCNQ2 cause intellectual deficiency without epilepsy: Broadening the phenotypic spectrum of a potassium channelopathy

Mary

Nourisson

Feger

et al. 2021

American J of Med Genetics Pt A

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High‐throughput sequencing (HTS) improved the molecular diagnosis in individuals with intellectual deficiency (ID) and helped to broaden the phenotype of previously known disease‐causing genes. We report herein four unrelated patients with isolated ID, carriers of a likely pathogenic variant in KCNQ2, a gene usually implicated in benign familial neonatal seizures (BFNS) or early onset epileptic encephalopathy (EOEE). Patients were diagnosed by targeted HTS or exome sequencing. Pathogenicity of the variants was assessed by multiple in silico tools. Patients' ID ranged from mild to severe with predominance of speech disturbance and autistic features. Three of the four variants disrupted the same amino acid. Compiling all the pathogenic variants previously reported, we observed a strong overlap between variants causing EOEE, isolated ID, and BFNS and an important intra‐familial phenotypic variability, although missense variants in the voltage‐sensing domain and the pore are significantly associated to EOEE (p < 0.01, Fisher test). Thus, pathogenic variants in KCNQ2 can be associated with isolated ID. We did not highlight strong related genotype–phenotype correlations in KCNQ2‐related disorders. A second genetic hit, a burden of rare variants, or other extrinsic factors may explain such a phenotypic variability. However, it is of interest to study encephalopathy genes in non‐epileptic ID patients.

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A two-hit story: Seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies

Cited by 56 publications

References 67 publications

Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure

Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure

SCN1A/Na_V1.1 channelopathies: Mechanisms in expression systems, animal models, and human iPSC models

Pathogenic variants in KCNQ2 cause intellectual deficiency without epilepsy: Broadening the phenotypic spectrum of a potassium channelopathy

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A two-hit story: Seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies

Cited by 56 publications

References 67 publications

Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure

Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure

SCN1A/NaV1.1 channelopathies: Mechanisms in expression systems, animal models, and human iPSC models

Pathogenic variants in KCNQ2 cause intellectual deficiency without epilepsy: Broadening the phenotypic spectrum of a potassium channelopathy

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SCN1A/Na_V1.1 channelopathies: Mechanisms in expression systems, animal models, and human iPSC models