Scientific Background
Dravet syndrome, also known as severe myoclonic epilepsy of early childhood (SMEI), typically occurs in an initially healthy child in the first year of life as seizures with fever, for example, after vaccinations. The seizures occur with or without fever, they are clonic, tonic-clonic, generalized, usually exceptionally long-lasting and can lead to a status epilepticus. After the age of one, myoclonic seizures, atypical absences and partial seizures are common. Initially, EEG and cranial magnetic resonance imaging often appear normal. The psychomotor development of the patients is usually delayed, and behavioral abnormalities such as hyperactivity or, in rare cases, autistic behavior have been observed. The diagnosis is often only made after several years of disease progression. Besides the typical SMEI, a borderline form (SMEB) without myoclonus is also described. The frequency is 1 in 40,000 newborns.
All types of seizures are pharmacoresistant. Valproic acid and topiramate have proven to be particularly effective. Certain drugs, such as phenytoin, might worsen the symptoms, and this includes groups of substances that inhibit cellular sodium channels.
The most common genetic cause of Dravet syndrome is pathogenic variants in the SCN1A gene, which codes for the alpha1 subunit of a neuronal sodium channel. Pathogenic SCN1A variants have been identified in up to 80% of patients with severe myoclonic epilepsy in early childhood (SMEI). Most of the functionally investigated SCN1A variants responsible for SMEI are translational stop mutations that lead either to haploinsufficiency or to inactivation and loss of function of the sodium channel. Amino acid exchanges in the SCN1A gene may cause both SMEI and generalized epilepsy with febrile seizures plus (GEFS+), whereby missense variants in the pore region of the sodium channel are more frequently associated with a severe form of SMEI.
Chromosomal deletions within the region 2q24, which contain the entire SCN1A gene, are described in 1.5-6% of patients. Genomic deletions involving one or more exons account for up to 7% of all mutations of the SCN1A gene.
Pathogenic variants in the gene that codes for protocadherin 19 (PCDH19 gene on chromosome Xq22) have been described in female patients with X-linked epilepsy with mental retardation. Clinical similarities to Dravet syndrome include the early manifestation of fever‑associated, fever-independent and hemiclonic seizures. The incidence of PCDH19 variants in Dravet syndrome is estimated to be 5%.
Pathogenic variants in three further genes for neuronal voltage-dependent sodium channels (SCN1B, SCN2A and SCN9A genes) as well as pathogenic variants in the genes for the gamma2 subunit and the delta subunit of the GABA receptor (GABRG2 and GABRD, respectively) have been identified in individual cases in SMEI.
References
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