Milder phenotype with SCN1A truncation mutation other than SMEI

Yu, Min; Shi, Yi‐Wu; Gao, Mei-Mei; Deng, Wei; Liu, Xiaorong; Chen, Li; Long, Yue-Sheng; Yi, Yong‐Hong; Liao, Wei‐Ping

doi:10.1016/j.seizure.2010.06.010

Cited by 21 publications

(17 citation statements)

References 22 publications

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“…Most truncating mutations terminated the protein at first 2 domains. Early truncating mutations are mostly associated with severe epileptic phenotypes in DS, although in a previous study, they caused only milder epilepsy with GEFS+ and focal seizures in 2 patients [30]. In the present study, all truncating and splice site mutations were de novo and linked to DS with severe ID.…”

Section: Discussionsupporting

confidence: 42%

Identification of SCN1A and PCDH19 Mutations in Chinese Children with Dravet Syndrome

et al. 2012

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BackgroundDravet syndrome is a severe form of epilepsy. Majority of patients have a mutation in SCN1A gene, which encodes a voltage-gated sodium channel. A recent study has demonstrated that 16% of SCN1A-negative patients have a mutation in PCDH19, the gene encoding protocadherin-19. Mutations in other genes account for only a very small proportion of families. TSPYL4 is a novel candidate gene within the locus 6q16.3-q22.31 identified by linkage study.ObjectiveThe present study examined the mutations in epileptic Chinese children with emphasis on Dravet syndrome.MethodsA hundred children with severe epilepsy were divided into Dravet syndrome and non-Dravet syndrome groups and screened for SCN1A mutations by direct sequencing. SCN1A-negative Dravet syndrome patients and patients with phenotypes resembling Dravet syndrome were checked for PCDH19 and TSPYL4 mutations.ResultsEighteen patients (9 males, 9 females) were diagnosed to have Dravet syndrome. Among them, 83% (15/18) had SCN1A mutations including truncating (7), splice site (2) and missense mutations (6). The truncating/splice site mutations were associated with moderate to severe degree of intellectual disability (p<0.05). During the progression of disease, 73% (11/15) had features fitting into the diagnostic criteria of autism spectrum disorder and 53% (8/15) had history of vaccination-induced seizures. A novel PCDH19 p.D377N mutation was identified in one SCN1A-negative female patient with Dravet syndrome and a known PCDH19 p.N340S mutation in a female non-Dravet syndrome patient. The former also inherited a TSPYL4 p.G60R variant.ConclusionA high percentage of SCN1A mutations was identified in our Chinese cohort of Dravet syndrome patients but none in the rest of patients. We demonstrated that truncating/splice site mutations were linked to moderate to severe intellectual disability in these patients. A de novo PCDH19 missense mutation together with an inherited TSPYL4 missense variant were identified in a patient with Dravet syndrome.

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Section: Discussionsupporting

confidence: 42%

Identification of SCN1A and PCDH19 Mutations in Chinese Children with Dravet Syndrome

et al. 2012

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“…In addition, Scn1a heterozygote animals also show markedly different effects depending on the genetic background, with one strain having a more severe phenotype compared with other strains (Yu et al, 2006). Also, truncation mutations in SCN1A in patients can lead to febrile seizures or GEFS+ instead of DS (Gennaro et al, 2003; Yu et al, 2010). These observations reflect the role of genetic background or modifier genes in the phenotypic outcome of DS patients.…”

Section: Discussionmentioning

confidence: 99%

Febrile temperatures unmask biophysical defects in Nav1.1 epilepsy mutations supportive of seizure initiation

Volkers

Kahlig

Das

et al. 2013

Journal of General Physiology

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Generalized epilepsy with febrile seizures plus (GEFS+) is an early onset febrile epileptic syndrome with therapeutic responsive (a)febrile seizures continuing later in life. Dravet syndrome (DS) or severe myoclonic epilepsy of infancy has a complex phenotype including febrile generalized or hemiclonic convulsions before the age of 1, followed by intractable myoclonic, complex partial, or absence seizures. Both diseases can result from mutations in the Nav1.1 sodium channel, and initially, seizures are typically triggered by fever. We previously characterized two Nav1.1 mutants—R859H (GEFS+) and R865G (DS)—at room temperature and reported a mixture of biophysical gating defects that could not easily predict the phenotype presentation as either GEFS+ or DS. In this study, we extend the characterization of Nav1.1 wild-type, R859H, and R865G channels to physiological (37°C) and febrile (40°C) temperatures. At physiological temperature, a variety of biophysical defects were detected in both mutants, including a hyperpolarized shift in the voltage dependence of activation and a delayed recovery from fast and slow inactivation. Interestingly, at 40°C we also detected additional gating defects for both R859H and R865G mutants. The GEFS+ mutant R859H showed a loss of function in the voltage dependence of inactivation and an increased channel use-dependency at 40°C with no reduction in peak current density. The DS mutant R865G exhibited reduced peak sodium currents, enhanced entry into slow inactivation, and increased use-dependency at 40°C. Our results suggest that fever-induced temperatures exacerbate the gating defects of R859H or R865G mutants and may predispose mutation carriers to febrile seizures.

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“…There are reports of truncation mutations in SCN1A that lead to febrile seizures or GEFS+ instead of DS (Gennaro et al. , 2003; Yu et al. , 2010), indicating that the genetic background can play a role in the outcome of the disease.…”

Section: Discussionmentioning

confidence: 99%

Nav1.1 dysfunction in genetic epilepsy with febrile seizures-plus or Dravet syndrome

Volkers

Kahlig

Verbeek

et al. 2011

European Journal of Neuroscience

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Relatively few SCN1A mutations associated with genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS) have been functionally characterized. In contrast to GEFS+, many mutations detected in DS patients are predicted to have complete loss-of-function. However, functional consequences are not immediately apparent for DS missense mutations. Therefore, we performed biophysical analysis of three SCN1A missense mutations (R865G, R946C, and R946H) we detected in six patients with DS. Furthermore, we compared the functionality of the R865G DS mutation with that of a R859H mutation detected in a GEFS+ patient; both mutations reside in the same voltage sensor domain of Nav1.1. The four mutations were co-expressed with β1 and β2-subunits in tsA201 cells and characterized using the whole-cell patch clamp technique. The two DS mutations, R946C and R946H, were non-functional. However, the novel voltage sensor mutants R859H (GEFS+) and R865G (DS) produced sodium current densities comparable to wild-type channels. Both mutants had negative shifts in the voltage dependence of activation, slower recovery from inactivation, and increased persistent current. Only the GEFS+ mutant exhibited a loss-of-function in voltage dependent channel availability. Our results suggest that the R859H mutation causes GEFS+ by a mixture of biophysical defects in Nav1.1 gating. Interestingly, while loss of Nav1.1 function is common in DS, the R865G mutation may cause DS by overall gain-of-function defects.

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Milder phenotype with SCN1A truncation mutation other than SMEI

Cited by 21 publications

References 22 publications

Identification of SCN1A and PCDH19 Mutations in Chinese Children with Dravet Syndrome

Identification of SCN1A and PCDH19 Mutations in Chinese Children with Dravet Syndrome

Febrile temperatures unmask biophysical defects in Nav1.1 epilepsy mutations supportive of seizure initiation

Nav1.1 dysfunction in genetic epilepsy with febrile seizures-plus or Dravet syndrome

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