De novo<i>SCN1A</i>mutations are a major cause of severe myoclonic epilepsy of infancy

Claes, Lieve; Ceulemans, Berten; Audenaert, Dominique; Smets, Katrien; Löfgren, Ann; Del-Favero, Jurgen; Ala‐Mello, Sirpa; Basel‐Vanagaite, Lina; Plecko, Barbara; Raskin, Salmo; Thiry, Paul; Wolf, Nicole I.; Broeckhoven, Christine Van; Jonghe, Peter De

doi:10.1002/humu.10217

Cited by 181 publications

(108 citation statements)

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“…Mutations in the sodium channel-encoding gene SCN1A account for the majority of Dravet syndrome cases [6,7] and have also been found to cause milder forms of epilepsy, migraine, and autism without epilepsy [8][9][10]. Mutations in SCN1B [11], SCN2A [12], and GABRG2 [13] are also known causes of Dravet syndrome, with additional genes such as PCDH19 and CHD2 found to cause Dravet-like phenotypes when mutated [14,15].…”

Section: Introductionmentioning

confidence: 96%

The European patient with Dravet syndrome: Results from a parent-reported survey on antiepileptic drug use in the European population with Dravet syndrome

Aras¹,

Isla²,

Mingorance³

2015

Epilepsy & Behavior

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Dravet syndrome is a rare form of epilepsy largely refractory to current antiepileptic medications. The only precedents of randomized placebo-controlled trials in Dravet syndrome are the two small trials that led to the approval of stiripentol. With the arrival of new clinical trials for Dravet syndrome, we sought to determine the characteristics of the patient population with Dravet syndrome in Europe today, which has possibly evolved subsequent to the approval of stiripentol and the ability to diagnose milder clinical cases via genetic testing. From May to June 2014, we conducted an online parent-reported survey to collect information about the demographics, disease-specific clinical characteristics, as well as current and past use of antiepileptic medications by European patients with Dravet syndrome. We present data from 274 patients with Dravet syndrome from 15 European countries. Most patients were between 4 and 8years of age, and 90% had known mutations in SCN1A. Their epilepsy was characterized by multiple seizure types, although only 45% had more than 4 tonic-clonic seizures per month on average. The most common drug combination was valproate, clobazam, and stiripentol, with 42% of the total population currently taking stiripentol. Over a third of patients with Dravet syndrome had taken sodium channel blockers in the past, and most had motor and behavioral comorbidities. Our study helps define the current typical European patient with Dravet syndrome. The results from this survey may have important implications for the design of future clinical trials that investigate new treatments for Dravet syndrome.

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Section: Introductionmentioning

confidence: 96%

The European patient with Dravet syndrome: Results from a parent-reported survey on antiepileptic drug use in the European population with Dravet syndrome

Aras¹,

Isla²,

Mingorance³

2015

Epilepsy & Behavior

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“…Seizures in this disorder typically do not respond to standard anticonvulsant pharmacotherapy. More than 80 heterozygous, predominantly de novo, SCN1A mutations have been reported in this disorder (3,(14)(15)(16)(17). Because many of the SCN1A mutations discovered in SMEI probands are nonsense and frameshift alleles, loss of neuronal sodium channel function as the cause of this syndrome seems most plausible.…”

mentioning

confidence: 99%

Noninactivating voltage-gated sodium channels in severe myoclonic epilepsy of infancy

