Severe Myoclonic Epilepsy of Infancy: Extended Spectrum of GEFS⁺?

Abstract

Summary:Purpose: Severe myoclonic epilepsy of infancy (SMEI) is an intractable epilepsy of early childhood of unknown etiology. It is often associated with a family history of seizure disorders, but epilepsy phenotypes have not been well described. We sought to characterize the seizure phenotypes of relatives to better understand to the genetic basis of SMEI.Methods: Probands with SMEI were identified, and systematic family studies were performed. Epilepsy syndromes were characterized in affected family members.Results: Twelve probands with SMEI were identified. Eleven of the 12 probands with SMEI had a family history of seizures, and the twelfth was the result of a consanguineous marriage. We found that 16.7% of full siblings and 8.3% of parents had definite seizures. A total of 39 affected family members was identified. The most common phenotype was febrile seizures in 14, febrile seizures plus in seven, partial epilepsy in two, and there were single individuals with SMEI, myoclonic-astatic epilepsy, Lennox-Gastaut syndrome, and 13 cases with unclassified or unconfirmed seizures.Conclusions: The family history of seizures in SMEI is in keeping with the spectrum of seizure phenotypes seen in generalized epilepsy with febrile seizures plus (GEFS + ). Our findings suggest that SMEI is the most severe phenotype in the GEFS + spectrum.

A rescuable folding defective Nav1.1 (SCN1A) sodium channel mutant causes GEFS+: Common mechanism in Nav1.1 related epilepsies?

“…We have shown that hyperthermia does not interfere with the trafficking of rescued Na v 1.1-R1916G and thus it should not be a mechanism implicated in the generation of FS in this family, differently from some GEFS+ GABA-A receptor mutants (Kang et al, 2006) The almost complete loss of function of Na v 1.1-R1916G that we have observed in some conditions is consistent with the possibility that this mutation could cause severe phenotypes if in vivo the rescuing interactions are inefficient. Phenotypic variability is expected in GEFS+ families (Scheffer and Berkovic, 1997), but the phenotypic spectrum is still uncertain in particular regarding severe phenotypes (Singh et al, 2001). Our data raise the risk that in the descendants of the family under study a very severe phenotype (e.g.…”

“…SMEI is a very severe drug-resistant epileptic encephalopathy characterized by frequent seizures, ataxia, slowed psychomotor development, mental decline and high mortality rate (Dravet et al, 2005), and is caused by mutations of Na v 1.1 that often cause complete loss of function (Claes et al, 2001;Meisler and Kearney, 2005). Most SMEI mutations arose de novo, but in few cases they have been inherited from mildly affected parents (Nabbout et al, 2003) and a family history of epilepsy has been observed in some SMEI cases; thus, it has been proposed to extend the GEFS+ spectrum including SMEI as the most severe phenotype (Singh et al, 2001).…”

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Nav1.1 Na+Channel Mutant

“…Most SMEI mutations arose de novo, but in few cases, they have been inherited from mildly affected parents (Claes et al, 2001;Nabbout et al, 2003). A family history of epilepsy has been reported for some SMEI cases, and it has been proposed to extend the GEFSϩ spectrum including SMEI as the most severe phenotype (Singh et al, 2001).…”

“…Moreover, GEFSϩ families show a large phenotypic variability that ranges from mild phenotypes to very severe ones (Scheffer and Berkovic, 1997). Thus, it has been hypothesized that genetic background could modulate disease severity modifying the properties of the mutant protein (Singh et al, 2001).…”

Parental mosaicism can cause recurrent transmission ofSCN1A mutations associated with severe myoclonic epilepsy of infancy

“…Mutations in SCN1A, located in 2p24.3, were initially identified in families with an autosomal dominant condition termed generalized epilepsy with febrile seizures-plus (GEFS+; MIM# 604233) [Escayg et al 2000]. In GEFS+, there is also a variable association of prolonged febrile seizures with different types of afebrile seizures types, which are nonetheless mild, in comparison to SMEI, and generally responsive to treatment Singh et al 2001]. The first SCN1A mutations detected in patients with GEFS+ were missense mutations, whereas those found in SMEI introduced premature stop codons in SCN1A.…”