Dataset Information

Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype.

ABSTRACT:

Objective

To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder.

Methods

A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation.

Results

We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable.

Conclusions

Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met.

SUBMITTER: Sadleir LG

PROVIDER: S-EPMC5589790 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Publications

Not all <i>SCN1A</i> epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype.

Sadleir Lynette G LG Mountier Emily I EI Gill Deepak D Davis Suzanne S Joshi Charuta C DeVile Catherine C Kurian Manju A MA Mandelstam Simone S Wirrell Elaine E Nickels Katherine C KC Murali Hema R HR Carvill Gemma G Myers Candace T CT Mefford Heather C HC Scheffer Ingrid E IE

Neurology 20170809 10

<h4>Objective</h4>To define a distinct <i>SCN1A</i> developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder.<h4>Methods</h4>A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and <i>SCN1A</i> mutation.<h4>Results</h4>We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had p ...[more]

PMID: 28794249

Similar Datasets

Project description:BACKGROUND: Dravet 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. OBJECTIVE: The present study examined the mutations in epileptic Chinese children with emphasis on Dravet syndrome. METHODS: A 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. RESULTS: Eighteen 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. CONCLUSION: A 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.