Clinical electrophysiological features of cyclin-dependent kinase-like 5 gene induced developmental epileptic encephalopathy_Journal of Epilepsy

Authors：

JIA Chenlu , FAN Shuhui , YANG Haipo , JIANG Yuwu ,  WANG Shuang

Children's Medical Center of Peking University First Hospital, Beijing 102627, China;

Corresponding author：

WANG Shuang, Email: drwangshuang@vip.sina.com

Keywords：

Cyclin-dependent kinase-like-5 gene; Developmental epileptic encephalopathy; Seizures; Electroencephalography

DOI：

10.7507/2096-0247.202407007

Video：

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Objective To investigate the clinical electrophysiological characteristics of Cyclin-dependent kinase-like 5 gene induced developmental epileptic encephalopathy (CDKL5-DEE). Methods The clinical data and series of video EEGs of children with CDKL5-associated developmental epileptic encephalopathy (CDKL5-DEE) who were admitted to the Children’s Medical Center of Peking University First Hospital from June 2016 to May 2024 were retrospectively analyzed. Results A total of 16 patients with CDKL5-DEE were enrolled, including 13 females and 3 males. All patients had de novo variants of CDKL5 gene, including 6 cases of missense variants, 5 cases of frameshift variants, 4 cases of nonsense variants, and 1 case of large fragment deletion. The age of onset was 8 days (d) after birth ~1 year (y) and 10 months (m), and the median age was (85.94±95.76) days. Types of seizures at onset: 4 cases of tonic seizures [age of onset 10~52 days, median age (25.5±15.84) days]; There were 5 cases of focal seizures [age of onset 8 d~8 m, median age (77.76±85.97) d]. There were 4 cases of epileptic spasmodic seizures [age of onset 3 m~1 y 10 m, median age (6.25±3.49) m]; There were 2 cases of bilateral tonic-clonic seizures [age of onset 30~40 days, median age (35.00±5.00) days]; focal concurrent epileptic spasm seizures 1 case (age of onset 2 m). A total of 59 VEEG sessions were performed in the pediatric EEG room of Peking University First Hospital for 4 hours. All the results were abnormal, including 26 normal background, 25 slow rhythm difference with background, and 8 no background. The interictal was 16 posterior or focal discharges, 19 multifocal discharges, 17 generalized or accompanied by focal/multifocal discharges, and 7 hypsarrhythmia; The ictal was 33 epileptic seizures, 6 myoclonic seizures, 5 focal seizures, 2 tonic-clonic seizures, 2 atypical absence seizures, 2 tonic seizures, 1 myoclonic sequential focal seizure, 1 focal sequential epileptic spasm, and 1 hypermotor-tonic-spasms. The background of patients within 6 months of age was normal, and the background abnormality increased significantly with age. generalized discharges are evident after 2 years of age between seizures. Conclusion CDKL5-DEE seizures have an early onset and are refractory to medications. Epileptic spasms are the most common type of seizure in every patient and long-lasting, with generalized seizures increasing markedly with age. EEG is characterized by a normal background within 6 months. With the increase of age, the background and interictal discharges have a tendency to deteriorate.

Citation： JIA Chenlu, FAN Shuhui, YANG Haipo, JIANG Yuwu, WANG Shuang. Clinical electrophysiological features of cyclin-dependent kinase-like 5 gene induced developmental epileptic encephalopathy. Journal of Epilepsy, 2024, 10(5): 384-392. doi: 10.7507/2096-0247.202407007 Copy

