Felippe Borlot1, Ahmed Abushama1, Nadine Morrison-Levy1,2, Puneet Jain1,3, Kollencheri Puthenveettil Vinayan4, Musaad Abukhalid5, Hesham M Aldhalaan5, Hanin S Almuzaini5, Sheffali Gulati6, Tova Hershkovitz7, Ramesh Konanki8, Lokesh Lingappa8, Aimee F Luat9, Shatha Shafi10, Brahim Tabarki10, Maya Thomas11, Sangeetha Yoganathan11, Majid Alfadhel12,13, Ravindra Arya14,15, Elizabeth J Donner1, Salleh N Ehaideb12, Vykuntaraju K Gowda16, Vivek Jain17, Priyanka Madaan18, Kenneth A Myers19,20,21, Hiroshi Otsubo1, Prateek Panda6, Jitendra K Sahu18, Letícia P B Sampaio22, Suvasini Sharma23, Elisabeth Simard-Tremblay19,20, Maria Zak1, Robyn Whitney1. 1. Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada. 2. Children's Hospital of Eastern Ottawa, Ottawa, Ontario, Canada. 3. Division of Pediatric Neurology, Department of Pediatrics, Danat Al Emarat Hospital for Women and Children, Abu Dhabi, United Arab Emirates. 4. Department of Pediatric Neurology, Amrita Institute of Medical Sciences, Cochin, India. 5. Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 6. Child Neurology Division, Department of Pediatrics, Center of Excellence & Advanced Research on Childhood Neurodevelopmental Disorders, All India Institute of Medical Sciences, New Delhi, India. 7. Genetic Institute, Rambam Medical Center, Haifa, Israel. 8. Department of Neurology, Rainbow Children's Hospital, Hyderabad, India. 9. Detroit Medical Center, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, Michigan. 10. Division of Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. 11. Pediatric Neurology, Department of Neurological Sciences, Christian Medical College, Vellore, India. 12. King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia. 13. Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia. 14. Division of Neurology, Comprehensive Epilepsy Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 15. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. 16. Indira Gandhi Institute of Child Health, Bangalore, India. 17. Santokba Durlabhji Hospital, Jaipur, India. 18. Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India. 19. Division of Neurology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada. 20. Department of Neurology & Neurosurgery, McGill University Health Centre, Montreal, Quebec, Canada. 21. Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. 22. Department of Neurology, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil. 23. Neurology Division, Department of Pediatrics, Lady Harding Medical College and Kalawati Saran Children's Hospital, New Delhi, India.
Abstract
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. Wiley Periodicals, Inc.
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 patientsdied (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. Wiley Periodicals, Inc.
Authors: Christina Cherian; Juan P Appendino; Setareh Ashtiani; Paolo Federico; Christine P Molnar; Marina Kerr; Aneal Khan; Ping Yee Billie Au; Karl Martin Klein Journal: J Neurol Date: 2021-09-19 Impact factor: 4.849