Variable neurologic phenotype in a GEFS+ family with a novel mutation in SCN1A

Mahoney, Krista; Moore, Susan; Buckley, David; Alam, Muhammed; Parfrey, Patrick S.; Penney, Sharon; Merner, Nancy D.; Hodgkinson, Kathy; Young, Terry‐Lynn

doi:10.1016/j.seizure.2009.04.009

Cited by 29 publications

(22 citation statements)

References 32 publications

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“…1D). Mutations in SCN1A are also linked to social deficits in idiopathic autism, GEFS+, and DS (Li et al, 2011; Mahoney et al, 2009; Weiss et al, 2003), and DS/B6 mice exhibited social interaction deficits when tested in the three-chamber paradigm (Han et al, 2012a). Likewise, DS/129 mice also had social interaction deficits (Fig.…”

Section: Resultsmentioning

confidence: 99%

Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome

Rubinstein¹,

Westenbroek²,

Yu³

et al. 2015

Neurobiology of Disease

119

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Dominant loss-of-function mutations in voltage-gated sodium channel NaV1.1 cause Dravet Syndrome, an intractable childhood-onset epilepsy. NaV1.1+/− Dravet Syndrome mice in C57BL/6 genetic background exhibit severe seizures, cognitive and social impairments, and premature death. Here we show that Dravet Syndrome mice in pure 129/SvJ genetic background have many fewer seizures and much less premature death than in pure C57BL/6 background. These mice also have a higher threshold for thermally induced seizures, fewer myoclonic seizures, and no cognitive impairment, similar to patients with Genetic Epilepsy with Febrile Seizures Plus. Consistent with this mild phenotype, mutation of NaV1.1 channels has much less physiological effect on neuronal excitability in 129/SvJ mice. In hippocampal slices, the excitability of CA1 Stratum Oriens interneurons is selectively impaired, while the excitability of CA1 pyramidal cells is unaffected. NaV1.1 haploinsufficiency results in increased rheobase and threshold for action potential firing and impaired ability to sustain high-frequency firing. Moreover, deletion of NaV1.1 markedly reduces the amplification and integration of synaptic events, further contributing to reduced excitability of interneurons. Excitability is less impaired in inhibitory neurons of Dravet Syndrome mice in 129/SvJ genetic background. Because specific deletion of NaV1.1 in forebrain GABAergic interneuons is sufficient to cause the symptoms of Dravet Syndrome in mice, our results support the conclusion that the milder phenotype in 129/SvJ mice is caused by lesser impairment of sodium channel function and electrical excitability in their forebrain interneurons. This mild impairment of excitability of interneurons leads to a milder disease phenotype in 129/SvJ mice, similar to Genetic Epilepsy with Febrile Seizures Plus in humans.

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Section: Resultsmentioning

confidence: 99%

Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome

Rubinstein¹,

Westenbroek²,

Yu³

et al. 2015

Neurobiology of Disease

119

View full text Add to dashboard Cite

show abstract

“…In addition to seizures, patients with SCN1A mutations also manifest behavioral comorbidities such as attention-deficit disorder (ADHD)/hyperactivity, deficits in learning and memory, autistic behaviors and motor impairments (Wolff et al 2006, Mahoney et al 2009, Brunklaus et al 2011, Genton et al 2011, Li et al 2011, Ragona 2011, Tan et al 2012). However, the association between recurrent and prolonged early-life FSs and the development of these clinically challenging phenotypes in patients with SCN1A mutations remains unclear and has never been experimentally investigated.…”

Section: Discussionmentioning

confidence: 99%

Early-life febrile seizures worsen adult phenotypes in Scn1a mutants

Dutton

Dutt

Papale

et al. 2017

Experimental Neurology

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Mutations in the voltage-gated sodium channel (VGSC) gene SCN1A, encoding the Nav1.1 channel, are responsible for a number of epilepsy disorders including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS). Patients with SCN1A mutations often experience prolonged early-life febrile seizures (FSs), raising the possibility that these events may influence epileptogenesis and lead to more severe adult phenotypes. To test this hypothesis, we subjected 21-23-day-old mice expressing the human SCN1A GEFS+ mutation R1648H to prolonged hyperthermia, and then examined seizure and behavioral phenotypes during adulthood. We found that early-life FSs resulted in lower latencies to induced seizures, increased severity of spontaneous seizures, hyperactivity, and impairments in social behavior and recognition memory during adulthood. Biophysical analysis of brain slice preparations revealed an increase in epileptiform activity in CA3 pyramidal neurons along with increased action potential firing, providing a mechanistic basis for the observed worsening of adult phenotypes. These findings demonstrate the long-term negative impact of early-life FSs on disease outcomes. This has important implications for the clinical management of this patient population and highlights the need for therapeutic interventions that could ameliorate disease progression.

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“…The link between molecular deficit and clinical phenotype, however, is poorly characterized due to clinical heterogeneity in familial epilepsies that is thought to arise from differences in genetic background (Osaka et al 2007;Mahoney et al 2009). In SCN1A, lesions that result in truncated proteins are almost always associated with the intractable disorders severe myoclonic epilepsy in infants (SMEI) or intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC).…”

Section: Discussionmentioning

confidence: 99%

Drosophila as a Model for Epilepsy:bssIs a Gain-of-Function Mutation in the Para Sodium Channel Gene That Leads to Seizures

et al. 2011

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We report the identification of bang senseless (bss), a Drosophila melanogaster mutant exhibiting seizure-like behaviors, as an allele of the paralytic (para) voltage-gated Na 1 (Na V ) channel gene. Mutants are more prone to seizure episodes than normal flies because of a lowered seizure threshold. The bss phenotypes are due to a missense mutation in a segment previously implicated in inactivation, termed the ''paddle motif'' of the Na V fourth homology domain. Heterologous expression of cDNAs containing the bss 1 lesion, followed by electrophysiology, shows that mutant channels display altered voltage dependence of inactivation compared to wild type. The phenotypes of bss are the most severe of the bang-sensitive mutants in Drosophila and can be ameliorated, but not suppressed, by treatment with anti-epileptic drugs. As such, bss-associated seizures resemble those of pharmacologically resistant epilepsies caused by mutation of the human Na V SCN1A, such as severe myoclonic epilepsy in infants or intractable childhood epilepsy with generalized tonic-clonic seizures.

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Variable neurologic phenotype in a GEFS+ family with a novel mutation in SCN1A

Abstract: A novel missense mutation in the pore-forming region of the sodium channel gene SCN1A causes GEFS+ with a variable phenotype that includes mood and anxiety disorders, as well as ataxia, expanding the GEFS+ spectrum to include neuropsychiatric disease.

Cited by 29 publications

References 32 publications

Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome

Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome

Early-life febrile seizures worsen adult phenotypes in Scn1a mutants

Drosophila as a Model for Epilepsy:bssIs a Gain-of-Function Mutation in the Para Sodium Channel Gene That Leads to Seizures

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