Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Dravet Syndrome (Severe Myoclonic Epilepsy of Infancy (SMEI)) [G40.3]

OMIM-Nummer: 607208, 182389 (SCN1A), 300460 (PCDH19), 182390 (SCN2A), 600235 (SCN1B), 137164 (GABRG2)

Dr. rer. nat. Karin Mayer

Scientific Background

Dravet syndrome is also known as severe myoclonic epilepsy of infancy (SMEI). Febrile seizures, for example after vaccination, typically occur in the first year of life in otherwise healthy children. The seizures can occur with or without fever, they are clonic, tonic-clonic, generalized, unusually long lasting and can result in a status epilepticus. After the first year of life myoclonic seizures, atypical absences, and partial seizures become present. EEG and cranial MRI are often normal in the beginning. Psychomotoric development of the patient is mostly delayed. Behavioural disorders such as hyperactivity or, more rarely, autistic behaviour is observed. The diagnosis is often only established after a course of several years. Besides the typical course of SMEI there is severe myoclonic epilepsy borderline (SMEB), a term that is used to describe a subset of Dravet syndrome patients having less severe symptoms and moderate, rather than severe, developmental delays. Myoclonic seizures are not typical in SMEB. Frequency of Dravet syndrome is about 1 in 40,000 newborns. 

All types of seizures are pharmacoresistant. Especially valproic acid and topiramate have been proved effective. Certain drugs like phenytoin which belong to the group that affect cellular sodium channels can worsen the symptoms. 

The most common genetic cause for Dravet`s syndrome are mutations in the SCN1A gene which encodes the ?1 subunit of a neuronal sodium channel. SCN1A mutations have been identified in up to 80% of patients with severe myoclonic epilepsiy of infancy (SMEI). Most of the SCN1A mutations causal for SMEI that have been functionally characterized are translational stop mutations. They either lead to a haploinsufficiency or an inactivation and loss of function of the sodium channel. Amino acid changes in the SCN1A gene can be causal both for SMEI but also for generalized epilepsy with febrile seizures plus (GEFS+), whereupon missense mutations in the pore region of the sodium channel are more often associated with the severe course of SMEI. 

Chromosomal deletions within region 2q24 covering the entire SCN1A gene are described in 1.5-6% of patients. Genomic deletions that affect one or more exons constitute up to 7% of all SCN1A mutations.

Mutations in the PCDH19 gene on chromosome Xq22 have been described in female patients with X-linked epilepsy with intellectual disability. Similar to Dravet syndrome is the early manifestation of hemiclonic seizures and febrile or non-febrile seizures. Frequency of PCDH19 mutations in Dravet syndrome is estimated 5%.

In individual cases mutations for SMEI have been found in two further genes for neuronal voltage-dependant sodium channels (SCN1B and SCN2A) and in genes for the ?2-subunit and the ?-subunit of the GABA receptor (GABRG2 and GABRD).