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The phenotypic spectrum of KCNT1: a new family with variable epilepsy syndromes including mild focal epilepsy

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Abstract

Background and objective

Pathogenic variants in KCNT1 have been associated with severe forms of epilepsy, typically sleep-related hypermotor epilepsy or epilepsy of infancy with migrating focal seizures. To show that pathogenic variants in KCNT1 can be associated with mild extra-frontal epilepsy, we report a KCNT1 family with a wide spectrum of phenotypes ranging from developmental and epileptic encephalopathy to mild focal epilepsy without cognitive regression and not consistent with sleep-related hypermotor epilepsy.

Methods

A large Canadian family of Caucasian descent including 9 affected family members was recruited. Family members were phenotyped by direct interview and review of existing medical records. Clinical epilepsy gene panel analysis and exome sequencing were performed.

Results

Phenotypic information was available for five family members of which two had developmental and epileptic encephalopathy and three had normal development and focal epilepsy with presumed extra-frontal onset. All three had predominantly nocturnal seizures that did not show hyperkinetic features. All three reported clusters of seizures at night with a feeling of being unable to breathe associated with gasping for air, choking and/or repetitive swallowing possibly suggesting insular or opercular involvement. Genetic analysis identified a heterozygous KCNT1 c.2882G > A, p.Arg961His variant that was predicted to be deleterious.

Discussion

This family demonstrates that the phenotypic spectrum associated with KCNT1 pathogenic variants is broader than previously assumed. Our findings indicate that variants in KCNT1 can be associated with mild focal epilepsy and should not be excluded during variant interpretation in such patients based solely on gene–disease validity.

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Availability of data and material

All de-identified data is included in the article.

Code availability

Not applicable.

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Acknowledgements

We thank the family for participation in our study. The study was supported by the Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, University of Calgary, to KMK.

Funding

The study was supported by the Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, University of Calgary, to KMK.

Author information

Authors and Affiliations

  1. Department of Clinical Neurosciences, Cumming School of Medicine, Foothills Medical Centre, University of Calgary, 1403 29 Street NW, Calgary, AB, T2N 2T9, Canada

    Christina Cherian, Paolo Federico & Karl Martin Klein

  2. Division of Clinical Neuroscience, Department of Pediatrics, Cumming School of Medicine, Alberta Children’s Hospital, University of Calgary, Calgary, AB, Canada

    Juan P. Appendino

  3. Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Setareh Ashtiani, Marina Kerr, Aneal Khan, Ping Yee Billie Au & Karl Martin Klein

  4. Cumming School of Medicine, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada

    Paolo Federico & Karl Martin Klein

  5. Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Paolo Federico & Christine P. Molnar

  6. Seaman Family MR Research Centre, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Paolo Federico

  7. Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada

    Marina Kerr, Aneal Khan, Ping Yee Billie Au & Karl Martin Klein

  8. Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Karl Martin Klein

  9. Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe-University, Frankfurt, Germany

    Karl Martin Klein

  10. Center for Personalized Translational Epilepsy Research (CePTER), Goethe University, Frankfurt, Germany

    Karl Martin Klein

Authors
  1. Christina Cherian
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  2. Juan P. Appendino
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  3. Setareh Ashtiani
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  4. Paolo Federico
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  5. Christine P. Molnar
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  6. Marina Kerr
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  7. Aneal Khan
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  8. Ping Yee Billie Au
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  9. Karl Martin Klein
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Contributions

CC: analyzed the data; drafted the manuscript for intellectual content. JPA: Designed and conceptualized study; analyzed the data; revised the manuscript for intellectual content. Setareh Ashtiani: Major role in the acquisition of data; revised the manuscript for intellectual content. PF: major role in the acquisition of data; analyzed the data; revised the manuscript for intellectual content. CPM: major role in the acquisition of data; analyzed the data; revised the manuscript for intellectual content. MK: major role in the acquisition of data; analyzed the data; revised the manuscript for intellectual content. AK: major role in the acquisition of data; analyzed the data; revised the manuscript for intellectual content. P-YBA: designed and conceptualized study; analyzed the data; revised the manuscript for intellectual content. KMK: designed and conceptualized study; analyzed the data; drafted the manuscript for intellectual content.

Corresponding author

Correspondence to Karl Martin Klein.

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Conflicts of interest

C. Cherian reports no disclosures relevant to the manuscript. J.P. Appendino reports personal and educational fees from UCB Pharma, PendoPharm Inc., and Sunovion Pharmaceuticals Inc. S. Ashtiani reports no disclosures relevant to the manuscript. P. Federico reports no disclosures relevant to the manuscript. C.P. Molnar reports no disclosures relevant to the manuscript. A. Khan and M. Kerr received part of the funding for the MITO-FIND project from MITOCANADA through the Alberta Children’s Hospital Research Foundation. P. Y. B. Au reports no disclosures relevant to the manuscript. K.M. Klein reports personal fees from UCB Pharma, Novartis Pharma AG, Eisai, and GW Pharmaceuticals, grants from the federal state Hessen, Germany, through the LOEWE program and from the Canadian Institutes of Health Research.

Ethical approval

The study was approved by the Conjoint Health Research Ethics Board at University of Calgary and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Consent to participate

All participants or their legal guardians provided written informed consent prior to inclusion in the study.

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The consent includes publication of de-identified health information.

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Cherian, C., Appendino, J.P., Ashtiani, S. et al. The phenotypic spectrum of KCNT1: a new family with variable epilepsy syndromes including mild focal epilepsy. J Neurol 269, 2162–2171 (2022). https://doi.org/10.1007/s00415-021-10808-y

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  • DOI: https://doi.org/10.1007/s00415-021-10808-y

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