Partial epilepsy with antecedent febrile seizures and seizure aggravation by antiepileptic drugs: Associated with loss of function of Nav1.1

Authors

  • Wei-Ping Liao,

    1. Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Yi-Wu Shi,

    1. Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Yue-Sheng Long,

    1. Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Yang Zeng,

    1. Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Tian Li,

    1. Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Mei-Juan Yu,

    1. Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Tao Su,

    1. Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Ping Deng,

    1. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.
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  • Zhi-Gang Lei,

    1. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.
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  • Shu-Jun Xu,

    1. Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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  • Wei-Yi Deng,

    1. Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Xiao-Rong Liu,

    1. Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Wei-Wen Sun,

    1. Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Yong-Hong Yi,

    1. Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Zao C. Xu,

    1. Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
    2. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.
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  • Shumin Duan

    1. Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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Address correspondence to Dr. Wei-Ping Liao, Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical College, Chang-gang-dong road 250, Guangzhou 510260, China. E-mail: wpliao@tom.com

Summary

Purpose:  Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI) are associated with sodium channel α-subunit type-1 gene (SCN1A) mutations. Febrile seizures and partial seizures occur in both GEFS+ and SMEI; sporadic onset and seizure aggravation by antiepileptic drugs (AEDs) are features of SMEI. We thus searched gene mutations in isolated cases of partial epilepsy with antecedent FS (PEFS+) that showed seizure aggravations by AEDs.

Methods:  Genomic DNA from four patients was screened for mutations in SCN1A, SCN2A, SCN1B, and GABRG2 using denaturing high-performance liquid chromatography (dHPLC) and sequencing. Whole-cell patch clamp analysis was used to characterize biophysical properties of two newly defined mutants of Nav1.1 in tsA201 cells.

Results:  Two heterozygous de novo mutations of SCN1A (R946H and F1765L) were detected, which were proven to cause loss of function of Nav1.1. When the functional defects of mutants reported previously are compared, it is found that all mutants from PEFS+ have features of loss of function, whereas GEFS+ shows mild dysfunction excluding loss of function, coincident with mild clinical manifestations. PEFS+ is similar to SMEI clinically with possible AED-induced seizure aggravation and biophysiologically with features of loss of function, and different from SMEI by missense mutation without changes in hydrophobicity or polarity of the residues.

Conclusions:  Isolated milder PEFS+ may associate with SCN1A mutations and loss of function of Nav1.1, which may be the basis of seizure aggravation by sodium channel–blocking AEDs. This study characterized phenotypes biologically, which may be helpful in understanding the pathophysiologic basis, and further in management of the disease.

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