<i>HCN1</i>mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond

Marini, Carla; Porro, Alessandro; Rastetter, Agnès; Dalle, Carine; Rivolta, Ilaria; Bauer, Daniel; Oegema, Renske; Nava, Caroline; Parrini, Elena; Mei, Davide; Mercer, Catherine; Dhamija, Radhika; Chambers, Chelsea; Coubes, Christine; Thévenon, Julien; Kuentz, Paul; Julia, Sophie; Pasquier, Laurent; Dubourg, Christèle; Carré, Wilfrid; Rosati, Anna; Melani, Federico; Pisano, Tiziana; Giardino, Maria; Innes, A. Micheil; Alembik, Yves; Scheidecker, Sophie; Santos, Manuela M.; Figueiroa, Sónia; Garrido, Carmen; Fusco, Carlo; Frattini, Daniele; Spagnoli, Carlotta; Binda, Anna; Granata, Tiziana; Ragona, Francesca; Freri, Elena; Franceschetti, Silvana; Canafoglia, Laura; Castellotti, Barbara; Gellera, Cinzia; Milanesi, Raffaella; Mancardi, Maria Margherita; Clark, Damien R; Kok, Fernando; Helbig, Ingo; Ichikawa, Shoji; Sadler, Laurie S.; Neupauerová, Jana; Laššuthová, Petra; Štěrbová, Katalin; Laridon, Annick; Brilstra, Eva H.; Koeleman, Bobby P. C.; Lemke, Johannes R.; Zara, Federico; Striano, Pasquale; Soblet, Julie; Smits, Guillaume; Deconinck, Nicolas; Barbuti, Andrea; DiFrancesco, Dario; LeGuern, Eric; Guerrini, Renzo; Santoro, Bina; Hamacher, Kay; Thiel, Gerhard; Moroni, Anna; Alberti, Jacopo; Depienne, Christel

doi:10.1093/brain/awy263

Cited by 103 publications

(150 citation statements)

References 44 publications

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“…Fifty-five cases have been previously reported, of which 42 had been solved genetically. 3,5,7,[9][10][11][12][13][14][15][16][17][18][19][20] The Austin Health Human Research Ethics Committee and the institutional review boards of collaborating groups approved the project. Informed written consent was obtained from the parents or legal guardians of all patients.…”

Section: Methodsmentioning

confidence: 99%

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

Burgess

Wang

McTague

et al. 2019

Annals of Neurology

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109

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Objective Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe developmental and epileptic encephalopathies. We delineate the genetic causes and genotype–phenotype correlations of a large EIMFS cohort. Methods Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study. Results We ascertained 135 patients from 128 unrelated families. Ninety‐three of 135 (69%) had causative variants (42/55 previously reported) across 23 genes, including 9 novel EIMFS genes: de novo dominant GABRA1, GABRB1, ATP1A3; X‐linked CDKL5, PIGA; and recessive ITPA, AIMP1, KARS, WWOX. The most frequently implicated genes were KCNT1 (36/135, 27%) and SCN2A (10/135, 7%). Mosaicism occurred in 2 probands (SCN2A, GABRB3) and 3 unaffected mothers (KCNT1). Median age at seizure onset was 4 weeks, with earlier onset in the SCN2A, KCNQ2, and BRAT1 groups. Epileptic spasms occurred in 22% patients. A total of 127 patients had severe to profound developmental impairment. All but 7 patients had ongoing seizures. Additional features included microcephaly, movement disorders, spasticity, and scoliosis. Mortality occurred in 33% at median age 2 years 7 months. Interpretation We identified a genetic cause in 69% of patients with EIMFS. We highlight the genetic heterogeneity of EIMFS with 9 newly implicated genes, bringing the total number to 33. Mosaicism was observed in probands and parents, carrying critical implications for recurrence risk. EIMFS pathophysiology involves diverse molecular processes from gene and protein regulation to ion channel function and solute trafficking. ANN NEUROL 2019;86:821–831

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Section: Methodsmentioning

confidence: 99%

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

Burgess

Wang

McTague

et al. 2019

Annals of Neurology

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109

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“…In TRIP8b knockout (TKO) mice, there is significant loss of dendritic HCN channels with a concomitant reduction in I h , highlighting the importance of TRIP8b for channel function (31). Genetic screens of patients with epilepsy have identified several mutations in HCN channels and their auxiliary subunits (32)(33)(34)(35)(36)(37)(38). In rodents, reduced HCN1 expression results in enhanced neuronal excitability as well as increased seizure susceptibility and seizure-related death (15,(39)(40)(41).…”

Section: Temporal Lobe Epilepsy (Tle) Is a Prevalent Neurological Dismentioning

confidence: 99%

Phosphorylation of the HCN channel auxiliary subunit TRIP8b is altered in an animal model of temporal lobe epilepsy and modulates channel function

Foote

Lyman

Han

et al. 2019

Journal of Biological Chemistry

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“…Powell et al, 2008; Strauss et al, 2004). There is also an association between neuronal hyperexcitability and genetic change in HCN1 , HCN2 and HCN4 (Becker et al, 2017; Bonzanni et al, 2018; Campostrini et al, 2018; Dibbens et al, 2010; Marini et al, 2018; Nava et al, 2014). This relationship is complex, with evidence for both increased and decreased I h associating with heightened neuronal excitability.…”

Section: Introductionmentioning

confidence: 99%

The hyperpolarization‐activated cyclic nucleotide‐gated 4 channel as a potential anti‐seizure drug target

Kharouf

Phillips

Bleakley

et al. 2020

British J Pharmacology

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Background and Purpose Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels are encoded by four genes (HCN1–4) with distinct biophysical properties and functions within the brain. HCN4 channels activate slowly at robust hyperpolarizing potentials, making them more likely to be engaged during hyperexcitable neuronal network activity seen during seizures. HCN4 channels are also highly expressed in thalamic nuclei, a brain region implicated in seizure generalization. Here, we assessed the utility of targeting the HCN4 channel as an anti‐seizure strategy using pharmacological and genetic approaches. Experimental Approach The impact of reducing HCN4 channel function on seizure susceptibility and neuronal network excitability was studied using an HCN4 channel preferring blocker (EC18) and a conditional brain specific HCN4 knockout mouse model. Key Results EC18 (10 mg·kg−1) and brain‐specific HCN4 channel knockout reduced seizure susceptibility and proconvulsant‐mediated cortical spiking recorded using electrocorticography, with minimal effects on other mouse behaviours. EC18 (10 μM) decreased neuronal network bursting in mouse cortical cultures. Importantly, EC18 was not protective against proconvulsant‐mediated seizures in the conditional HCN4 channel knockout mouse and did not reduce bursting behaviour in AAV‐HCN4 shRNA infected mouse cortical cultures. Conclusions and Implications These data suggest the HCN4 channel as a potential pharmacologically relevant target for anti‐seizure drugs that is likely to have a low side‐effect liability in the CNS.

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HCN1mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond

Cited by 103 publications

References 44 publications

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

Phosphorylation of the HCN channel auxiliary subunit TRIP8b is altered in an animal model of temporal lobe epilepsy and modulates channel function

The hyperpolarization‐activated cyclic nucleotide‐gated 4 channel as a potential anti‐seizure drug target

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