Cherian Christina, Appendino Juan P, Ashtiani Setareh, Federico Paolo, Molnar Christine P, Kerr Marina, Khan Aneal, Au Ping Yee Billie, Klein Karl Martin
Department of Clinical Neurosciences, Cumming School of Medicine, Foothills Medical Centre, University of Calgary, 1403 29 Street NW, Calgary, AB, T2N 2T9, Canada.
Division of Clinical Neuroscience, Department of Pediatrics, Cumming School of Medicine, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada.
J Neurol. 2022 Apr;269(4):2162-2171. doi: 10.1007/s00415-021-10808-y. Epub 2021 Sep 19.
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.
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.
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.
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.
KCNT1基因的致病性变异与严重形式的癫痫有关，通常为睡眠相关性运动过多型癫痫或婴儿期伴有游走性局灶性发作的癫痫。为了证明KCNT1基因的致病性变异可与轻度额外癫痫相关，我们报告了一个KCNT1基因家族，其具有广泛的表型谱，从发育性和癫痫性脑病到无认知衰退且不符合睡眠相关性运动过多型癫痫的轻度局灶性癫痫。
招募了一个来自加拿大的、具有高加索血统的大家庭，其中包括9名受影响的家庭成员。通过直接访谈和查阅现有病历对家庭成员进行表型分析。进行了临床癫痫基因panel分析和外显子组测序。
获得了5名家庭成员的表型信息，其中2名患有发育性和癫痫性脑病，3名发育正常且患有推测为额外发作起始的局灶性癫痫。这3人主要在夜间发作，无运动过多特征。这3人都报告夜间有发作簇，伴有无法呼吸的感觉，与喘气、呛噎和/或反复吞咽有关，这可能提示岛叶或岛盖受累。基因分析鉴定出一个杂合的KCNT1基因c.2882G＞A、p.Arg961His变异，预测该变异有害。
这个家族表明，与KCNT1基因致病性变异相关的表型谱比以前认为的更广泛。我们的研究结果表明，KCNT1基因变异可与轻度局灶性癫痫相关，在对此类患者进行变异解读时，不应仅基于基因-疾病相关性就排除该变异。
