Severe infantile epilepsies: molecular genetics challenge clinical classification.

In 1978, Charlotte Dravet described thècryptogenic' epilepsy syndrome severe myoclonic epilepsy of infancy (SMEI) (Dravet, 1978). This severe generalized epileptic encephalopathy begins at around 6 months of age with febrile hemiclonic or generalized status epilepticus. Hemiclonic status typically recurs involving each side independently. After 1 year of age, other seizure types appear including absence, partial, atonic and often myoclonic seizures. Early development is normal, with slowing and regression after 1 to 2 years; pyramidal features and ataxia may also evolve. The prognosis is poor. The recent draft proposal of the ILAE classi®cation suggests the eponymous name Dravet syndrome instead of SMEI in recognition that not all cases experience myoclonic seizures (Engel, 2001). SMEI is associated with a family history of seizures in 50% of patients. Affected relatives of SMEI probands have epilepsy subsyndromes such as febrile seizures and mild generalized epilepsies. These phenotypes are consistent with the generalized epilepsy with febrile seizures plus (GEFS +) spectrum (Singh et al., 2001). GEFS + is a familial epilepsy syndrome characterized by heterogeneous phenotypes with most individuals having benign childhood seizure disorders ranging from classicaìfebrile seizures' tòfebrile seizures plus' where febrile seizures continue past early childhood or afebrile convulsions occur (Scheffer and Berkovic, 1997). Within the GEFS + spectrum, more severe phenotypes can occur including myoclonic-astatic epilepsy and temporal lobe epilepsy. GEFS + is associated with mutations in SCN1A, SCN1B, SCN2A (genes encoding the alpha 1, alpha 2, beta 1 sodium channel subunits) and GABRG2 (gamma 2 subunit of the GABA A receptor) (Mulley et al., 2003). The relationship between SMEI and GEFS + became more intriguing when, in 2001, Claes and colleagues shed new light on the aetiology of SMEI. De novo mutations of SCN1A were identi®ed in all seven SMEI patients studied (Claes et al., 2001). They reasoned that GEFS + and SMEI share a predilection for fever-induced seizures and examined SCN1A as a candidate gene, following its proven association with GEFS +. Mutations in SCN1A were con®rmed by Japanese groups with mutation rates of 77±82% in SMEI series (Ohmori et al. signi®cantly lower rates with only ~35% SMEI cases positive for SCN1A defects (F. Zara, personal communication; I. Scheffer, unpublished data). Where examined, most cases arise from de novo mutations. To some extent this disparity between mutation rates in different centres may be due to bias of ascertainment, such as diagnostic inclusion only of patients with SMEI with severe intellectual …