1.	Fuchs C, Trazzi S, Torricella R, et al. Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3β signaling. Neurobiol Dis, 2014, 70(100): 53-68.
2.	Hector RD, Kalscheuer VM, Hennig F, et al. CDKL5 variants: improving our understanding of a rare neurologic disorder. Neurol Genet, 2017, 3(6): e200.
3.	Yoko Takahashi, Parikh Sumit, Elia M, et al. CDKL5 gene-related encephalopathy: pathophysiology, clinical presentation, developmental prognosis, and treatment. J Pediatr Epilepsy, 2018, 7: 1-7.
4.	Kalscheuer VM, Tao J, Donnelly A, et al. Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation. Am J Hum Genet, 2003, 72(6): 1401-1411.
5.	Tao J, Van Esch H, Hagedorn-Greiwe M, et al. Mutations in the X-linked cyclin-dependent kinaselike 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. Am J Hum Genet, 2004, 75: 1149-1154.
6.	Weaving LS, Christodoulou J, Williamson SL, et al. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet, 2004, 75: 1079-1093.
7.	Sameer M Zuberi, Elaine Wirrell, Elissa Yozawitz, et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia, 2022, 63(4): 1349-1397.
8.	Olson HE, Demarest ST, Pestana-Knight EM, et al. Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder: clinical review. Pediatr Neurol, 2019, 97: 18-25.
9.	Cutri-French C, Armstrong D, Saby J, et al. Comparison of core features in four developmental encephalopathies in the rett natural history study. Ann Neurol, 2020, 88(2): 396-406.
10.	Nicola Specchio, Marina Trivisano, Matteo Lenge, et al. CDKL5 deficiency disorder: progressive brain atrophy may be part of the syndrome. Cerebral Cortex, 2023, 33: 9709-9717.
11.	梅道启, 陈国洪 , 王媛 , 等 . CDKL5 基因相关早发性癫痫性脑病临床特征及基因突变分析. 中华神经科杂志, 2021, 54(4): 320-328.
12.	熊娟, 彭镜, 段浩林, 等. CDKL5 综合征 7 例病例报告. 中国循证儿科杂志, 2017, 12(6): 442-445.
13.	Fehr S, Wong K, Chin R, et al. Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder. Neurology, 2016, 87: 2206-2213.
14.	Demarest ST, Olson HE, Moss A, et al. CDKL5 deficiency disorder: relationship between genotype, epilepsy, cortical visual impairment, and development. Epilepsia, 2019, 60(6): 1733-1742.
15.	Ronit M Pressler, Maria Roberta Cilio, Eli M. Mizrahi, et al. The ILAE classification of seizures and the epilepsies: modification for seizures in the neonate. Position paper by the ILAE Task Force on Neonatal Seizures. Epilepsia. 2021, 62: 615–628.
16.	Zhao Y, Zhang X, Bao X, et al. Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients. BMC Med Genet, 2014, 15: 24.
17.	李鹤婷, 罗小青, 江军, 等. CDKL5 基因相关早发性癫痫性脑病临床及脑电图特点. 临床儿科杂志, 2023, 41(4): 272-277.
18.	章清萍, 赵滢, 包新华, 等. 早发性癫痫脑病患儿的CDKL5基因突变特点与临床特征. 中华医学遗传学杂, 2016, 33(3): 404-447.
19.	刘舒蕾, 甘思仪, 吴丽文, 等. CDKL5 缺乏症患儿的临床特征与遗传学分析. 癫痫与神经电生理学杂志, 2023, 32(6): 330-334.
20.	Klein KM, Yendle SC, Harvey AS, et al. A distinctive seizure type in patients with CDKL5 mutations: hypermotor-tonic-spasms sequence. Neurology, 2011, 76(16): 1436-1438.
21.	Müller A, Helbig I, Jansen C, et al. Retrospective evaluation of low long-term efficacy of antiepileptic drugs and ketogenic diet in 39 patients with CDKL5 related epilepsy. Eur J Paediatr Neurol, 2016, 20(1): 147-151.
22.	Hong W, Haviland I, Olson HE, et al. CDKL5 deficiency disorder-related epilepsy: a review of current and emerging treatment. CNS Drugs, 2022, 36(6): 591-604.
23.	刘晓燕, 临床脑电图学(第2版). 北京: 人民卫生出版社, 2017: 114, 116.
24.	Bourel-Ponchel E, Gueden S, Hasaerts D, et al. Normal EEG during the neonatal period: maturational aspects from premature to full-term newborns. Neurophysiologie Clinique/Clinical Neurophysiology, 2021, 51(1): 61-88.
25.	Brock D, Fidell A, Thomas J, et al. Cerebral visual impairment in CDKL5 deficiency disorder correlates with developmental achievement. Journal of Child Neurology, 2021, 36(11): 974-980.
26.	Good WV, Jan JE, DeSa L, et al. Cortical visual impairment in children. Surv Ophthalmol, 1994, 38: 351-364.
27.	Michela Quintiliani, Daniela Ricci, Maria Petrianni, et al. Cortical visual impairment in CDKL5 deficiency disorder. Neurology, 2021, 12: 805745.
28.	MacKay CI, Wong K, Demarest ST, et al. Exploring genotype-phenotype relationships in the CDKL5 deficiency disorder using an international dataset. Clinical Genetics, 2021, 99: 157-165.

