Late diagnoses of Dravet syndrome: How many individuals are we missing?

Katri Silvennoinen,Kirsty Hudgell,Helena Martins Custodio,Sanjay M Sisodiya,Meneka K Sidhu,Clinda Puvirajasinghe,Wendy D Jones,Simona Balestrini

doi:10.1002/epi4.12525

Abstract

We report new genetic diagnoses of Dravet syndrome in a group of adults with complex epilepsy of unknown cause, under follow‐up at a tertiary epilepsy center. Individuals with epilepsy and other features of unknown cause from our unit underwent whole‐genome sequencing through the 100 000 Genomes Project. Virtual gene panels were applied to frequency‐filtered variants based on phenotype summary. Of 1078 individuals recruited, 8 (0.74%) were identified to have a pathogenic or likely pathogenic variant in SCN1A. Variant types were as follows: nonsense (stopgain) in five (62.5%) and missense in three (37.5%). Detailed review of childhood history confirmed a phenotype compatible with Dravet syndrome. Median age at genetic diagnosis was 44.5 years (range 28‐52 years). Tonic‐clonic seizures were ongoing in all despite polytherapy including valproate. All had a history of fever sensitivity and myoclonic seizures, which were ongoing in two (25%) and three (37.5%) individuals, respectively. Salient features of Dravet syndrome may be less apparent in adulthood, making clinical diagnosis difficult. Regardless of age, benefits of a genetic diagnosis include access to syndrome‐specific treatment options, avoidance of harmful drugs, and monitoring for common complications.

Highlights

Dravet syndrome (DS) is one of the commonest, best-characterised, severe, monogenic epilepsies
Our experience highlights the need to consider a genetic diagnosis among older individuals with treatment-resistant epilepsy
In our group of adults with epilepsy and other features, a new genetic diagnosis of DS could be made in 0.74%, a relatively high proportion for a single syndrome

Summary

Introduction

Dravet syndrome (DS) is one of the commonest, best-characterised, severe, monogenic epilepsies. Individuals with DS typically present within the first year of life with convulsive seizures, often precipitated by pyrexia.[1] Seizures become recurrent and later often include myoclonic and atypical absence seizures. Focal-onset seizures of various semiologies are common.[1] Developmental delay becomes evident typically from the second year onwards.[1] The majority of individuals have moderate to severe intellectual disability by adulthood.[2,3] DS is typically caused by loss of function variants in the gene SCN1A, affecting inhibitory interneurons.[4] The majority of pathogenic variants arise de novo.[5] DS is widely recognised by paediatricians and neurologists, and SCN1A molecular testing is available in many countries. We describe a series of individuals diagnosed with DS in adulthood based on whole genome sequencing

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Conclusion