The<i>SCN1A</i>variant database: a novel research and diagnostic tool

Claes, Lieve; Deprez, Liesbet; Suls, Arvid; Baets, Jonathan; Smets, Katrien; Dyck, Tine Van; Deconinck, Tine; Jordanova, Albena; Jonghe, Peter De

doi:10.1002/humu.21083

Cited by 118 publications

(116 citation statements)

References 29 publications

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“…We then examined disynaptic responses after stimulating presynaptic pyramidal neurons with different numbers of APs (5,8,10,12,15,20, and 30 pulses) at the same frequency (70 Hz) (Fig. 8A).…”

Section: Impaired Monosynaptic Transmission Between Layer V Pyramidalmentioning

confidence: 99%

“…DS is caused by loss-of-function mutations in SCN1A, the gene encoding type I voltage-gated sodium channel Na V 1.1, which usually arise de novo in the affected individuals (4)(5)(6)(7). Like DS patients, mice with heterozygous lossof-function mutations in Scn1a exhibit ataxia, sleep disorder, cognitive deficit, autistic-like behavior, and premature death (8)(9)(10)(11)(12)(13)(14).…”

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confidence: 99%

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Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome

Tai

Abe

Westenbroek

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

249

215

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Haploinsufficiency of the voltage-gated sodium channel Na V 1.1 causes Dravet syndrome, an intractable developmental epilepsy syndrome with seizure onset in the first year of life. Specific heterozygous deletion of Na V 1.1 in forebrain GABAergic-inhibitory neurons is sufficient to cause all the manifestations of Dravet syndrome in mice, but the physiological roles of specific subtypes of GABAergic interneurons in the cerebral cortex in this disease are unknown. Voltage-clamp studies of dissociated interneurons from cerebral cortex did not detect a significant effect of the Dravet syndrome mutation on sodium currents in cell bodies. However, current-clamp recordings of intact interneurons in layer V of neocortical slices from mice with haploinsufficiency in the gene encoding the Na V 1.1 sodium channel, Scn1a, revealed substantial reduction of excitability in fast-spiking, parvalbumin-expressing interneurons and somatostatin-expressing interneurons. The threshold and rheobase for action potential generation were increased, the frequency of action potentials within trains was decreased, and action-potential firing within trains failed more frequently. Furthermore, the deficit in excitability of somatostatin-expressing interneurons caused significant reduction in frequency-dependent disynaptic inhibition between neighboring layer V pyramidal neurons mediated by somatostatin-expressing Martinotti cells, which would lead to substantial disinhibition of the output of cortical circuits. In contrast to these deficits in interneurons, pyramidal cells showed no differences in excitability. These results reveal that the two major subtypes of interneurons in layer V of the neocortex, parvalbumin-expressing and somatostatin-expressing, both have impaired excitability, resulting in disinhibition of the cortical network. These major functional deficits are likely to contribute synergistically to the pathophysiology of Dravet syndrome. D ravet syndrome (DS), also referred to as "severe myoclonic epilepsy in infancy," is a rare genetic epileptic encephalopathy characterized by frequent intractable seizures, severe cognitive deficits, and premature death (1-3). DS is caused by loss-of-function mutations in SCN1A, the gene encoding type I voltage-gated sodium channel Na V 1.1, which usually arise de novo in the affected individuals (4-7). Like DS patients, mice with heterozygous lossof-function mutations in Scn1a exhibit ataxia, sleep disorder, cognitive deficit, autistic-like behavior, and premature death (8)(9)(10)(11)(12)(13)(14). Like DS patients, DS mice first become susceptible to seizures caused by elevation of body temperature and subsequently experience spontaneous myoclonic and generalized tonic-clonic seizures (11). Global deletion of Na V 1.1 impairs Na + currents and action potential (AP) firing in GABAergic-inhibitory interneurons (8-10), and specific deletion of Na V 1.1 in forebrain interneurons is sufficient to cause DS in mice (13,15). These data suggest that the loss of interneuron excitability and resulting di...