Rhodes

Lossin

Vanoye

et al. 2004

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

164

171

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Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel ␣1 subunit (NaV1.1), are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of five SMEI mutations by using wholecell patch-clamp analysis of heterologously expressed recombinant human SCN1A. Two mutations (F902C and G1674R) rendered SCN1A channels nonfunctional, and a third allele (G1749E) exhibited minimal functional alterations. However, two mutations within or near the S4 segment of the fourth repeat domain (R1648C and F1661S) conferred significant impairments in fast inactivation, including persistent, noninactivating channel activity resembling the pattern of channel dysfunction observed for alleles associated with generalized epilepsy with febrile seizures plus. Our data provide evidence for a range of SCN1A functional abnormalities in SMEI, including gain-of-function defects that were not anticipated in this disorder. Our results further indicate that a complex relationship exists between phenotype and aberrant sodium channel function in these inherited epilepsies.seizure ͉ generalized epilepsy with febrile seizures plus ͉ SCN1A ͉ electrophysiology M utations in genes encoding neuronal voltage-gated sodium channels have been linked to inherited forms of epilepsy. Genetic defects in two pore-forming ␣ subunits (encoded by SCN1A and SCN2A) and the accessory ␤ 1 subunit (encoded by SCN1B) have been discovered in four distinguishable clinical syndromes with overlapping features (1-6). Generalized epilepsy with febrile seizures plus (GEFSϩ) is an autosomal dominant disorder characterized by childhood febrile seizures that persist beyond age 6 years, as well as afebrile generalized or partial seizures of various types. In 1998, Wallace et al.(1) described a single missense mutation in SCN1B, the gene encoding the voltage-gated sodium channel ␤ 1 subunit, in a large GEFSϩ pedigree. However, SCN1B mutations are rare causes of GEFSϩ (7,8). By contrast, mutations in SCN1A, the gene encoding the neuronal sodium channel ␣-subunit Na V 1.1, have been identified in several GEFSϩ families (2, 9-11).SCN1A mutations occur also in severe myoclonic epilepsy of infancy (SMEI), a rare convulsive disorder characterized by febrile seizures with onset during the first year of life, followed by intractable epilepsy, impaired psychomotor development, and ataxia (12, 13). Seizures in this disorder typically do not respond to standard anticonvulsant pharmacotherapy. More than 80 heterozygous, predominantly de novo, SCN1A mutations have been reported in this disorder (3,(14)(15)(16)(17). Because many of the SCN1A mutations discovered in SMEI probands are nonsense and frameshift alleles, loss of neuronal sodium channel function as the cause of this syndrome seems most plausible. This hypothesis is supported by the observation that certain missense mutations in this condition render SCN1A channels nonfunctional or severely impair...

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“…However, one theme stands out both this year and in other years: there is a concentration on particular genes, mostly channel genes, that were indicated either in studies of single families or because they fit the channelopathy paradigm for epilepsy, or both [53]. Some channel genes have been shown to be causative of some rare forms of epilepsy (eg, the sodium channel gene SCNA1 and severe myoclonic epilepsy of infancy [54] and benign familial neonatal convulsions and the potassium channel genes KCNQ2 and KCNQ3 [55]), but few others have been proven and none has been shown to play any role in common varieties of IGE. Interestingly, few genes have been identified through linkage scans of collections of families chosen through distinct phenotypes, and of those that have, only BRD2 has been replicated, but it is not a channel gene.…”

Section: (Continued)mentioning

confidence: 97%

The state of the art in the genetic analysis of the epilepsies

Greenberg

Pal²

2007

Curr Neurol Neurosci Rep

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Genetic influences as causal factors in the epilepsies continue to be vigorously investigated, and we review several important studies of genes reported in 2006. To date, mutations in ion channel and neuroreceptor component genes have been reported in the small fraction of cases with clear Mendelian inheritance. These findings confirm that the so-called "channelopathies" are generally inherited as monogenic disorders. At the same time, the literature in common epilepsies abounds with reports of associations and reports of nonreplication of those association studies, primarily with channel genes. These contradictory reports can mostly be explained by confounding factors unique to genetic studies. The methodology of genetic studies and their common biases and confounding factors are also explained in this review. Amid the controversy, steady progress is being made on the epilepsies of complex inheritance, which represent the most common idiopathic epilepsy. Recent discoveries show that genes influencing the developmental assembly of neural circuits and neuronal metabolism may play a more prominent role in the common epilepsies than genes affecting membrane excitability and synaptic transmission.

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De novoSCN1Amutations are a major cause of severe myoclonic epilepsy of infancy

Cited by 181 publications

References 32 publications

The European patient with Dravet syndrome: Results from a parent-reported survey on antiepileptic drug use in the European population with Dravet syndrome

The European patient with Dravet syndrome: Results from a parent-reported survey on antiepileptic drug use in the European population with Dravet syndrome

Noninactivating voltage-gated sodium channels in severe myoclonic epilepsy of infancy

The state of the art in the genetic analysis of the epilepsies

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