Neuropediatrics 2016; 47(06): 361-367
DOI: 10.1055/s-0036-1586730
Original Article
Georg Thieme Verlag KG Stuttgart · New York

CDKL5 Gene-Related Epileptic Encephalopathy in Estonia: Four Cases, One Novel Mutation Causing Severe Phenotype in a Boy, and Overview of the Literature

Stella Lilles
1   Department of Neurology and Neurorehabilitation, Children's Clinic, Tartu University Hospital, Tartu, Estonia
2   Department of Pediatrics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
,
Inga Talvik
1   Department of Neurology and Neurorehabilitation, Children's Clinic, Tartu University Hospital, Tartu, Estonia
2   Department of Pediatrics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
3   Department of Neurology and Rehabilitation, Tallinn Children's Hospital, Tallinn, Estonia
,
Klari Noormets
1   Department of Neurology and Neurorehabilitation, Children's Clinic, Tartu University Hospital, Tartu, Estonia
,
Ulvi Vaher
1   Department of Neurology and Neurorehabilitation, Children's Clinic, Tartu University Hospital, Tartu, Estonia
,
Katrin Õunap
2   Department of Pediatrics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
4   Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia
,
Tiia Reimand
2   Department of Pediatrics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
4   Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia
5   Department of Biomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
,
Valentin Sander
3   Department of Neurology and Rehabilitation, Tallinn Children's Hospital, Tallinn, Estonia
,
Pilvi Ilves
6   Department of Radiology, Radiology Clinic, Tartu University Hospital, Tartu, Estonia
7   Department of Radiology, University of Tartu, Tartu, Estonia
,
Tiina Talvik
1   Department of Neurology and Neurorehabilitation, Children's Clinic, Tartu University Hospital, Tartu, Estonia
2   Department of Pediatrics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
8   Committee of Clinical Ethics of Tartu University Hospital, Tartu, Estonia
› Author Affiliations
Further Information

Publication History

13 January 2016

21 June 2016

Publication Date:
06 September 2016 (online)

Abstract

Cyclin-dependent kinase-like 5 (CDKL5) gene mutations have mainly been found in females with early infantile epileptic encephalopathy (EIEE), severe intellectual disability, and Rett-like features. To date, only 22 boys have been reported, presenting with far more severe phenotypic features. We report the first cases of CDKL5 gene-related EIEE in Estonia diagnosed using panels of epilepsy-associated genes and describe the phenotype–genotype correlations in three male and one female patient. One of the mutations, identified in a male patient, was a novel de novo hemizygous frameshift mutation (NM_003159.2:c.2225_2228del (p.Glu742Afs*41)) in exon 15 of CDKL5. All boys have a more severe phenotype than the female patient. In boys with early onset of seizures and poor development with absent or poor eye contact, CDKL5 gene-related EIEE can be suspected and epilepsy-associated genes should be analyzed for early etiological diagnosis. Early genetic diagnosis would be the cornerstone in personalized treatment in the future.

Author Contributions

S. L., I. T., and K. N. are the first authors who equally contributed to this work. T. T. is the mentor of this work. I. T. and T. T. conceived the study. S. L., I. T., K. N., and T. T. participated in its design and coordination. S. L. drafted the manuscript. I. T., K. N., and T. T. critically revised the manuscript for important intellectual content. S. L., I. T., K. N., and V. S. cared for the patients. U. V. conducted and interpreted the EEG studies. T. R. and K. Õ. were responsible of the genetic testing and interpretation of the findings. P. I. was responsible of the neuroradiologic investigations and the interpretation of the findings. All authors critically read the final manuscript and gave final approval before submitting the article.


 
  • References

  • 1 Moseley BD, Dhamija R, Wirrell EC, Nickels KC. Historic, clinical, and prognostic features of epileptic encephalopathies caused by CDKL5 mutations. Pediatr Neurol 2012; 46 (2) 101-105
  • 2 Bahi-Buisson N, Nectoux J, Rosas-Vargas H , et al. Key clinical features to identify girls with CDKL5 mutations. Brain 2008; 131 (Pt 10) 2647-2661
  • 3 Evans JC, Archer HL, Colley JP , et al. Early onset seizures and Rett-like features associated with mutations in CDKL5. Eur J Hum Genet 2005; 13 (10) 1113-1120
  • 4 Archer HL, Evans J, Edwards S , et al. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J Med Genet 2006; 43 (9) 729-734
  • 5 Bahi-Buisson N, Bienvenu T. CDKL5-Related disorders: from clinical description to molecular genetics. Mol Syndromol 2012; 2 (3–5) 137-152
  • 6 Liang JS, Shimojima K, Takayama R , et al. CDKL5 alterations lead to early epileptic encephalopathy in both genders. Epilepsia 2011; 52 (10) 1835-1842
  • 7 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 (6) 1079-1093
  • 8 Elia M, Falco M, Ferri R , et al. CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy. Neurology 2008; 71 (13) 997-999
  • 9 Fichou Y, Bieth E, Bahi-Buisson N , et al. Re: CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy. Neurology 2009; 73 (1) 77-78 , author reply 78
  • 10 Masliah-Plachon J, Auvin S, Nectoux J, Fichou Y, Chelly J, Bienvenu T. Somatic mosaicism for a CDKL5 mutation as an epileptic encephalopathy in males. Am J Med Genet A 2010; 152A (8) 2110-2111
  • 11 Sartori S, Di Rosa G, Polli R , et al. A novel CDKL5 mutation in a 47,XXY boy with the early-onset seizure variant of Rett syndrome. Am J Med Genet A 2009; 149A (2) 232-236
  • 12 Mirzaa GM, Paciorkowski AR, Marsh ED , et al. CDKL5 and ARX mutations in males with early-onset epilepsy. Pediatr Neurol 2013; 48 (5) 367-377
  • 13 Raymond L, Diebold B, Leroux C , et al. Validation of high-resolution DNA melting analysis for mutation scanning of the CDKL5 gene: identification of novel mutations. Gene 2013; 512 (1) 70-75
  • 14 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
  • 15 Wong VC, Kwong AK. CDKL5 variant in a boy with infantile epileptic encephalopathy: case report. Brain Dev 2015; 37 (4) 446-448
  • 16 ExAC Browser (Beta). Exome Aggregation Consortium Web site. . Available at: http://exac.broadinstitute.org . Accessed December 17, 2015
  • 17 Pintaudi M, Baglietto MG, Gaggero R , et al. Clinical and electroencephalographic features in patients with CDKL5 mutations: two new Italian cases and review of the literature. Epilepsy Behav 2008; 12 (2) 326-331
  • 18 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) 266-273
  • 19 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) 1149-1154
  • 20 Talvik I, Møller RS, Vaher M , et al. Clinical phenotype of de novo GNAO1 mutation: case report and review of literature. Child Neurology Open 2015; 2015 (April - June): 1-7
  • 21 Russo S, Marchi M, Cogliati F , et al. Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes. Neurogenetics 2009; 10 (3) 241-250
  • 22 Rademacher N, Hambrock M, Fischer U , et al. Identification of a novel CDKL5 exon and pathogenic mutations in patients with severe mental retardation, early-onset seizures and Rett-like features. Neurogenetics 2011; 12 (2) 165-167