Dravet syndrome

Dravet syndrome is a rare dominant genetic disorder, most commonly associated with heterozygous pathogenic variants in the SCN1A gene. It causes a severe developmental and epileptic encephalopathy that typically presents in infancy with prolonged febrile and afebrile seizures and evolves into treatment-resistant epilepsy. There can be associated cognitive, behavioural and motor difficulties and/or developmental regression.

Clinical features of Dravet syndrome include those listed below.

•  Seizures:
  • onset typically within the first year of life;
  • usually prolonged, recurrent and resistant to treatment;
  • often triggered by hyperthermia, for example due to a hot bath, physical exercise or fever; and
  • varied in type (seizure types evolve with age, and tend to lesson in severity after puberty).
    • At onset phase (under one year of age), seizures are clonic, generalised and/or unilateral, and are typically fever-induced and prolonged. Electroencephalogram (EEG) findings are usually normal or show minimal anomalies.
    • At the worsening phase (one to five years of age), seizures are myoclonic, focal and/or absence, and photosensitivity develops. Seizures are more frequent but less prolonged. EEG findings show that interictal anomalies have developed; patterns can include generalised spike and wave activity, polyspike and wave discharges, and multifocal spikes.
    • At the stabilisation phase (over 10 years of age), seizures can be of multiple types and are of reduced frequency and duration – though there is a worsening of comorbidities. EEG findings show background slowing, multifocal and/or generalised epileptiform discharges.
• Developmental, psychiatric and behavioural features:
  • developmental regression and delay:
    • development is normal up to seizure onset, with regression occurring typically between the ages of two and four years; and
    • speech and language are particularly affected;
  • intellectual disability (moderate to severe);
  • features of autism spectrum disorder and/or attention deficit hyperactivity disorder;
  • anxiety;
  • obsessive personality traits; and
  • challenging behaviour.
• Motor features:
  • balance difficulties, including gait disturbance (crouched gait in older children);
  • ataxia; and
  • incoordination.
• Other features:
  • hypotonia;
  • dysautonomia;
  • sleep disturbance; and
  • increased chance of sudden unexpected death in epilepsy.

Over 85% of cases of Dravet syndrome are due to heterozygous pathogenic variants in the SCN1A gene. SCN1A encodes for part of a voltage-gated sodium channel essential for neuronal firing, which is found in inhibitory neurons in the brain and muscle. Impaired function of this sodium channel causes an overall increase in neuronal excitability.

Many SCN1A pathogenic variants have been reported, including nonsense, frameshift, splice-site and copy number changes (deletions/duplications). Missense variants in critical regions are also associated with the more classic Dravet presentation. Most arise de novo and result in loss of function of the sodium channel. Missense variants in non-conserved, non-critical regions may present with milder SCN1A-related conditions.

Dravet syndrome lies at the severe end of SCN1A-related conditions, which includes familial hemiplegic migraine, familial febrile seizures and several other severe epilepsy syndromes. The condition demonstrates variable expressivity and incomplete penetrance, explaining why some individuals with an SCN1A variant do not develop symptoms.

Other genes with which Dravet syndrome has been associated include SCN2A, SCN8A, SCN1B, PCDH19, GABRA1, GABRG2, STXBP1, HCN1, CHD2 and KCN2A.

Diagnosis of Dravet syndrome is usually based on:

• clinical features;
• EEG findings; and 
• genomic testing.

EEG findings are usually normal at onset of symptoms, with abnormalities developing over time (see ‘Clinical features’ above). Brain MRI is typically normal, but atrophic features or other abnormalities may develop as the condition progresses.

For information about genomic testing, see Presentation: Infant with early onset epilepsy or epileptic encephalopathy.

SCN1A-related Dravet syndrome is an autosomal dominant condition.

• Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
• The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
• Incomplete penetrance can occur when not everyone who has the variant develops the disease.

The majority of cases of Dravet syndrome occur de novo, although there have been reports of SCN1A pathogenic variants being inherited from an affected or mosaic parent. There is a 50% chance that an individual with an SCN1A variant will have an affected child.

If a pathogenic variant is identified in an affected child, their parents should be offered testing for the same variant. If it is not found, the probability of them having a subsequent child affected with Dravet syndrome would be low (less than 1%), though not quite back to population level, reflecting the possibility of germline mosaicism.

Management of children with Dravet syndrome is very difficult given the drug-resistant nature of the seizures, and affected individuals should have a paediatric neurologist with expertise in epilepsy involved in their care.

Gene-related therapies and trials

A type of gene-related therapy called an antisense oligonucleotide is currently being trialled as a potential treatment for Dravet syndrome. This therapy increases the amount of SCN1A protein produced by the normal copy of the SCN1A gene, restoring the number of functional sodium channels to normal levels. Information about therapies and relevant clinical trials can be found on the Dravet Syndrome UK website.

For clinicians

• Dravet Syndrome UK: Current clinical trials
• GeneReviews: SCN1A seizure disorders
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• NICE: Dravet syndrome
• OMIM: 607208 Dravet syndrome
• US National Library of Medicine: ClinicalTrials.gov database

References:

• Steel D, Symonds JD, Zuberi SM and Brunklaus A. ‘Dravet syndrome and its mimics: Beyond SCN1A’. Epilepsia 2017: volume 58, issue 11, pages 1,807–1,816. DOI: 10.1111/epi.13889
• Wheless JW, Fulton SP and Mudigoudar BD. ‘Dravet syndrome: A review of current management’. Pediatric Neurology 2020: volume 107, pages 28–40. DOI: 10.1016/j.pediatrneurol.2020.01.005

For patients

• Dravet Syndrome Foundation
• DRAVET Syndrome UK
• Epilepsy Action: Dravet syndrome
• National Institute for Health and Care Research