open access

Vol 49, No 4 (2015)
Original research articles
Submitted: 2015-03-13
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From focal epilepsy to Dravet syndrome – Heterogeneity of the phenotype due to SCN1A mutations of the p.Arg1596 amino acid residue in the Nav1.1 subunit

Dorota Hoffman-Zacharska, Elżbieta Szczepanik, Iwona Terczynska, Alicja Goszczanska-Ciuchta, Zofia Zalewska-Miszkurka, Renata Tataj, Jerzy Bal
DOI: 10.1016/j.pjnns.2015.06.006
·
Neurol Neurochir Pol 2015;49(4):258-266.

open access

Vol 49, No 4 (2015)
Original research articles
Submitted: 2015-03-13

Abstract

Objective

The aim of this study was to analyze the intra-/interfamilial phenotypic heterogeneity due to variants at the highly evolutionary conservative p.Arg1596 residue in the Nav1.1 subunit.

Materials/participants

Among patients referred for analysis of the SCN1A gene one recurrent, heritable mutation was found in families enrolled into the study. Probands from those families even clinically diagnosed with atypical Dravet syndrome (DS), generalized epilepsy with febrile seizures plus (GEFS+), and focal epilepsy, had heterozygous p.Arg1596 His/Cys missense substitutions, c.4787G>T and c.4786C>T in the SCN1A gene.

Method

Full clinical evaluation, including cognitive development, neurological examination, EEGs, MRI was performed in probands and affected family members in developmental age. The whole SCN1A gene sequencing was performed for all probands. The exon 25, where the identified missense substitutions are localized, was directly analyzed for the other family members.

Results

Mutation of the SCN1A p.1596Arg was identified in three families, in one case substitution p.Arg1596Cys and in two cases p.Arg1596His. Both mutations were previously described as pathogenic and causative for DS, GEFS+ and focal epilepsy. Spectrum of phenotypes among presented families with p.Arg1596 mutations shows heterogeneity ranged from asymptomatic cases, through FS and FS+ to GEFS+/Panayiotopoulos syndrome and epilepsies with and without febrile seizures, and epileptic encephalopathy such as DS. Phenotypes differ among patients displaying both focal and generalized epilepsies. Some patients demonstrated additionally Asperger syndrome and ataxia.

Conclusion

Clinical picture heterogeneity of the patients carrying mutation of the same residue indicates the involvement of the other factors influencing the SCN1A gene mutations’ penetrance.

Abstract

Objective

The aim of this study was to analyze the intra-/interfamilial phenotypic heterogeneity due to variants at the highly evolutionary conservative p.Arg1596 residue in the Nav1.1 subunit.

Materials/participants

Among patients referred for analysis of the SCN1A gene one recurrent, heritable mutation was found in families enrolled into the study. Probands from those families even clinically diagnosed with atypical Dravet syndrome (DS), generalized epilepsy with febrile seizures plus (GEFS+), and focal epilepsy, had heterozygous p.Arg1596 His/Cys missense substitutions, c.4787G>T and c.4786C>T in the SCN1A gene.

Method

Full clinical evaluation, including cognitive development, neurological examination, EEGs, MRI was performed in probands and affected family members in developmental age. The whole SCN1A gene sequencing was performed for all probands. The exon 25, where the identified missense substitutions are localized, was directly analyzed for the other family members.

Results

Mutation of the SCN1A p.1596Arg was identified in three families, in one case substitution p.Arg1596Cys and in two cases p.Arg1596His. Both mutations were previously described as pathogenic and causative for DS, GEFS+ and focal epilepsy. Spectrum of phenotypes among presented families with p.Arg1596 mutations shows heterogeneity ranged from asymptomatic cases, through FS and FS+ to GEFS+/Panayiotopoulos syndrome and epilepsies with and without febrile seizures, and epileptic encephalopathy such as DS. Phenotypes differ among patients displaying both focal and generalized epilepsies. Some patients demonstrated additionally Asperger syndrome and ataxia.

Conclusion

Clinical picture heterogeneity of the patients carrying mutation of the same residue indicates the involvement of the other factors influencing the SCN1A gene mutations’ penetrance.

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Keywords

Dravet syndrome, Focal epilepsy, GEFS+, Panayiotopoulos syndrome, SCN1A

About this article
Title

From focal epilepsy to Dravet syndrome – Heterogeneity of the phenotype due to SCN1A mutations of the p.Arg1596 amino acid residue in the Nav1.1 subunit

Journal

Neurologia i Neurochirurgia Polska

Issue

Vol 49, No 4 (2015)

Pages

258-266

DOI

10.1016/j.pjnns.2015.06.006

Bibliographic record

Neurol Neurochir Pol 2015;49(4):258-266.

Keywords

Dravet syndrome
Focal epilepsy
GEFS+
Panayiotopoulos syndrome
SCN1A

Authors

Dorota Hoffman-Zacharska
Elżbieta Szczepanik
Iwona Terczynska
Alicja Goszczanska-Ciuchta
Zofia Zalewska-Miszkurka
Renata Tataj
Jerzy Bal

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