1. Fuchs C, Trazzi S, Torricella R, et al. Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3β signaling. Neurobiol Dis, 2014, 70(100): 53-68.
2. Hector RD, Kalscheuer VM, Hennig F, et al. CDKL5 variants: improving our understanding of a rare neurologic disorder. Neurol Genet, 2017, 3(6): e200.
3. Yoko Takahashi, Parikh Sumit, Elia M, et al. CDKL5 gene-related encephalopathy: pathophysiology, clinical presentation, developmental prognosis, and treatment. J Pediatr Epilepsy, 2018, 7: 1-7.
4. Kalscheuer VM, Tao J, Donnelly A, et al. Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation. Am J Hum Genet, 2003, 72(6): 1401-1411.
5. Tao J, Van Esch H, Hagedorn-Greiwe M, et al. Mutations in the X-linked cyclin-dependent kinaselike 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. Am J Hum Genet, 2004, 75: 1149-1154.
6. Weaving LS, Christodoulou J, Williamson SL, et al. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet, 2004, 75: 1079-1093.
7. Sameer M Zuberi, Elaine Wirrell, Elissa Yozawitz, et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia, 2022, 63(4): 1349-1397.
8. Olson HE, Demarest ST, Pestana-Knight EM, et al. Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder: clinical review. Pediatr Neurol, 2019, 97: 18-25.
9. Cutri-French C, Armstrong D, Saby J, et al. Comparison of core features in four developmental encephalopathies in the rett natural history study. Ann Neurol, 2020, 88(2): 396-406.
10. Nicola Specchio, Marina Trivisano, Matteo Lenge, et al. CDKL5 deficiency disorder: progressive brain atrophy may be part of the syndrome. Cerebral Cortex, 2023, 33: 9709-9717.
11. 梅道启, 陈国洪 , 王媛 , 等 . CDKL5 基因相关早发性癫痫性脑病临床特征及基因突变分析. 中华神经科杂志, 2021, 54(4): 320-328.
12. 熊娟, 彭镜, 段浩林, 等. CDKL5 综合征 7 例病例报告. 中国循证儿科杂志, 2017, 12(6): 442-445.
13. Fehr S, Wong K, Chin R, et al. Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder. Neurology, 2016, 87: 2206-2213.
14. Demarest ST, Olson HE, Moss A, et al. CDKL5 deficiency disorder: relationship between genotype, epilepsy, cortical visual impairment, and development. Epilepsia, 2019, 60(6): 1733-1742.
15. Ronit M Pressler, Maria Roberta Cilio, Eli M. Mizrahi, et al. The ILAE classification of seizures and the epilepsies: modification for seizures in the neonate. Position paper by the ILAE Task Force on Neonatal Seizures. Epilepsia. 2021, 62: 615–628.
16. Zhao Y, Zhang X, Bao X, et al. Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients. BMC Med Genet, 2014, 15: 24.
17. 李鹤婷, 罗小青, 江军, 等. CDKL5 基因相关早发性癫痫性脑病临床及脑电图特点. 临床儿科杂志, 2023, 41(4): 272-277.
18. 章清萍, 赵滢, 包新华, 等. 早发性癫痫脑病患儿的CDKL5基因突变特点与临床特征. 中华医学遗传学杂, 2016, 33(3): 404-447.
19. 刘舒蕾, 甘思仪, 吴丽文, 等. CDKL5 缺乏症患儿的临床特征与遗传学分析. 癫痫与神经电生理学杂志, 2023, 32(6): 330-334.
20. Klein KM, Yendle SC, Harvey AS, et al. A distinctive seizure type in patients with CDKL5 mutations: hypermotor-tonic-spasms sequence. Neurology, 2011, 76(16): 1436-1438.
21. Müller A, Helbig I, Jansen C, et al. Retrospective evaluation of low long-term efficacy of antiepileptic drugs and ketogenic diet in 39 patients with CDKL5 related epilepsy. Eur J Paediatr Neurol, 2016, 20(1): 147-151.
22. Hong W, Haviland I, Olson HE, et al. CDKL5 deficiency disorder-related epilepsy: a review of current and emerging treatment. CNS Drugs, 2022, 36(6): 591-604.
23. 刘晓燕, 临床脑电图学(第2版). 北京: 人民卫生出版社, 2017: 114, 116.
24. Bourel-Ponchel E, Gueden S, Hasaerts D, et al. Normal EEG during the neonatal period: maturational aspects from premature to full-term newborns. Neurophysiologie Clinique/Clinical Neurophysiology, 2021, 51(1): 61-88.
25. Brock D, Fidell A, Thomas J, et al. Cerebral visual impairment in CDKL5 deficiency disorder correlates with developmental achievement. Journal of Child Neurology, 2021, 36(11): 974-980.
26. Good WV, Jan JE, DeSa L, et al. Cortical visual impairment in children. Surv Ophthalmol, 1994, 38: 351-364.
27. Michela Quintiliani, Daniela Ricci, Maria Petrianni, et al. Cortical visual impairment in CDKL5 deficiency disorder. Neurology, 2021, 12: 805745.
28. MacKay CI, Wong K, Demarest ST, et al. Exploring genotype-phenotype relationships in the CDKL5 deficiency disorder using an international dataset. Clinical Genetics, 2021, 99: 157-165.

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