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Dravet syndrome

Orpha number ORPHA33069
Synonym(s) DS
SMEI
Severe myoclonic epilepsy of infancy
Severe myoclonus epilepsy of infancy
Prevalence Unknown
Inheritance Autosomal dominant
Age of onset Infancy
Neonatal
ICD-10
  • G40.4
ICD-O -
OMIM
UMLS -
MeSH -
MedDRA -

Summary

Dravet syndrome (DS) is a genetic epilepsy of childhood characterized by a variety of drug-resistant seizures often induced by fever, presenting in previously healthy children, and which frequently leads to cognitive and motor impairment.

Worldwide birth prevalence is thought to be <1/40,000. In the UK it is estimated at 1/28,000.

Onset of the first seizure is mainly in the 1st year of life (usually at 5-8 months of age) in previously healthy infants and most often consists of a unilateral or generalized, clonic seizure. Fever often triggers the seizures that include generalized tonic-clonic, alternating unilateral clonic and generalized tonic-clonic seizures. Afebrile complex partial and focal seizures are also reported during the course of the disease. Some seizures may present as febrile status epilepticus (SE), lasting for more than 20 minutes. The frequency of SE in the first year may be high, but generally decreases with time. Complex partial, absence and atonic seizures may also occur. Photosensitivity, high temperatures, intermittent photic stimulation and exercise may also provoke seizures. By age 2, developmental delay is often apparent, followed by cognitive plateauing and impairment. Impaired speech, ataxia, sleeping difficulties and sometimes pyramidal signs may also appear at this stage. Seizures can regress in adulthood but most patients have ongoing seizures that are refractory to medication. Borderline DS describes variants with most but not all manifestations of DS.

Around 85% of DS cases are due to a mutation or deletion in the SCN1A gene (2q24.3), encoding a voltage-gated sodium channel essential for the excitability of neurons. Most mutations are de novo but in 5-10% they are familial and often part of the generalized epilepsy with febrile seizures-plus (GEFS+; see this term) spectrum. Mutations in the PCDH19 gene (Xq22.1), also seen in female restricted epilepsy with intellectual deficit (see this term), are thought to account for about 5% of female DS cases. In about 10% of cases the etiology is unknown but other genes are likely implicated. Mutations in GABRG2 (5q34), SCN1B (19q13.12), SCN2A (2q24.3), CHD2 (15q26) and HCN1 (5p12) have been reported in a few patients with DS.

Diagnosis is based on clinical and electroencephalic (EEG) findings. At onset, EEG is usually normal but later spikes or poly spike-waves with a slowing of background activity are noted as well as multifocal discharges. Brain MRI is usually normal. Molecular genetic testing can identify a SCN1A alteration, confirming the diagnosis.

Differential diagnoses include Lennox-Gastaut syndrome and myoclonic-astatic epilepsy (see these terms).

In families with a known SCN1A mutation, inheritance is autosomal dominant and genetic counseling is possible, even though the phenotypic range in families can be wide. In cases with de novo mutations, counseling may help with the decision making process for future children.

The main aim of treatment is to reduce seizure frequency and prevent SE occurrence. Valproate, clobazam, stiripentol and bromide may control the recurrence of febrile seizures early in the disease. Stiripentol may be effective in reducing the frequency of seizures when combined with valproate and clobazam. The ketogenic diet, topiramate and levetiracetam may provide substantial efficacy as adjunctive therapy. Carbamazepine and lamotrigine should be avoided as they may provoke seizures. Midazolam may be used to treat acute seizures. Supportive therapy (i.e. protective head gear) may be recommended in children with prominent atonic seizures.

Moderate to severe cognitive impairment and intractable epilepsy into adulthood is common. Preventing the occurrence of convulsive SE in children may improve the long-term prognosis.

Expert reviewer(s)

  • Dr Ingo HELBIG

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Detailed information

Summary information
Emergency guidelines
  • EN (2008,pdf)
  • FR (2008,pdf)
  • PT (2008,pdf)
  • IT (2008,pdf)
Article for general public
  • FR (2011,pdf)
Clinical genetics review
  • EN (2014)
Disability factsheet
  • FR (2013,pdf)
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