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

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Project description:The SCN1A gene encodes the alpha subunit of a voltage-gated sodium channel (Nav1.1), which is essential for the function of inhibitory neurons in the brain. Mutations in this gene cause severe encephalopathies such as Dravet syndrome (DS). Upregulation of SCN1A expression by different approaches has demonstrated promising therapeutic effects in preclinical models of DS. Limiting the effect to inhibitory neurons may contribute to the restoration of brain homeostasis, increasing the safety and efficacy of the treatment. In this work, we have evaluated different approaches to obtain preferential expression of the full SCN1A cDNA (6 Kb) in GABAergic neurons, using high-capacity adenoviral vectors (HC-AdV). In order to favour infection of these cells, we considered ErbB4 as a surface target. Incorporation of the EGF-like domain from neuregulin 1 alpha (NRG1α) in the fiber of adenovirus capsid allowed preferential infection in cells lines expressing ErbB4. However, it had no impact on the infectivity of the vector in primary cultures or in vivo. For transcriptional control of transgene expression, we developed a regulatory sequence (DP3V) based on the Distal-less homolog enhancer (Dlx), the vesicular GABA transporter (VGAT) promoter, and a portion of the SCN1A gene. The hybrid DP3V promoter allowed preferential expression of transgenes in GABAergic neurons both in vitro and in vivo. A new HC-AdV expressing SCN1A under the control of this promoter showed improved survival and amelioration of the epileptic phenotype in a DS mouse model. These results increase the repertoire of gene therapy vectors for the treatment of DS and indicate a new avenue for the refinement of gene supplementation in this disease. KEY MESSAGES: Adenoviral vectors can deliver the SCN1A cDNA and are amenable for targeting. An adenoviral vector displaying an ErbB4 ligand in the capsid does not target GABAergic neurons. A hybrid promoter allows preferential expression of transgenes in GABAergic neurons. Preferential expression of SCN1A in GABAergic cells is therapeutic in a Dravet syndrome model.

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