Clinical and genetic characteristics of patients with type 2 early infantile epileptic encephalopathy caused by CDKL5 gene mutations

Cover Page

Cite item

Full Text

Abstract

Early infantile epileptic encephalopathies (EIEE) are a group of disorders characterized by pharmacoresistant epileptic seizures manifesting in infancy and leading to psychomotor retardation. The most common genetic variant with X-linked dominant inheritance is type 2 EIEE associated with CDKL5 gene mutations.
We evaluated the prevalence of this type of EIEE among Russian patients (n = 148) with epileptic seizures manifesting in infancy and analyzed their clinical and genetic characteristics. We performed exome sequencing for all patients; 15 (10 %) of them (aged between 2 months and 5 years) were found to have CDKL5 gene mutations and were, therefore, diagnosed with type 2 EIEE.
The results of correlation analysis suggest that the severity of clinical manifestations of type 2 EIEE is largely determined by the location of mutations affecting the function of the protein encoded by this gene. This is important to ensure better understanding of type 2 EIEE etiology and predict it severity in patients with different allelic variants.

About the authors

E. L. Dadali

Medical Genetic Research Center named after acad. N.P. Bochkov;
N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia;

ORCID iD: 0000-0001-5602-2805
1 Moskvorechye St., Moscow 115522, Russia;
1 Ostrovityanova St., Moscow 117997, Russia; Russian Federation

I. A. Akimova

Medical Genetic Research Center named after acad. N.P. Bochkov;
1 Moskvorechye St., Moscow 115522, Russia;

Author for correspondence.
Email: akimova@med-gen.ru
ORCID iD: 0000-0002-9092-6581

Medical Genetic Research Center named after acad. N.P. Bochkov;
1 Moskvorechye St., Moscow 115522, Russia;

Russian Federation

F. A. Konovalov

Genomed LLC;

8/5 Podolskoe Shosse, Moscow 115093, Russia; Russian Federation

P. A. Shatalov

Genotek LLC;

17/1 Nastavnicheskiy Per., Moscow 105120, Russia Russian Federation

A. Yu. Krasnenko

Genotek LLC;

17/1 Nastavnicheskiy Per., Moscow 105120, Russia Russian Federation

V. V. Strelnikov

Medical Genetic Research Center named after acad. N.P. Bochkov;

1 Moskvorechye St., Moscow 115522, Russia; Russian Federation

M. A. Ampleeva

Genomed LLC;

ORCID iD: 0000-0003-2185-4753
8/5 Podolskoe Shosse, Moscow 115093, Russia; Russian Federation

References

  1. Bahi-Buisson N., Bienvenu T. CDKL5-related disorders: from clinical description to molecular genetics. Mol Syndromol 2012;2(3– 5):137–52. DOI: 000331333.
  2. Bahi-Buisson N., Villeneuve N., Caietta E. et al. Recurrent mutations in the CDKL5 gene: genotype-phenotype relationships. Am J Med Genet A 2012;158A(7):1612–9. doi: 10.1002/ajmg.a.35401.
  3. Bertani I., Rusconi L., Bolognese F. et al. Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation. J Biol Chem 2006;281(42):32048–56. doi: 10.1074/jbc. M606325200.
  4. Neuroimaging in epilepsy. Ed. by H. Chugani. Oxford Scholarship, 2010. doi: 10.1093/acpr of:oso/9780195342765.003.0001.
  5. Elia M., Falco M., Ferri R. et al. CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy. Neurology 2008;71:997–9. doi: 10.1212/01. wnl.0000326592.37105.88.
  6. 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(21):2206–13. doi: 10.1212/WNL.0000000000003352.
  7. Kalscheuer V.M., 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;72:1401–11. doi: 10.1086/375538.
  8. Kilstrup-Nielsen C., Rusconi L., La Montanara P. et al. What we know and would like to know about CDKL5 and its involvement in epileptic encephalopathy. Neural Plast 2012;2012:728267. doi: 10.1155/2012/728267.
  9. Lemke J.R., Syrbe S. Epileptic encephalopathies in childhood: the role of genetic testing. Semin Neurol 2015;35(3):310–22. doi: 10.1055/s-0035-1552623.
  10. Liang J.S., Shimojima K., Takayama R. et al. CDKL5 alterations lead to early epileptic encephalopathy in both genders. Epilepsia 2011;52(10):1835–42. doi: 10.1111/j.1528-1167.2011.03174.x.
  11. Lilles S., Talvik I., Noormets K. et al. CDKL5 gene-related epileptic encephalopathy in estonia: four cases, one novel mutation causing severe phenotype in a boy, and overview of the literature. Neuropediatrics 2016;47(6):361–7. doi: 10.1055/s-0036-1586730.
  12. Nemos C., Lambert L., Giuliano F. et al. Mutational spectrum of CDKL5 in earlyonset encephalopathies: a study of a large collection of French patients and review of the literature. Clin Genet 2009;76:357–71. doi: 10.1111/j.1399-0004.2009.01194.x.
  13. Psoni S., Willems P.J., Kanavakis E. et al. A novel p.Arg970X mutation in the last exon of the CDKL5 gene resulting in lateonset seizure disorder. Eur J Paediatr Neurol 2010;14(2):188–91. DOI: 10.1016/j. ejpn.2009.03.006.
  14. Rehm H.L., Bale S.J., Bayrak-Toydemir P. et al. ACMG clinical laboratory standards for next-generation sequencing. Genet Med 2013;15(9):733–47. DOI: 10.1038/ gim.2013.92.
  15. Tao J., Van Esch H., Hagedorn-Greiwe M. et al. Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. Am J Hum Genet 2004;75(6):1149–54. doi: 10.1086/426460.
  16. Weaving L.S., Christodoulou J., Williamson S.L. et al. 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.
  17. Williamson S.L., Giudici L., KilstrupNielsen C. et al. A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain. Hum Genet 2012;131(2):187–200. DOI: 10.1007/ s00439-011-1058-x.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2019 Dadali E.L., Akimova I.A., Konovalov F.A., Shatalov P.A., Krasnenko A.Y., Strelnikov V.V., Ampleeva M.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 22926 от  12.01.2006.