Dravet syndrome (ORPHA:33069)
A rare, genetic, developmental and epileptic encephalopathy characterized by infantile onset of intractable seizures that are often febrile, and associated with cognitive and motor impairment.
Epidemiology
The average prevalence at birth of Dravet syndrome is 1/30,000 (range 1/15,000-40,000).
Clinical description
Onset of the first seizure is mainly in the first year of life (usually at 5-8 months) in previously healthy infants. Seizures include clonic seizure, often unilateral that alternates between left and right, and generalized tonic-clonic seizures. Seizures are often febrile and long lasting, presenting as febrile status epilepticus (SE). SE is mainly frequent in the first years. Other seizures types may also occur, such as focal or atypical absence seizures, as well as possible clusters of nocturnal tonic or tonic-clonic seizures between age 4 and 11. Photosensitivity, high temperatures, photic stimulation and exercise may trigger seizures. Developmental delay is often apparent by age 2, followed by cognitive plateauing. Speech impairment, progressive gait deterioration with crouching, and sleeping difficulties may also appear at this stage.
Etiology
Around 85% of cases are due to a mutation or deletion in the SCN1A gene (2q24.3), encoding a voltage-gated sodium channel. Most mutations are de novo but might be part of a familial spectrum of genetic epilepsy with febrile seizures-plus (GEFS+) in 5-10%. Mutations in the PCDH19 gene (Xq22.1), might account for about 5% of female cases. In about 10% of cases, the etiology is unknown. Somatic mosaic deletions or mutations in SCN1A are found in about 3% of the patients that are initially negative. Few patients are reported with pathogenic variants in other genes such as GABRG2 (5q34), GABRA1 (5q34), STXBP1 (9q34.11), SCN1B (19q13.12), and SCN2A (2q24.3).
Diagnostic methods
Diagnosis is based on clinical and electroencephalographic (EEG) findings. At onset, EEG is usually normal but later spikes or poly spike-waves with a slowing of background and multifocal discharges are recorded. Brain magnetic resonance imaging is usually normal. SCN1A pathogenic variants can confirm the diagnosis in the clinical setting of Dravet syndrome.
Differential diagnosis
Differential diagnosis includes myoclonic atonic epilepsy.
Genetic counseling
In families with a known SCN1A mutation, inheritance is autosomal dominant and genetic counselling is possible, even though the phenotypic range in families can be wide. In cases with de novo mutations, counselling may helpful.
Management and treatment
The main aim of treatment is to reduce seizure frequency and prevent SE. Valproate, clobazam, stiripentol and bromide may control the febrile seizures early in the disease. Stiripentol may be effective in reducing the duration and the frequency of seizures in combination with valproate and clobazam. The ketogenic diet, topiramate and levetiracetam may provide substantial efficacy as adjunctive therapy as well as cannabidiol in association with clobazam. Ongoing clinical trials showed substantial efficacy of fenfluramine as an add-on. Vagus nerve stimulation can be also considered. Sodium channel blockers (carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine and phenytoin) should be avoided as they worsen seizures. Benzodiazepines are used to treat acute seizures. Children with prominent seizures with falls need protective head gear. Treatment management should be handled by clinicians with expertise in rare and complex epilepsies.
Prognosis
Seizures can decrease in frequency in adulthood but often remain refractory to therapies. Moderate to severe cognitive impairment and intractable epilepsy into adulthood is common. Children present a progressive cognitive decline after early language and visual function impairment. Intellectual deficiency is present in around 86% of patients. Autism spectrum disorder can also appear in 31%. Preventing the occurrence of convulsive SE in children may improve the long-term prognosis.

                            Last update: 
                            April 2021


                            - Expert reviewer(s): 
                            Dr Nicole CHEMALY | EpiCARE* - Pr Rima NABBOUT | EpiCARE*


                                * European Reference Network