Dravet syndrome: the main issues.
Dravet syndrome (DS) is a severe form of infantile onset epilepsy characterized by multiple seizure types, prolonged convulsive seizures and frequent episodes of status epilepticus. Seizures precipitated by fever are a main characteristic. Affected children exhibit normal early development. Cognitive impairment, behavioral disturbances with hyperactivity and sometimes autistic traits occur after seizure onset. Seizures persist into adulthood but become less frequent. In about 85% of patients, a mutation of the SCN1A gene is present. DS fully illustrates the concept of epileptic encephalopathy. However, it is difficult to determine the causative role of the underlying sodium channel dysfunction and that of the consequent seizures in influencing cognitive outcome. An overwhelmingly high number of SCN1A mutations have been associated with DS. Intragenic or whole gene deletions, duplications and amplifications are additional rare molecular mechanisms. Most mutations are de novo, but familial mutations also occur. Somatic mosaic mutations should be considered when estimating the recurrence. MRI imaging is usually normal, and no neuropathologic signature of the condition seems to exist. In heterozygous Scn1a+/- mice, GABAergic interneurons exhibit substantially reduced sodium current density with reduced ability for sustained action potential firing. GABAergic output is reduced and excitability of downstream synaptic targets increased. Stiripentol was effective in combination with valproate and clobazam in two pivotal phase III trials. Phenytoin, carbamazepine, and lamotrigine can worsen seizures and should be avoided. Prospective studies will clarify to what extent earlier diagnosis and efforts at seizure control with the most appropriate drug combinations will reduce clinical deterioration.
Pediatric Neurology and Neurogenetics Unit and Laboratories, Children's Hospital A Meyer, University of Florence, Firenze, Italy. r.guerrini@meyer.it
Renzo
R
Guerrini
D000818:Animals; D004831:Epilepsies, Myoclonic / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D009154:Mutation / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics; D012640:Seizures / Q000235:genetics
D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human