Dravet syndrome Represented at NIH/NINDS meeting

NINDS, August 26-27, 2010

Michelle Welborn, PharmD
Intractable Childhood Epilepsy Alliance (ICE)

Mission:
The mission of ICE is to advance identification, understanding, and cure for ion channel and other genetic epilepsies through a strategic alignment of advocacy groups, industry, government, academia, parents, and investors internationally. ICE holds Dravet syndrome as the highest priority for disease modification and cure.

Perspective on Anti-epileptogenesis (AEG):
Despite the growing number of causes of epilepsy, 70% of cases are deemed “idiopathic” or “cryptogenic”. Dravet syndrome, formerly known as Severe Myoclonic Epilepsy of Infancy, is an epilepsy syndrome in which greater than 80% of those affected have a monogenic cause – a mutation in the SCN1A gene. Identification of the genetic causes of epilepsy through further research in the ion channel will allow a better understanding of this mysterious disease and take us a step closer to a cure.

Dravet syndrome is a neurodevelopmental disorder that begins in a previously normal infant at around 6 months of age, and always before 14 months. The infant presents with febrile status epilepticus, which may be hemi-clonic or generalized. Within the next one to two months and over the next six months, the infant presents monthly with convulsive seizures. If they have hemic-lonic attacks, subsequent seizures may be on the other side. Between ages one and four, the child develops other seizure types including myoclonic, partial, atonic, and absence seizures. Modest temperature elevations such as a warm bath can precipitate seizures and about ten percent of patients are photosensitive. Development in the first year is normal but subsequently slows and may regress. Ataxia and pyramidal signs often develop over time. The EEG is typically normal until around age 2 years when generalized spike wave activity is seen, and MRI scan is either normal or with nonspecific features such as atrophy.

Dravet syndrome offers an appealing model for studying antiepileptogenesis because 1)a well-established animal models exist; 2) status epilepticus is a major seizure type, yet brain damage caused by SE is uncommon as MRIs are typically normal in affected humans; 3) latency period for the onset of unprovoked seizures is short (weeks) and predictable as opposed to traumatic brain injury or stroke models, thereby limiting the number of subjects needed to power the study; 4) seizures are treatment resistant, therefore studying effect of intervention to modify epileptogenesis as it relates to drug resistant epilepsy is feasible ; 5) the genetic cause is monogenic and detected in more than 80% of cases; 6) developmental delays and other neurologic co-morbidities such as ataxia typically appear later in the course of disease; therefore, prevention of co-morbidities through intervention directed to prevent further seizures is readily measurable and 7) inhibitory interneurons are particularly affected by SCN1A mutations, so that provides a specific neuronal target for intervention.