Elsevier

Gene

Volume 531, Issue 2, 1 December 2013, Pages 467-471
Gene

Short Communication
A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy

https://doi.org/10.1016/j.gene.2013.08.096Get rights and content

Highlights

  • A missense KCNT1 mutation at the pore region causes MMPSI.

  • There are hot spots of KCNT1 mutation at CG dinucleotide sequences.

  • Vagus nerve stimulation and clorazepate may be effective for MMPSI.

Abstract

We performed analysis of KCNT1 in two unrelated patients with malignant migrating partial seizures in infancy. Both patients had intractable focal seizures since two months of age. Their seizures were characterized by a shift of epileptic focus during a single seizure and were resistant to most antiepileptic drugs but responded to vagus nerve stimulation in one and clorazepate in the other. Bidirectional sequencing for KCNT1 was analyzed by standard Sanger sequencing method. A de novo c.862G > A (p.Gly288Ser) missense mutation was identified at the pore region of KCNT1 channel in both patients, whereas all KCNT1 mutations in the previous reports were identified mostly in the intracellular C-terminal region. Computational analysis suggested possible changes in the molecular structure and the ion channel property induced by the Gly288Ser mutation. Because the G-to-A transition was located at CG dinucleotide sequences as previously reported for KCNT1 mutations, the recurrent occurrence of de novo KCNT1 mutations indicated the hot spots of these locations.

Introduction

Malignant migrating partial seizures in infancy (MMPSI) is categorized into early onset epileptic encephalopathy characterized by seizures beginning before 6 months of age, migrating focal motor seizures at onset, nearly continuous multifocal seizures migrating between cortical regions and hemispheres, resistance to antiepileptic drugs, lack of demonstrable etiology, and severe psychomotor delay on follow-up (Coppola, 2009). Although the sodium channel voltage-gated type I alpha subunit gene (SCN1A) and the phospholipase C beta 1 gene (PLCB1) mutations have been reported in patients with MMPSI (Carranza Rojo et al., 2011, Freilich et al., 2011, Poduri et al., 2012), its genetic background has not been fully understood. Recent study showed that missense mutations in the potassium channel subfamily T member 1 gene (KCNT1) cause MMPSI (Barcia et al., 2012). KCNT1 mutations have also been found in patients with severe autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (Heron et al., 2012). McTague et al. (2013) reported KCNT1 mutations in 2 of 14 patients with MMPSI. We identified the same novel missense KCNT1 mutation located in a pore region of KCNT1 protein in two unrelated patients with MMPSI. Here we report the clinical and genetic features of these patients.

Section snippets

Patient 1

The patient was a girl born after uneventful term delivery. She was the second product of non-consanguineous healthy Japanese parents. Her father and elder sister had a history of febrile seizures, whereas family history of epilepsy was not present (Fig. 1).

Since two months of age, she had seizures characterized by focal motor movements that alternated from one side of the body to another, sometimes associated with lateral deviation of the head and eyes and twitching of the tongue. Although she

Discussion

Previously, three studies on KCNT1 mutations in patients with MMPSI or ADNFLE were reported and a total of nine missense mutations were reported (Barcia et al., 2012, Heron et al., 2012, McTague et al., 2013). Among them, more than the half located at c.1193, c.1283, c.1421, c.2688, and c.2800 were G-to-A transitions. In the same way as this manner, we identified a novel G-to-A transition at c.862 (p.Gly288Ser) in two unrelated patients with typical MMPSI. Intriguingly, five mutations including

Disclosure

This work was supported in part by a Grant-in-Aid for Scientific Research (A) 21249062, a Grant-in-Aid for Challenging Exploratory Research (23659529), Japan Society for the Promotion of Science (JSPS); Research Grants for Nervous and Mental Disorder (21B-5) and Health and Labor Science Research Grant KB230019, KB230004 from the Ministry of Health, Labor and Welfare; and the 2013–2017 “Central Research Institute for the Molecular Pathomechanisms of Epilepsy of Fukuoka University” (117016).

Acknowledgments

We are indebted to Ms. Akiyo Hamachi and Ms. Minako Yonetani for excellent technical assistance and Mr. Kinya Tohda for supporting in silico analyses.

References (17)

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Conflict of interest: None of the authors has any conflict of interest to disclose.

1

Atsushi Ishii and Akihisa Okumura are equally contributing first authors.

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