Familial severe myoclonic epilepsy of infancy: truncation of Nav1.1 and genetic heterogeneity.
BACKGROUND
Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome has been long suspected of having a genetic origin. Recently, mutations in SCN1A and GABRG2 have been described in SMEI patients. The sporadic nature of the SMEI syndrome and the occurrence of SCN1A and GABRG2 mutations in a mild familial phenotype, termed generalized epilepsy with febrile seizure plus complicates genotype-phenotype correlations. In order to further investigate the role of SCN1A and GABRG2 in the pathogenesis of SMEI we have screened for mutations three families with at least two members affected by Dravet syndrome.


METHODS
Clinical criteria followed the international classification of epileptic syndromes. Mutational screening of SCN1A and GABRG2 genes was performed by denaturing high performance liquid chromatography (DHPLC) and direct sequencing of DNA fragments showing a variant chromatogram.


RESULTS
Thirty-eight fragments spanning 26 exons of SCN1A and nine exons of GABRG2 were analysed in three probands. Five variant chromatograms were identified; four corresponded to known polymorphisms, one to a novel dinucleotide insertion on exon 26 of SCN1A. The mutation leads to a frameshift and a premature stop codon at amino acid 1 779 of the protein. The mutation was present in the affected sibling and was inherited from the mother who had experienced a single febrile seizure in childhood.


CONCLUSIONS
Among three families analysed, a single family was mutant for SCN1A. Our study suggests that the syndrome is genetically heterogeneous. The variable expressivity we observed for the c5240insAA mutation suggests that other factors are needed for the development of the full SMEI phenotype.
Gennaro
Elena
E
Laboratory of Human Genetics, E.O. Galliera Hospital, Genova, Italy.
Veggiotti
Pierangelo
P
Malacarne
Michele
M
Madia
Francesca
F
Cecconi
Massimiliano
M
Cardinali
Simonetta
S
Cassetti
Alessandra
A
Cecconi
Ilaria
I
Bertini
Enrico
E
Bianchi
Amedeo
A
Gobbi
Giuseppe
G
Zara
Federico
F
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D002658:Developmental Disabilities / Q000150:complications; D004569:Electroencephalography; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics; D020190:Myoclonic Epilepsy, Juvenile / Q000235:genetics* / Q000503:physiopathology; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D011963:Receptors, GABA-A / Q000235:genetics; D018080:Receptors, GABA-B / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*
C106350:GABRR2 protein, human; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; C568242:SCN1A protein, human; D015222:Sodium Channels; D004247:DNA