Short CommunicationA recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy☆
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.
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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.
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2022, Neurobiology of DiseaseCitation Excerpt :In particular, the frequency of action potentials during high-frequency stimulation is fine-tuned by the level of KNa1.1 activity (Yang et al., 2006). Since the first reported association with epilepsy pathogenesis in 2012 (Barcia et al., 2012), pathogenic variants in KCNT1 are increasingly reported with a broad phenotypic spectrum from early-onset developmental and epileptic encephalopathies including epilepsy of infancy with migrating focal seizures (EIMFS) to later-onset focal epilepsy and sleep-related hypermotor epilepsy (SHE) (Borlot et al., 2020; Heron et al., 2012; Ishii et al., 2013; Kingwell, 2012; Lim et al., 2016; McTague et al., 2013; McTague et al., 2018; Ohba et al., 2015). Functional studies performed in heterologous expression systems have demonstrated for nearly all pathogenic variants (with the exception of p.Ile924Phe (Evely et al., 2017; Vanderver et al., 2014) an enhanced potassium conductance mediated by larger current amplitudes, more hyperpolarized voltage dependence of activation, and more rapid activation kinetics compared to WT channels (Kim et al., 2014; McTague et al., 2018; Milligan et al., 2014; Tang et al., 2016).
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2020, Molecular and Cellular NeuroscienceCitation Excerpt :Heterozygous mutations in KCNT1, which encodes the KNa1.1 (formerly named Kca4.1) sodium-activated potassium channel (Kaczmarek et al., 2017) or “Slack channel,” result in two types of epilepsy. One is a DEE called epilepsy of infancy with migrating focal seizures (EIMFS) [OMIM: 614959, EIEE14] (Barcia et al., 2012; Ishii et al., 2013), and the other is a phenotypically milder focal epilepsy called autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) [OMIM: 615005, EFNL5] (Heron et al., 2012; Kurahashi and Hirose, 1993). The onset of EIMFS occurs within the first 6 months of life.
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Conflict of interest: None of the authors has any conflict of interest to disclose.
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Atsushi Ishii and Akihisa Okumura are equally contributing first authors.