A Novel Kv7.3 Variant in the Voltage-Sensing S4 Segment in a Family With Benign Neonatal Epilepsy: Functional Characterization and in vitro Rescue by β-Hydroxybutyrate

Miceli, Francesco; Carotenuto, Lidia; Barrese, Vincenzo; Soldovieri, Maria Virginia; Heinzen, Erin L.; Mandel, Arthur; Lippa, Natalie; Bier, Louise; Goldstein, David B.; Cooper, Edward C.; Cilio, Maria Roberta; Taglialatela, Maurizio; Sands, Tristan T.

doi:10.3389/fphys.2020.01040

Cited by 10 publications

(4 citation statements)

References 50 publications

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“…Among the investigational drugs, XEN496, a novel immediate-release formulation of retigabine, remains under a Phase III clinical trial. Not surprisingly, patients with encephalopathy resulting from GoF KCNQ3 variations do not benefit from treatment with sodium channel blockers, while retigabine can even aggravate encephalopathy symptoms [40][41][42][43][44][45].…”

Section: Discussionmentioning

confidence: 99%

“…Together, KV7.2/KV7.3 form the homo-and heterotetrameric voltage-gated potassium channels responsible for the M-current, a noninactivating current that raises the threshold for firing an action potential. Both KCNQ2 and KCNQ3 are co-expressed in the same brain areas, which contributes to the development of similar clinical phenotypes related to specific mutations [40][41][42][43][44][45][46].…”

Section: Mutations In Kcnq2 and Kcnq3 Genesmentioning

confidence: 99%

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Genetic Background of Epilepsy and Antiepileptic Treatments

Borowicz-Reutt,

Czernia,

Krawczyk

2023

IJMS

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Advanced identification of the gene mutations causing epilepsy syndromes is expected to translate into faster diagnosis and more effective treatment of these conditions. Over the last 5 years, approximately 40 clinical trials on the treatment of genetic epilepsies have been conducted. As a result, some medications that are not regular antiseizure drugs (e.g., soticlestat, fenfluramine, or ganaxolone) have been introduced to the treatment of drug-resistant seizures in Dravet, Lennox-Gastaut, maternally inherited chromosome 15q11.2-q13.1 duplication (Dup 15q) syndromes, and protocadherin 19 (PCDH 19)-clusterig epilepsy. And although the effects of soticlestat, fenfluramine, and ganaxolone are described as promising, they do not significantly affect the course of the mentioned epilepsy syndromes. Importantly, each of these syndromes is related to mutations in several genes. On the other hand, several mutations can occur within one gene, and different gene variants may be manifested in different disease phenotypes. This complex pattern of inheritance contributes to rather poor genotype–phenotype correlations. Hence, the detection of a specific mutation is not synonymous with a precise diagnosis of a specific syndrome. Bearing in mind that seizures develop as a consequence of the predominance of excitatory over inhibitory processes, it seems reasonable that mutations in genes encoding sodium and potassium channels, as well as glutamatergic and gamma-aminobutyric (GABA) receptors, play a role in the pathogenesis of epilepsy. In some cases, different pathogenic variants of the same gene can result in opposite functional effects, determining the effectiveness of therapy with certain medications. For instance, seizures related to gain-of-function (GoF) mutations in genes encoding sodium channels can be successfully treated with sodium channel blockers. On the contrary, the same drugs may aggravate seizures related to loss-of-function (LoF) variants of the same genes. Hence, knowledge of gene mutation–treatment response relationships facilitates more favorable selection of drugs for anticonvulsant therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Mutations In Kcnq2 and Kcnq3 Genesmentioning

confidence: 99%

Genetic Background of Epilepsy and Antiepileptic Treatments

Borowicz-Reutt,

Czernia,

Krawczyk

2023

IJMS

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“…Other variants that have been reported in this region of the protein (A381V, N468S) are of uncertain significance and associated with reduced penetrance. 23,24 Variants reported in typical familial forms of benign epilepsies are commonly missense alterations located within the pore region (S5-S6 intervening loop), 25,26 resulting in loss of function (LOF) effect on channel activity. 23,[27][28][29][30] More recently, de novo missense alterations located outside of the pore region (R227G, R230C/S/H) have been reported in multiple individuals with global developmental delay, autism spectrum disorder, and sleep-activated epileptiform discharges on EEG.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Spectrum in a Family Sharing a Heterozygous KCNQ3 Variant

et al. 2022

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Background and Purpose Mutations in KCNQ3 have classically been associated with benign familial neonatal and infantile seizures and more recently identified in patients with neurodevelopmental disorders and abnormal electroencephalogram (EEG) findings. We present 4 affected patients from a family with a pathogenic mutation in KCNQ3 with a unique constellation of clinical findings. Methods A family of 3 affected siblings and mother sharing a KCNQ3 pathogenic variant are described, including clinical history, genetic results, and EEG and magnetic resonance imaging (MRI) findings. Results This family shows a variety of clinical manifestations, including neonatal seizures, developmental delays, autism spectrum disorder, and anxiety. One child developed absence epilepsy, 2 children have infrequent convulsive seizures that have persisted into childhood, and their parent developed adult-onset epilepsy. An underlying c.1091G>A (R364H) variant in KCNQ3 was found in all affected individuals. Conclusions The phenotypic variability of KCNQ3 channelopathies continues to expand as more individuals and families are described, and the variant identified in this family adds to the understanding of the manifestations of KCNQ3-related disorders.

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“…Notably, heterozygous truncating/deletion variants account for a substantial proportion (39%) of KCNQ2 variants associated with SLFNE. 3 Less commonly, SLFNE is caused by heterozygous missense variants in KCNQ3 (15 with good evidence, affecting 12 clustered residues) [90]. Heterozygous truncating KCNQ3 variants have not been associated with a human phenotype.…”

Section: Self-limited Familial Neonatal Epilepsymentioning

confidence: 99%

<i>KCNQ2</i>- and <i>KCNQ3</i>-Associated Epilepsy

2022

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KCNQ2 and KCNQ3 encode subunits (KV7.2, KV7.3) that combine to form a voltage-gated potassium ion (K+) channel responsible for generating an ionic current (M-current) important for controlling activity in the nervous system. Pathogenic variants in both genes are associated with a spectrum of genetic neurological disorders that feature epilepsy of variable severity and can be accompanied by debilitating impaired neurodevelopment. These two genes were among the first discovered causes of monogenic epilepsy, and are frequently identified in persons with early-life epilepsy. This Element provides a comprehensive review of the clinical features, genetic basis, pathophysiology, pharmacology and treatment of these prototypical neurological disorders accompanied by perspectives shared by affected families and scientists who have made seminal contributions to the field. This title is also available as Open Access on Cambridge Core.

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A Novel Kv7.3 Variant in the Voltage-Sensing S4 Segment in a Family With Benign Neonatal Epilepsy: Functional Characterization and in vitro Rescue by β-Hydroxybutyrate

Cited by 10 publications

References 50 publications

Genetic Background of Epilepsy and Antiepileptic Treatments

Genetic Background of Epilepsy and Antiepileptic Treatments

Phenotypic Spectrum in a Family Sharing a Heterozygous KCNQ3 Variant

<i>KCNQ2</i>- and <i>KCNQ3</i>-Associated Epilepsy

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