Remarkable effect of transdermal nicotine in children with CHRNA4-related autosomal dominant sleep-related hypermotor epilepsy

Lossius, Kristine; Saint‐Martin, Anne de; Myren‐Svelstad, Sverre; Bjørnvold, Marit; Minken, Guro; Seegmüller, Caroline; Hirsch, Maria Paola Valenti; Chelly, Jamel; Steinlein, Ortrud K.; Picard, Fabienne; Brodtkorb, Eylert

doi:10.1016/j.yebeh.2020.106944

Cited by 27 publications

(7 citation statements)

References 31 publications

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“…A recent study published looking specifically at pediatric patients with CHRNA4-related autosomal dominant sleep-related hypermotor epilepsy showed a significant seizure reduction following the placement of a nicotine patch. 15 Our data further substantiate the efficacy of nicotine as a targeted therapy in this select pediatric population, showing significant results in a patient with CHRNA4-related autosomal dominant sleep-related hypermotor epilepsy, but also one with CHRNB2-related autosomal dominant sleep-related hypermotor epilepsy and another with a VUS in CHRNA4.…”

Section: Discussionsupporting

confidence: 78%

Nicotine: A Targeted Therapy for Epilepsy Due to nAChR Gene Variants

2020

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Objective: Genetic variants of the neuronal nicotinic acetylcholine receptor (nAChR) cause autosomal dominant sleep-related hypermotor epilepsy. Approximately 30% of autosomal dominant sleep-related hypermotor epilepsy patients are medically intractable. In preclinical models, pathogenic nAChR variants cause a gain of function mutation with sensitivity to acetylcholine antagonists and agonists. Nicotine modifies the activity of nAChRs and can be used as targeted therapy. Methods: We reviewed next-generation sequencing epilepsy panels from a single laboratory (GeneDx) from patients at Children’s Medical Center Dallas between 2011 and 2015 and identified patients with nAChR variants. Retrospective review of records included variant details, medical history, neuroimaging findings, and treatment history. Results: Twenty-one patients were identified. Four patients were prescribed nicotine patches for intractable seizures. Three of 4 patients had a clinical response, with >50% seizure reduction. Conclusions: Treatment with a nicotine patch can be an effective therapy in epilepsy patients with nAChR gene variants. We propose consideration of transdermal nicotine treatment in intractable epilepsy with known nAChR variants as an experimental therapy. Further clinical trials are needed to fully define therapeutic effects.

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Section: Discussionsupporting

confidence: 78%

Nicotine: A Targeted Therapy for Epilepsy Due to nAChR Gene Variants

2020

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“…First, it has been demonstrated in genetic studies and animal models of seizures that nAChR activity is altered in ADNFLE/SHE. [11][12][13][14] Moreover, a few authors have reported a significant antiseizure effect of transdermal nicotine patches in ADNFLE/SHE cases involving CHRNA4 15,16 or CHRNB2 17 mutations. This effect, partially observed in case 2, has mainly been attributed to a desensitization of nAChR resulting from therapeutic excessive exposure to nicotine.…”

Section: Discussionmentioning

confidence: 99%

Variants inCHRNB2andCHRNA4Identified in Patients with Insular Epilepsy

Cadieux-Dion

Meneghini

Clara

et al. 2020

Can. J. Neurol. Sci.

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Purpose: Our purpose was to determine the role of CHRNA4 and CHRNB2 in insular epilepsy. Method: We identified two patients with drug-resistant predominantly sleep-related hypermotor seizures, one harboring a heterozygous missense variant (c.77C>T; p. Thr26Met) in the CHRNB2 gene and the other a heterozygous missense variant (c.1079G>A; p. Arg360Gln) in the CHRNA4 gene. The patients underwent electrophysiological and neuroimaging studies, and we performed functional characterization of the p. Thr26Met (c.77C>T) in the CHRNB2 gene. Results: We localized the epileptic foci to the left insula in the first case (now seizure-free following epilepsy surgery) and to both insulae in the second case. Based on tools predicting the possible impact of amino acid substitutions on the structure and function of proteins (sorting intolerant from tolerant and PolyPhen-2), variants identified in this report could be deleterious. Functional expression in human cell lines of α4β2 (wild-type), α4β2-Thr26Met (homozygote), and α4β2/β2-Thr26Met (heterozygote) nicotinic acetylcholine receptors revealed that the mutant subunit led to significantly higher whole-cell nicotinic currents. This feature was observed in both homo- and heterozygous conditions and was not accompanied by major alterations of the current reversal potential or the shape of the concentration-response relation. Conclusions: This study suggests that variants in CHRNB2 and CHRNA4, initially linked to autosomal dominant nocturnal frontal lobe epilepsy, are also found in patients with predominantly sleep-related insular epilepsy. Although the reported variants should be considered of unknown clinical significance for the moment, identification of additional similar cases and further functional studies could eventually strengthen this association.

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“…In the last chapter of this section, we discuss a few monogenic epilepsy syndromes for which there is limited evidence (e.g., case series or reports) for certain repurposed medications. Autosomal dominant sleep-related hypermotor epilepsy caused by mutations in CHRNA4 (cholinergic receptor, nicotinic, and alpha polypeptide 4) responds strikingly well to transdermal nicotine patches in a pediatric case series ( 66 ). Hypermotor seizures disappeared entirely, but sporadic arousals persisted.…”

Section: Therapies For Genetic Epilepsiesmentioning

confidence: 99%

A Review of Targeted Therapies for Monogenic Epilepsy Syndromes

2022

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Genetic sequencing technologies have led to an increase in the identification and characterization of monogenic epilepsy syndromes. This increase has, in turn, generated strong interest in developing “precision therapies” based on the unique molecular genetics of a given monogenic epilepsy syndrome. These therapies include diets, vitamins, cell-signaling regulators, ion channel modulators, repurposed medications, molecular chaperones, and gene therapies. In this review, we evaluate these therapies from the perspective of their clinical validity and discuss the future of these therapies for individual syndromes.

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Remarkable effect of transdermal nicotine in children with CHRNA4-related autosomal dominant sleep-related hypermotor epilepsy

Cited by 27 publications

References 31 publications

Nicotine: A Targeted Therapy for Epilepsy Due to nAChR Gene Variants

Nicotine: A Targeted Therapy for Epilepsy Due to nAChR Gene Variants

Variants inCHRNB2andCHRNA4Identified in Patients with Insular Epilepsy

A Review of Targeted Therapies for Monogenic Epilepsy Syndromes

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