Familial severe myoclonic epilepsy of infancy: Truncation of Nav1.1 and genetic heterogeneity

Elena Gennaro, Pierangelo Veggiotti, Michele Malacarne, Francesca Madia, Massimiliano Cecconi, Simonetta Cardinali, Alessandra Cassetti, Ilaria Cecconi, Enrico Bertini, Amedeo Bianchi, Giuseppe Gobbi, Federico Zara

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Abstract

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.

Original languageEnglish
Pages (from-to)21-25
Number of pages5
JournalEpileptic Disorders
Volume5
Issue number1
Publication statusPublished - Mar 2003

Fingerprint

Myoclonic Epilepsy
Genetic Heterogeneity
Mutation
Exons
Phenotype
Febrile Seizures
Nonsense Codon
Genetic Association Studies
DNA Sequence Analysis
Siblings
Epilepsy
High Pressure Liquid Chromatography
Mothers
Amino Acids

Keywords

  • Children
  • DNA mutations
  • Dravet syndrome
  • Epilepsy genetics
  • GEFS
  • SMEI

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Gennaro, E., Veggiotti, P., Malacarne, M., Madia, F., Cecconi, M., Cardinali, S., ... Zara, F. (2003). Familial severe myoclonic epilepsy of infancy: Truncation of Nav1.1 and genetic heterogeneity. Epileptic Disorders, 5(1), 21-25.

Familial severe myoclonic epilepsy of infancy : Truncation of Nav1.1 and genetic heterogeneity. / Gennaro, Elena; Veggiotti, Pierangelo; Malacarne, Michele; Madia, Francesca; Cecconi, Massimiliano; Cardinali, Simonetta; Cassetti, Alessandra; Cecconi, Ilaria; Bertini, Enrico; Bianchi, Amedeo; Gobbi, Giuseppe; Zara, Federico.

In: Epileptic Disorders, Vol. 5, No. 1, 03.2003, p. 21-25.

Research output: Contribution to journalArticle

Gennaro, E, Veggiotti, P, Malacarne, M, Madia, F, Cecconi, M, Cardinali, S, Cassetti, A, Cecconi, I, Bertini, E, Bianchi, A, Gobbi, G & Zara, F 2003, 'Familial severe myoclonic epilepsy of infancy: Truncation of Nav1.1 and genetic heterogeneity', Epileptic Disorders, vol. 5, no. 1, pp. 21-25.
Gennaro E, Veggiotti P, Malacarne M, Madia F, Cecconi M, Cardinali S et al. Familial severe myoclonic epilepsy of infancy: Truncation of Nav1.1 and genetic heterogeneity. Epileptic Disorders. 2003 Mar;5(1):21-25.
Gennaro, Elena ; Veggiotti, Pierangelo ; Malacarne, Michele ; Madia, Francesca ; Cecconi, Massimiliano ; Cardinali, Simonetta ; Cassetti, Alessandra ; Cecconi, Ilaria ; Bertini, Enrico ; Bianchi, Amedeo ; Gobbi, Giuseppe ; Zara, Federico. / Familial severe myoclonic epilepsy of infancy : Truncation of Nav1.1 and genetic heterogeneity. In: Epileptic Disorders. 2003 ; Vol. 5, No. 1. pp. 21-25.
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abstract = "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.",
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AU - Gennaro, Elena

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AU - Malacarne, Michele

AU - Madia, Francesca

AU - Cecconi, Massimiliano

AU - Cardinali, Simonetta

AU - Cassetti, Alessandra

AU - Cecconi, Ilaria

AU - Bertini, Enrico

AU - Bianchi, Amedeo

AU - Gobbi, Giuseppe

AU - Zara, Federico

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N2 - 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.

AB - 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.

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