TY - JOUR
T1 - KCNT1-related epilepsy
T2 - An international multicenter cohort of 27 pediatric cases
AU - Borlot, Felippe
AU - Abushama, Ahmed
AU - Morrison-Levy, Nadine
AU - Jain, Puneet
AU - Puthenveettil Vinayan, Kollencheri
AU - Abukhalid, Musaad
AU - Aldhalaan, Hesham M.
AU - Almuzaini, Hanin S.
AU - Gulati, Sheffali
AU - Hershkovitz, Tova
AU - Konanki, Ramesh
AU - Lingappa, Lokesh
AU - Luat, Aimee F.
AU - Shafi, Shatha
AU - Tabarki, Brahim
AU - Thomas, Maya
AU - Yoganathan, Sangeetha
AU - Alfadhel, Majid
AU - Arya, Ravindra
AU - Donner, Elizabeth J.
AU - Ehaideb, Salleh N.
AU - Gowda, Vykuntaraju K.
AU - Jain, Vivek
AU - Madaan, Priyanka
AU - Myers, Kenneth A.
AU - Otsubo, Hiroshi
AU - Panda, Prateek
AU - Sahu, Jitendra K.
AU - Sampaio, Letícia P.B.
AU - Sharma, Suvasini
AU - Simard-Tremblay, Elisabeth
AU - Zak, Maria
AU - Whitney, Robyn
N1 - Publisher Copyright:
Wiley Periodicals, Inc. © 2020 International League Against Epilepsy
PY - 2020/4/1
Y1 - 2020/4/1
N2 - Objective: Through international collaboration, we evaluated the phenotypic aspects of a multiethnic cohort of KCNT1-related epilepsy and explored genotype-phenotype correlations associated with frequently encountered variants. Methods: A cross-sectional analysis of children harboring pathogenic or likely pathogenic KCNT1 variants was completed. Children with one of the two more common recurrent KCNT1 variants were compared with the rest of the cohort for the presence of particular characteristics. Results: Twenty-seven children (15 males, mean age = 40.8 months) were included. Seizure onset ranged from 1 day to 6 months, and half (48.1%) exhibited developmental plateauing upon onset. Two-thirds had epilepsy of infancy with migrating focal seizures (EIMFS), and focal tonic seizures were common (48.1%). The most frequent recurrent KCNT1 variants were c.2800G>A; p.Ala934Thr (n = 5) and c.862G>A; p.Gly288Ser (n = 4). De novo variants were found in 96% of tested parents (23/24). Sixty percent had abnormal magnetic resonance imaging (MRI) findings. Delayed myelination, thin corpus callosum, and brain atrophy were the most common. One child had gray-white matter interface indistinctness, suggesting a malformation of cortical development. Several antiepileptic drugs (mean = 7.4/patient) were tried, with no consistent response to any one agent. Eleven tried quinidine; 45% had marked (>50% seizure reduction) or some improvement (25%-50% seizure reduction). Seven used cannabidiol; 71% experienced marked or some improvement. Fourteen tried diet therapies; 57% had marked or some improvement. When comparing the recurrent variants to the rest of the cohort with respect to developmental trajectory, presence of EIMFS, >500 seizures/mo, abnormal MRI, and treatment response, there were no statistically significant differences. Four patients died (15%), none of sudden unexpected death in epilepsy. Significance: Our cohort reinforces common aspects of this highly pleiotropic entity. EIMFS manifesting with refractory tonic seizures was the most common. Cannabidiol, diet therapy, and quinidine seem to offer the best chances of seizure reduction, although evidence-based practice is still unavailable.
AB - Objective: Through international collaboration, we evaluated the phenotypic aspects of a multiethnic cohort of KCNT1-related epilepsy and explored genotype-phenotype correlations associated with frequently encountered variants. Methods: A cross-sectional analysis of children harboring pathogenic or likely pathogenic KCNT1 variants was completed. Children with one of the two more common recurrent KCNT1 variants were compared with the rest of the cohort for the presence of particular characteristics. Results: Twenty-seven children (15 males, mean age = 40.8 months) were included. Seizure onset ranged from 1 day to 6 months, and half (48.1%) exhibited developmental plateauing upon onset. Two-thirds had epilepsy of infancy with migrating focal seizures (EIMFS), and focal tonic seizures were common (48.1%). The most frequent recurrent KCNT1 variants were c.2800G>A; p.Ala934Thr (n = 5) and c.862G>A; p.Gly288Ser (n = 4). De novo variants were found in 96% of tested parents (23/24). Sixty percent had abnormal magnetic resonance imaging (MRI) findings. Delayed myelination, thin corpus callosum, and brain atrophy were the most common. One child had gray-white matter interface indistinctness, suggesting a malformation of cortical development. Several antiepileptic drugs (mean = 7.4/patient) were tried, with no consistent response to any one agent. Eleven tried quinidine; 45% had marked (>50% seizure reduction) or some improvement (25%-50% seizure reduction). Seven used cannabidiol; 71% experienced marked or some improvement. Fourteen tried diet therapies; 57% had marked or some improvement. When comparing the recurrent variants to the rest of the cohort with respect to developmental trajectory, presence of EIMFS, >500 seizures/mo, abnormal MRI, and treatment response, there were no statistically significant differences. Four patients died (15%), none of sudden unexpected death in epilepsy. Significance: Our cohort reinforces common aspects of this highly pleiotropic entity. EIMFS manifesting with refractory tonic seizures was the most common. Cannabidiol, diet therapy, and quinidine seem to offer the best chances of seizure reduction, although evidence-based practice is still unavailable.
KW - KCNT1
KW - cannabidiol
KW - epilepsy of infancy with migrating focal seizures
KW - ketogenic diet
KW - microcephaly
KW - quinidine
UR - http://www.scopus.com/inward/record.url?scp=85081750440&partnerID=8YFLogxK
U2 - 10.1111/epi.16480
DO - 10.1111/epi.16480
M3 - Article
C2 - 32167590
AN - SCOPUS:85081750440
SN - 0013-9580
VL - 61
SP - 679
EP - 692
JO - Epilepsia
JF - Epilepsia
IS - 4
ER -