Seizure 2021, Vol 86, Editor’s Choice: A systematic review of adults with Dravet syndrome
Dravet Syndrome (DS) was first described by Charlotte Dravet in 1978. It was initially known as “Severe Myoclonic Epilepsy of Infancy”, but was renamed after its describer in 1989, not least because it had become clear that the condition is not restricted to infancy.
DS starts during the first year of life, often with frequent febrile seizures around six months of age. It is recognised in between 1 in 15,000 and 1 in 41,000 children. Once it has manifested, the condition progresses and goes on to cause cognitive impairment, behavioural problems such as hyperactivity and impulsivity and motor deficits such as ataxia. DS is often associated with sleep disorders. Many of those affected remain at risk of febrile or hyperthermia-related seizures. Like the seizures, the EEG changes of DS get worse with increasing age (1). DS causes is associated with a markedly increased mortality – many patients die in childhood. At least 50% of deaths are directly attributable to seizures which respond poorly to most antiepileptic drugs and can even be aggravated by some (especially sodium channel blockers) (2).
DS is an autosomal dominant genetic disorder. Seventy to 80% of DS patients have been shown to carry disease-causing abnormalities in one of the two copies of their SCN1A gene. It is possible that all those with DS who do not carry one of the readily identifiable deletions, truncating or missense abnormalities may have smaller SCN1A exon deletions or chromosomal rearrangements and that DS is therefore always related to one poor copy of the SCN1A gene. However, patients with abnormalities in a number of other genes can present with symptoms that can be very similar to those of DS. The SCN1A gene carries the genetic code for the neuronal voltage-gated sodium channel Nav1.1. The genetic abnormalities in DS mean that patients do not produce sufficient amounts of this protein, which plays a key role in the electrical behaviour of neurons. In most cases DS mutations appear to have occurred spontaneously and neither parents nor other family members carry the abnormal gene.
While it is never good to carry a copy of the SCN1A gene that is abnormal enough to cause DS, there are grounds for optimism that the near future will be a better time to be diagnosed with DS than the recent past. Thanks to the relatively well-established understanding of the SCN1A gene and how its transcription is regulated, the antiseizure medicines which have become available for this disorder (stiripentol, cannabidiol and fenfluramine) or which may become available in the near future (soticlestat) are not the only reasons to be hopeful. Researchers are also pursuing a number of different approaches targeting the root cause of the disease. Different viruses are being used to infect neurons and carry correct copies of the defective gene into the brain. Another approach involves the use of one of several mechanisms to enhance the transcription of the good copy of the SCN1A gene which all patients with DS have (3).
While it may take a while yet before this research benefits patients with DS, the experience with Spinal Muscular Atrophy (SMA) demonstrates that genetic treatment can successfully control a condition caused by one abnormal copy of a gene leading to reduced protein production. SMA is a previously lethal condition for which several genetic treatments capable of ensuring patients’ longterm survival are now available.
One of the practical problem which many patients with DS – especially adults – will face, even in rich countries where access to these exciting treatments may be possible, is a lack of a genetic diagnosis. Individuals with DS who have survived into adulthood are likely to be under the care of neurologists or specialists in Intellectual Disabilities. The genetic tests which are now used to confirm the diagnosis may not have been available before these patients transitioned to adult care. There is still a lack of awareness of specific, genetically diagnosable epileptic encephalopathies among adult neurologists (or a lack of the belief that genetic diagnoses make a difference to their patient’s management). Even those adult neurologists trying to make specific diagnoses, may not have access to childhood records and may have an incomplete understanding of the course of their patients’ disorder.
My editor’s choice from the current issue of Seizure, a systematic review of the literature about DS in adults by Arunan Selvarajah et al. should help to make adult neurologists more familiar with a disorder which they can do a lot for already (if they recognise it) and which they may have even more exciting treatments for in the not too distant future (4).
(1) Anwar A, Saleem S, Patel UK, Arumaithurai K, Malik P. Dravet Syndrome: An Overview. Cureus 2019;11:e5006. Published 2019 Jun 26. doi:10.7759/cureus.5006
(2) Shmuely S, Sisodiya SM, Boudewijn Gunning W, Sander JW, Thijs RD, Mortality in Dravet syndrome: A review. Epilepsy & Behavior 2016; 64:69-74.
(4) Selvarajah A, Ali QZ, Marques P, Rong M, Andrade DM. A Systematic Review of Adults with Dravet Syndrome. Seizure 2021; 87:39-45.