Genetic epilepsy caused by CDKL5 gene mutations as an example of epileptic encephalopathy and developmental encephalopathy: literature review and own observations
https://doi.org/10.17650/2073-8803-2021-16-1-2-10-41
Abstract
The disease caused by mutations in the CDKL5 gene (encoding cyclin-dependent kinase 5, CDK5) belongs to the group of early (infantile) epileptic encephalopathies caused by alterations in the genome. Currently, the disease is called “developmental encephalopathy and epileptic encephalopathy type 2”. This disorder is a complex combination of symptoms that develop due to deficiency or absence of the CDKL5 gene product, which is serine/threonine kinase. The CDKL5 gene is located on X chromosome; the disease has an X-linked dominant inheritance pattern. This literature review summarizes relevant studies analyzing the disease caused by CDKL5 gene mutations, including its genetic and epidemiological aspects, clinical manifestations, characteristics of epilepsy, principles of diagnosis, and therapeutic approaches. We present a case series of several patients with genetic disorders involving the CDKL5 gene.
About the Authors
K. Yu. Mukhin
Svt. Luka’s Institute of Child Neurology and Epilepsy; Svt. Luka’s Institute of Pediatric and Adult Neurology and Epilepsy
Russian Federation
Russian Federation
Konstantin Yuryevich Mukhin
5 Nagornaya St., Troitsk, Moscow 108840
9 Akad. Anokhina St., Moscow 119571
O. A. Pylaeva
Svt. Luka’s Institute of Child Neurology and Epilepsy; Svt. Luka’s Institute of Pediatric and Adult Neurology and Epilepsy
Russian Federation
Russian Federation
Olga Anatolyevna Pylaeva
5 Nagornaya St., Troitsk, Moscow 108840
9 Akad. Anokhina St., Moscow 119571
M. Yu. Bobylova
Svt. Luka’s Institute of Child Neurology and Epilepsy; Svt. Luka’s Institute of Pediatric and Adult Neurology and Epilepsy
Russian Federation
Russian Federation
5 Nagornaya St., Troitsk, Moscow 108840
9 Akad. Anokhina St., Moscow 119571
V. A. Chadaev
Svt. Luka’s Institute of Pediatric and Adult Neurology and Epilepsy
Russian Federation
Russian Federation
9 Akad. Anokhina St., Moscow 119571
References
1. Белоусова Е.Д. Эпилептическая энцефалопатия с продолженной спайк-волновой активностью во сне. Русский журнал детской неврологии 2012;7(1):3–8. [Belousova E.D. Epileptic encephalopathy with continuous spikeswaves activity during sleep. Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2012;7(1):31–8. (In Russ.)].
2. Белоусова Е.Д., Шарков А.А. Трудности в диагностике, прогнозе и лечении генетических эпилептических энцефалопатий: взгляд невролога. Журнал неврологии и психиатрии им. С.С. Корсакова. Спецвыпуски 2019;119(11–2): 34–40. [Belousova E.D., Sharkov A.A. Difficulties in the diagnosis, prognosis, and treatment of genetic epileptic encephalopathies: a neurologist’s view. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry. Special issues 2019;119(11–2):34–40. (In Russ.)]. DOI: 10.17116/jnevro201911911234.
3. Дадали Е.Л., Акимова И.А., Коновалов Ф.А. и др. Клинико-генетические особенности пациентов с ранней эпилептической энцефалопатией 2-го типа, обусловленной мутациями в гене CDKL5. Русский журнал детской неврологии 2019;14(3):28–36. [Dadali E.L., Akimova I.A., Konovalov F.A. et al. Clinical and genetic characteristics of patients with type 2 early infantile epileptic encephalopathy caused by CDKL5 gene mutations. Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2019;14(3): 28–36. (In Russ.)]. DOI: 10.17650/2073-8803-2019-14-3-28-36.
4. Зенков Л.Р. Бессудорожные эпилептические энцефалопатии с психиатрическими, коммуникативными и поведенческими расстройствами. Вестник эпилептологии 2004;(2):7–11. [Zenkov L.R. Nonconvulsive epileptic encephalopathies with mental, communicative, and behavioral disorders. Vestnik epileptologii = Bulletin of Epileptology 2004;1(2):7–11. (In Russ.)].
5. Зенков Л.Р. Непароксизмальные эпилептические расстройства. М.: МЕДпресс-информ, 2007. 278 с. [Zenkov L.R. Non-paroxysmal epileptic disorders. Moscow: Medpress-Inform, 2007. Pp. 106–115. (In Russ.)].
6. Карлов В.А. Эпилепсия у детей и взрослых женщин и мужчин. М.: Медицина, 2010. 720 с. [Karlov V.A. Epilepsy in children and adult men and women. Moscow: Meditsina, 2010. 720 p. (In Russ.)].
