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

Dravet Syndrome (Severe Myoclonic Epilepsy of Infancy (SMEI))

Dr. rer. nat. Karin Mayer, M.Sc Anna Munzig

Scientific Background

Dravet syndrome, also known as severe myoclonic epilepsy of infancy (SMEI) typically first occurs in an otherwise healthy child in the first year of life as seizures in the presence of fever, for example after vaccination. The seizures can occur with or without fever, 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 are seen. EEG and cranial MRI are often normal at first. The patient’s psychomotor development is delayed in most cases and behavioural disorders such as hyperactivity or, more rarely, autistic behavior are observed. Establishing a diagnosis often takes several years. As well as the typical course of SMEI, a borderline form (SMEB) without myoclonus has been described. The frequency is 1 in 40,000 newborns. 

All types of seizures are pharmacoresistant, although valproic acid and topiramate have proved effective. Certain drugs, like phenytoin that belong to the group of substances that inhibit cellular sodium channels, can worsen the symptoms.

The most common genetic cause of Dravet syndrome is mutations in the SCN1A gene which encodes the alpha1 subunit of a neuronal sodium channel. SCN1A mutations have been identified in up to 80% of patients with severe myoclonic epilepsy of infancy (SMEI). Most of the SCN1A mutations causal for SMEI that have been functionally studied are translational stop mutations that 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 for SMEI but also for generalized epilepsy with febrile seizures plus (GEFS+); missense mutations in the pore region of the sodium channel are more often associated with a severe course of SMEI.

Chromosomal deletions within region 2q24, which includes 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 gene mutations.

Pathogenic mutations in the gene for protocadherin 19 (PCDH19 on chromosome Xq22) have been described in female patients with X-linked epilepsy with intellectual disability. Clinical similarities to Dravet syndrome include the early manifestation of fever-related, fever-independent and hemiclonic seizures. The frequency of PCDH19 mutations in Dravet syndrome is estimated 5%.

In individual SMEI cases, mutations have been found in three further genes for neuronal voltage-dependant sodium channels (SCN1B, SCN2A, SCN9A) and in genes for the gamma2-subunit and the delta-subunit of the GABA receptor (GABRG2 and GABRD).


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