Reduction in seizure burden in a child with a A350V IQSEC2 mutation using heat therapy with a Jacuzzi

Levy, Andrew P.; Levy, Nina S.; Heyman, Eli; Schertz, Mitchell; Genizi, Jacob

doi:10.1002/ccr3.4734

Cited by 4 publications

(3 citation statements)

References 16 publications

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“…IQSEC2 disease is a disorder in which seizures are generally pharmacoresistant and the heavy seizure burden in children with IQSEC2 disease plays an important role in the development of their epileptic encephalopathy [ 23 , 24 ]. The benefit on seizure reduction in the A350V murine model with daily 15-min treatments mirrors what we have previously reported in a child with the A350V mutation undergoing 15-min Jacuzzi treatments [ 4 ]. Moreover, we have identified other children with different IQSEC2 mutations whose seizures decrease with fever and it appears that some of these children have a reduction in seizure frequency with daily heat therapy [ 5 ].…”

Section: Discussionsupporting

confidence: 82%

“…In recent years, our laboratory has worked closely with a group of parents of IQSEC2 children to understand features of the natural history of the disorder that may provide insights into treatment. One such insight, initially made in a child with an A350V IQSEC2 mutation, was that fever was associated with a marked clinical improvement manifested as an abatement in seizures and an improvement in social interactions [ 4 ]. Moreover, purposefully raising the body temperature of the child with the A350V IQSEC2 mutation, by having the child sit in a Jacuzzi set at 39 °C twice a day for 15 min, resulted in a dramatic reduction in epileptic seizures and reduced epileptiform activity on EEG [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…One such insight, initially made in a child with an A350V IQSEC2 mutation, was that fever was associated with a marked clinical improvement manifested as an abatement in seizures and an improvement in social interactions [ 4 ]. Moreover, purposefully raising the body temperature of the child with the A350V IQSEC2 mutation, by having the child sit in a Jacuzzi set at 39 °C twice a day for 15 min, resulted in a dramatic reduction in epileptic seizures and reduced epileptiform activity on EEG [ 4 ]. This association between fever and clinical improvement, and a reduction in seizures from purposefully raising the body temperature, has been observed in several children with different IQSEC2 mutations [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Daily Brief Heat Therapy Reduces Seizures in A350V IQSEC2 Mice and Is Associated with Correction of AMPA Receptor-Mediated Synaptic Dysfunction

Jada

Borisov

Laury

et al. 2023

IJMS

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Purposeful induction of fever for healing, including the treatment of epilepsy, was used over 2000 years ago by Hippocrates. More recently, fever has been demonstrated to rescue behavioral abnormalities in children with autism. However, the mechanism of fever benefit has remained elusive due in large part to the lack of appropriate human disease models recapitulating the fever effect. Pathological mutations in the IQSEC2 gene are frequently seen in children presenting with intellectual disability, autism and epilepsy. We recently described a murine A350V IQSEC2 disease model, which recapitulates important aspects of the human A350V IQSEC2 disease phenotype and the favorable response to a prolonged and sustained rise in body core temperature in a child with the mutation. Our goal has been to use this system to understand the mechanism of fever benefit and then develop drugs that can mimic this effect and reduce IQSEC2-associated morbidity. In this study, we first demonstrate a reduction in seizures in the mouse model following brief periods of heat therapy, similar to what was observed in a child with the mutation. We then show that brief heat therapy is associated with the correction of synaptic dysfunction in neuronal cultures of A350V mice, likely mediated by Arf6-GTP.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Daily Brief Heat Therapy Reduces Seizures in A350V IQSEC2 Mice and Is Associated with Correction of AMPA Receptor-Mediated Synaptic Dysfunction

Jada

Borisov

Laury

et al. 2023

IJMS

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Housing of A350V IQSEC2 pups at 37 °C ambient temperature prevents seizures and permits the development of social vocalizations in adulthood

Jada

Zag

Borisov

et al. 2021

International Journal of Hyperthermia

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Molecular Insights into IQSEC2 Disease

Levy

Borisov

Lache

et al. 2023

IJMS

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Recent insights into IQSEC2 disease are summarized in this review as follows: (1) Exome sequencing of IQSEC2 patient DNA has led to the identification of numerous missense mutations that delineate at least six and possibly seven essential functional domains present in the IQSEC2 gene. (2) Experiments using IQSEC2 transgenic and knockout (KO) mouse models have recapitulated the presence of autistic-like behavior and epileptic seizures in affected animals; however, seizure severity and etiology appear to vary considerably between models. (3) Studies in IQSEC2 KO mice reveal that IQSEC2 is involved in inhibitory as well as stimulatory neurotransmission. The overall picture appears to be that mutated or absent IQSEC2 arrests neuronal development, resulting in immature neuronal networks. Subsequent maturation is aberrant, leading to increased inhibition and reduced neuronal transmission. (4) The levels of Arf6-GTP remain constitutively high in IQSEC2 knockout mice despite the absence of IQSEC2 protein, indicating impaired regulation of the Arf6 guanine nucleotide exchange cycle. (5) A new therapy that has been shown to reduce the seizure burden for the IQSEC2 A350V mutation is heat treatment. Induction of the heat shock response may be responsible for this therapeutic effect.

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Reduction in seizure burden in a child with a A350V IQSEC2 mutation using heat therapy with a Jacuzzi

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 4 publications

References 16 publications

Daily Brief Heat Therapy Reduces Seizures in A350V IQSEC2 Mice and Is Associated with Correction of AMPA Receptor-Mediated Synaptic Dysfunction

Daily Brief Heat Therapy Reduces Seizures in A350V IQSEC2 Mice and Is Associated with Correction of AMPA Receptor-Mediated Synaptic Dysfunction

Housing of A350V IQSEC2 pups at 37 °C ambient temperature prevents seizures and permits the development of social vocalizations in adulthood

Molecular Insights into IQSEC2 Disease

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