7. Мухин К.Ю. Когнитивная эпилептиформная дезинтеграция: дефиниция, диагностика, терапия. Русский журнал детской неврологии 2012;7(1):3–20. [Mukhin K.Yu. Cognitive epileptiform disintegration: definition, diagnosis, therapy. Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2012;7(1):3–20. (In Russ.)]. DOI: 10.17650/2073-8803-2012-7-1-3-20.
8. Мухин К.Ю. Определение и классификация эпилепсии. Проект Классификации эпилептических приступов 2016 года. Русский журнал детской неврологии 2017;12(1):8–20. [Mukhin K.Yu. Definition and classification of epilepsy. Classification of epileptic seizures 2016. Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2017; 12(1):8–20. (In Russ.)]. DOI: 10.17650/2073-8803-2017-12-1-08-20.
9. Мухин К.Ю., Глухова Л.Ю., Макиевская Е.Р. Эпилепсия с электрическим эпилептическим статусом в фазу медленного сна с фокусом на электроэнцефалографические критерии. Русский журнал детской неврологии 2017;12(1):21–35. [Mukhin K.Yu., Glukhova L.Yu., Makievskaya E.R. Epilepsy with electrical status epilepticus during slow-wave sleep with a focus on electroencephalographic criteria. Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2017;12(1): 21–35. (In Russ.)]. DOI: 10.17650/2073-8803-2017-12-1-21-35.
10. Мухин К.Ю., Пылаева О.А. Формирование когнитивных и психических нарушений при эпилепсии: роль различных факторов, связанных с заболеванием и лечением (обзор литературы и описания клинических случаев). Русский журнал детской неврологии 2017;12(3):7–33. [Mukhin K.Yu., Pylaeva O.A. The formation of cognitive and mental disorders in epilepsy: the role of various factors associated with disease and treatment (a review of literature and case reports). Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2017;12(3):7–33. (In Russ.)]. DOI: 10.17650/2073-8803-2017-12-3-7-33.
11. Amin S., Majumdar A., Mallick A.A. Caregiver’s perception of epilepsy treatment, quality of life and comorbidities in an international cohort of CDKL5 patients. Hippokratia 2017;21:130–5.
12. Baba S., Sugawara Y., Moriyama K. Amelioration of intractable epilepsy by adjunct vagus nerve stimulation therapy in a girl with a CDKL5 mutation. Brain Dev 2017;39:341–4. DOI: 10.1016/j.braindev.2016.10.007.
13. Bahi-Buisson N., Bienvenu T. CDKL5- related disorders: From clinical description to molecular genetics. Mol Syndromol 2011;2:137–52. DOI: 10.1159/000331333.
14. Bahi-Buisson N., Kaminska A., Boddaert N. et al. The three stages of epilepsy in patients with CDKL5 mutations. Epilepsia 2008;49(6):1027–37.
15. Bahi-Buisson N., Nectoux J., RosasVargas R. et al. Key clinical features to identify girls with CDKL5 mutations. Brain 2008;131:2647–61. DOI: 10.1093/brain/awn197.
16. Barbiero I., Peroni D., Siniscalchi P. et al. Pregnenolone and pregnenolone-methylether rescue neuronal defects caused by dysfunctional CLIP170 in a neuronal model of CDKL5 Deficiency Disorder. Neuropharmacology 2019;164:107897. DOI: 10.1016/j.neuropharm.2019.107897.
17. Barbiero I., Peroni D., Tramarin M. et al. The neurosteroid pregnenolone reverts microtubule derangement induced by the loss of a functional CDKL5- IQGAP1 complex. Hum Mol Genet 2017;26:3520–30. DOI: 10.1093/hmg/ddx237.
18. Berg A.T., Berkovic S.F., Brodie M.J. et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005– 2009. Epilepsia 2010;51:676–85.
19. Biagini G., Panuccio G., Avoli M. Neurosteroids and epilepsy. Curr Opin Neurol 2010;23(2):170–6. DOI: 10.1097/WCO.0b013e32833735cf.
20. Della Sala G., Putignano E., Chelini G. et al. Dendritic spine instability in a mouse model of CDKL5 disorder is rescued by insulin-like growth factor 1. Biol Psychiatry 2016;80:302–11. DOI: 10.1016/j.biopsych.2015.08.028.
21. Devinsky O., Verducci C., Thiele E.A. Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Epilepsy Behav 2018;86:131–1. DOI: 10.1016/j.yebeh.2018.05.013.
22. Fehr S., Leonard H., Ho G. et al. There is variability in the attainment of developmental milestones in the CDKL5 disorder. J Neurodev Dis 2015;7:2. DOI: 10.1186/1866-1955-7-2.
23. Fehr S., Wong K., Chin R. Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder. Neurology 2016;87:2206–13. DOI: 10.1212/WNL.0000000000003352.
24. Fehr S., Wilson M., Downs J. et al. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur J Hum Genet 2013;21(3):266–73. DOI: 10.1038/ejhg.2012.156.
25. Frullanti E., Papa F., Grillo E. et al. Analysis of the phenotypes in the Rett Networked Database. Int J Genom 2019;2019:6956934. DOI: 10.1155/2019/6956934.
