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Severe myoclonic epilepsy in infancy (Dravet syndrome) 30 years later

2011; Wiley; Volume: 52; Issue: s2 Linguagem: Inglês

10.1111/j.1528-1167.2011.02993.x

1528-1167

Charlotte Dravet, Michelle Bureau, Bernardo Dalla Bernardina, Renzo Guerrini,

Metabolism and Genetic Disorders

Severe myoclonic epilepsy in infancy (SMEI) was first described in 1978 by Charlotte Dravet at Marseille, and it was briefly reported in a French medical journal (Dravet, 1978). Soon afterward it was recognized in Italy by Bernardo Dalla Bernardina and they together presented the first 42 cases diagnosed in Marseille at the International Epilepsy Congress in Kyoto in 1981 (Dravet et al., 1982). It became subsequently obvious that some patients exhibited overlapping characteristics, with the exception of myoclonic seizures, which led to the subdivision of typical and atypical, or borderline, forms (SMEIB), without obvious difference in the prognosis. For this reason, and because this form of epilepsy was not limited to infancy, the name was changed to the eponym Dravet syndrome (Commission on Classification and Terminology of the ILAE, 1989). In subsequent years, mutations of the SCN1A gene were identified in some families with the generalized epilepsy with the febrile seizures plus (GEFS+) spectrum. Because some patients with Dravet syndrome belonged to similar families, Claes et al. (2001) tested seven children with the syndrome and found all of them to be mutation positive (Claes et al., 2001). This finding was the starting point for a long series of studies that confirmed the genetic origin of both SMEI and SMEIB. A large number of mutations (>500) of the SCN1A gene have been described, and copy number variations causing deletions or duplication of SCN1A have also been detected (Marini et al., 2009), bringing the number of patients in whom an involvement of this gene can be demonstrated to about 80% of all the patients who are tested. Recently Depienne et al. (2009b) reported PCDH19 familial and "de novo" point mutations in 13 female patients with early onset epileptic encephalopathy mimicking Dravet syndrome. A male patient with a similar phenotype carried a mosaic PCDH19 mutation. The authors estimated that PCDH19 mutations might account for 5% overall of Dravet syndrome (Depienne et al., 2009b). However, approximately 15% of affected patients do not harbor an SCN1A or a PCDH19 gene mutation, even when the clinical picture is typical. It is unknown whether alterations of these two genes that are not demonstrable by current techniques may still be at play or if additional, unknown, causative genes are involved. As the number of reported patients has increased markedly, some variability of the clinical picture has become apparent regarding seizure type and frequency, triggering factors, neuropsychological impairment, response to drugs, and comorbidities. Genotype–phenotype correlations have not been clearly defined, however, and it is now obvious that mutations of SCN1A or PCDH19 are not the single determinants of phenotype, and that modifier genes, the genetic background, or epigenetic and environmental factors can also play a role. In the scheme proposed by the International League Against Epilepsy (ILAE) (Engel, 2001), Dravet syndrome is considered as an "epileptic encephalopathy," defined as a condition in which the epileptiform abnormalities themselves are believed to contribute to the progressive disturbance in cerebral function. However, it is not proven that the cognitive decline observed in the first stages of the disease is simply the direct consequence of epilepsy. Studies focusing on neuropsychological outcomes are now being conducted prospectively by several groups in order to disentangle the causative factors underlying cognitive impairment. These studies are showing that there are different degrees of cognitive decline and that the patients most recently diagnosed seem to be less affected than patients in older studies. The animal models of the syndrome that have been developed are convincing and have already provided important insights on the mechanisms of epileptogenesis (Yu et al., 2006; Ogiwara et al., 2007; Oakley et al., 2009). Additional insights are emerging on the gait disorder that may accompany the clinical syndrome and, hopefully, on the mechanisms underlying cognitive impairment (Kalume et al., 2007). There are encouraging progresses in treatment as new molecules have emerged that allow a better control of seizures and that decrease the episodes of status epilepticus in a significant proportion of patients. Unfortunately, seizure freedom remains an exception. Early mortality, often due to sudden unexpected death in epilepsy (SUDEP), is a big concern, but has been seldom studied. Thirty years after its first description, Dravet syndrome is considered as a model of channelopathy that raises wide interest in the scientific and medical community. However, clinical and experimental implications related to the syndrome spectrum have a much wider meaning than was originally foreseen in SMEI. For this reason, we thought, it was the time, in 2009, to present state-of-the-art findings on this disease during an international workshop held in Verona, Italy, on October 5 and 6. The organizers of this workshop— Charlotte Dravet, MD; Michelle Bureau, MD; Bernardo Dalla Bernardina, MD; and Renzo Guerrini, MD—made an effort to bring into discussion all possible relevant aspects of the research and clinical domains, including the point of view of the families who live with an affected child. The latter aspect was fully represented by the participation at the meeting of members of the International Dravet Syndrome Epilepsy Action League (IDEA League), an international, parent-led association that provides excellent psychological support for families and also stimulates research and contributes to a large diffusion of the knowledge of the disease among nonspecialist doctors and the lay public. The contents of this supplement of Epilepsia reflect the material that was discussed in the Verona Workshop and the subsequent discussions that were prompted by the various presentations, although they do not merely represent the conference proceedings. We warmly acknowledge all the participants who responded positively to our invitation, actively participated in the workshop, and provided the texts that comprise this issue. We address our best thanks to Biocodex and Nutricia, which sponsored the Verona Workshop and to the IDEA League and again Biocodex and Nutricia for financing this supplement. The authors declare no relevant conflicts of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.