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Section: Impaired Monosynaptic Transmission Between Layer V Pyramidalmentioning

confidence: 99%

mentioning

confidence: 99%

Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome

Tai

Abe

Westenbroek

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

249

215

View full text Add to dashboard Cite

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“…1 Dravet syndrome is primarily a clinical diagnosis, frequently supported by the identification of a mutation in SCN1A, as the majority of children (70-80%) carry such a mutation. 3 At all stages seizures are usually refractory to standard antiepileptic medication. 4 While some studies have linked a greater degree of cognitive and behavioural impairment to a higher convulsive and nonconvulsive seizure frequency, the extent to which comorbidities and their severity arise and develop independently from seizures is still unknown.…”

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confidence: 99%

Quality of life and comorbidities associated with Dravet syndrome severity: a multinational cohort survey

Lagae

Brambilla²,

Mingorance³

et al. 2017

Develop Med Child Neuro

148

219

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Aim To test the hypothesis that higher seizure burden in Dravet syndrome is associated with increased comorbidities and lower quality of life (QoL) in a large cohort of patients with Dravet syndrome and their caregivers in Europe. Method An extensive survey of caregivers of patients with Dravet syndrome on experiences of diagnosis, seizure burden, management, social and financial impact, and health services use was administered online in 10 languages. Results The survey received 584 unique responses from caregivers of paediatric (83%) and adult (17%) patients with Dravet syndrome (aged <1–48y). Despite broadly following current treatment guidance, less than 10% of patients were seizure free in the previous 3 months. Nearly all (99.6%) patients aged 5 years or older experienced at least one or more motor, speech, learning, or behavioural impairment. High seizure frequency was related to more reports of emergency treatment, comorbidities, and a lower QoL (as measured by the standardized instrument EQ‐5D‐5L). If not diagnosed at the first instance, the majority (83%) of adults, but less than 20% of 6‐ to 11‐year‐olds were diagnosed after 4 or more years. Interpretation Patients with Dravet syndrome with the highest current seizure frequency suffer from more comorbidities and have a lower QoL. Therefore, more effective antiepileptic treatments are needed. What this paper adds The survey captured about 15% of all patients with Dravet syndrome in Europe. Less than 10% of patients had current seizure freedom. Patients with a high current seizure burden have more comorbidities and lower quality of life.

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“…18 A total of 40-50% of mutations associated with the SMEI phenotype are missense in nature with 50-60% truncating, whereas almost all the mutations associated with GEFS-phenotypes are missense. 4 It is not well-understood why certain missense mutations are linked to severe phenotypes and others are not. Controversies remain as to whether missense mutations are clustered in specific regions of the SCN1A protein or whether they occur randomly across ion transport sequences, regions sharing significant homology with other ion channels and transporters.…”

Section: Discussionmentioning

confidence: 99%

“…It is known that SCN1A mutations are most notably linked to two epilepsy syndromes, severe myoclonic epilepsy of infancy (SMEI), also known as Dravet syndrome (DS; MIM#607208) and the mild familial epilepsy syndrome of genetic epilepsy with febrile seizures (FS) plus (GEFS+; MIM#604233). [1][2][3][4] All of the SCN1A mutations are dominantly inherited and they can result most commonly as observed in either loss of function in DS or altered function in GEFS+. DS is one of the most common and well-defined epileptic encephalopathy.…”

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confidence: 99%

Expanding spectrum of SCN1A-related phenotype with novel mutations

et al. 2017

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Mutations in the genes encoding voltage-gated sodium channels cause a variety of epilepsy syndromes, with most of the mutations occurring in SCN1A gene. It is one of the most well-researched epilepsy genes. The SCN1A gene, which seems to be a relevant regulator of excitability of the CNS, is implicated in various epilepsy phenotypes through various genetic mechanisms ranging from common variants to rare monogenic variants. It is known that SCN1A gene is tightly linked to severe myoclonic epilepsy of infancy (SMEI). However, its phenotypic spectrum is expanding. Here, we report clinical and genetic findings of 10 patients with SCN1A mutations where two of them were found to have novel mutations. Our findings support understanding and updating knowledge on the correlation between phenotype distribution and location and type of mutations in SCN1A-related disorders.

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TheSCN1Avariant database: a novel research and diagnostic tool

Cited by 118 publications

References 29 publications

Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome

Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome

Quality of life and comorbidities associated with Dravet syndrome severity: a multinational cohort survey

Expanding spectrum of SCN1A-related phenotype with novel mutations

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