26. Hanefeld F. The clinical pattern of the Rett syndrome. Brain Dev 1985;7:320–5. DOI: 10.1016/S0387-7604(85)80037-1.
27. Jakimiec M., Paprocka J., Smigiel R. CDKL5 deficiency disorder – a complex epileptic encephalopathy. Brain Sci 2020;10(2):107. DOI: 10.3390/brainsci10020107.
28. Kalscheuer V.M., Tao J., Donnelly A. Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation. Am J Hum Genet 2003;72:1401–11. DOI: 10.1086/375538.
29. Khan S., Baradie R.A. Epileptic encephalopathies: A overview. Epilepsy Res Treat 2012;2012:403592. DOI: 10.1155/2012/403592.
30. Ko A., Jung D.E., Kim S.H. et al. Efficacy of ketogenic diet for specific genetic mutation in developmental and epileptic encephalopathy. Front Neurol 2018;9: 530–9. DOI: 10.3389/fneur.2018.0053.
31. Krishnaraj R., Ho G., Christodoulou J. RettBASE: Rett syndrome database update. Hum Mutat 2017;38:922–31. DOI: 10.1002/humu.23263.
32. Lim Z., Wong K., Downs J. et al. Vagus nerve stimulation for the treatment of refractory epilepsy in the CDKL5 Deficiency Disorder. Epilepsy Res 2018;146:36–40. DOI: 10.1016/j.eplepsyres.2018.07.013.
33. Lim Z., Wong K., Olson H.E. et al. Use of the ketogenic diet to manage refractory epilepsy in CDKL5 disorder: Experience of >100 patients. Epilepsia 2017;58:1415–22. DOI: 10.1111/epi.13813.
34. Mangatt M., Wong K., Anderson B. et al. Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome. Orphanet J Rare Dis 2016;11:39. DOI: 10.1186/s13023-016-0418-y.
35. Mei D., Darra F., Barba C. et al. Optimizing the molecular diagnosis of CDKL5 gene-related epileptic encephalopathy in boys. Epilepsia 2014; 55:1748–53. DOI: 10.1111/epi.12803.
36. Muller A., Helbig I., Jansen C. 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; 20:147–51. DOI: 10.1016/j.ejpn.2015.09.001.
37. Nabbout R., Dulac O. Epileptic encephalopathies: a brief overview. J Clin Neurophysiol 2003;20(6):393–7.
38. Olson H.E., Demarest S.T., PestanaKnight E.M. et al. Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder: Clinical review. Pediatr Neurol 2019;97:18–25. DOI: 10.1016/j.pediatrneurol.2019.02.015.
39. OMIM: Online Mendelian Inheritance in Man, an online catalog of human genes and genetic disorders. Available at: https://omim.org.
40. Russo S., Marchi M., Cogliati F. et al. Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes. Neurogenetics 2009;10:241–50. DOI: 10.1007/s10048-009-0177-1.
41. Scala E., Ariani F., Mari F. CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms. J Med Genet 2005;42:103–7. DOI: 10.1136/jmg.2004.026237.
42. Scheffer I.E., Berkovic S., Capovilla G. et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58(4):512–21.
43. Stosser M.B., Lindy A.S., Butler E. High frequency of mosaic pathogenic variants in genes causing epilepsy-related neurodevelopmental disorders. Genet Med 2018;20:403–10. DOI: 10.1038/gim.2017.114.
44. Swaiman K.F., Ashwal S., Ferriero D.M. et al. Swaiman’s Pediatric Neurology. Principles and Practice. 6th edn. Elsevier, 2017. 2969 p.
45. Tang S., Terzic B., Wang I.J. et al. Altered NMDAR signaling underlies autistic-like features in mouse models of CDKL5 deficiency disorder. Nat Commun 2019;10:2655. DOI: 10.1038/s41467-019-10689-w.
46. Tramarin M., Rusconi L., Pizzamiglio L. et al. The antidepressant tianeptine reverts synaptic AMPA receptor defects caused by deficiency of CDKL5. Hum Mol Genet 2018;27:2052–63. DOI: 10.1093/hmg/ddy108.
47. Weaving L.S., Christodoulou J., Williamson S.L. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet 2004;75: 1079–93. DOI: 10.1086/426462.
48. Wong V.C.-N., Kwong A.K.-Y. CDKL5 variant in a boy with Infantile Epileptic Encephalopathy: Case report. Brain Dev 2014;37:446–8. DOI: 10.1016/j.braindev.2014.07.003.
49. 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. DOI: 10.1186/1471-2350-15-24.
Review
For citations:
Mukhin K.Yu., Pylaeva O.A., Bobylova M.Yu., Chadaev V.A. Genetic epilepsy caused by CDKL5 gene mutations as an example of epileptic encephalopathy and developmental encephalopathy: literature review and own observations. Russian Journal of Child Neurology. 2021;16(1-2):10-41. (In Russ.) https://doi.org/10.17650/2073-8803-2021-16-1-2-10-41
Views:
1502
Email this article 