Case study
Epilepsy caused by CDKL5 mutations

https://doi.org/10.1016/j.ejpn.2010.04.005Get rights and content

Abstract

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been identified in female patients with early onset epileptic encephalopathy and severe mental retardation with a Rett-like phenotype. Subsequently CDKL5 mutations were shown to be associated with more diverse phenotypes including mild epilepsy and autism without epilepsy. Furthermore, CDKL5 mutations were found in patients with Angelman-like phenotype. The severity of epilepsy associated with CDKL5 mutations was recently shown to correlate with the type of CDKL5 mutations and epilepsy was identified to involve three distinct sequential stages. Here, we describe the phenotype of a severe form of neurodevelopmental disease in a female patient with a de novo nonsense mutation of the CDKL5 gene c.175C > T (p.R59X) affecting the catalytic domain of CDKL5 protein. Mutations in the CDKL5 gene are less common in males and can be associated with a genomic deletion as found in our male patient with a deletion of 0.3 Mb at Xp22.13 including the CDKL5 gene. We review phenotypes associated with CDKL5 mutations and examine putative relationships between the clinical epilepsy phenotype and the type of the mutation in the CDKL5 gene.

Introduction

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5; also known as serine threonine kinase 9, STK9; OMIM #300203) cause an early infantile epileptic encephalopathy-2 (EIEE2; OMIM #300672), a severe early onset seizure disorder with a phenotype overlapping with that of Rett syndrome and X-linked infantile spasms. The EIEE2 manifests itself as infantile spasms and intractable seizures which occur before the appearance of the typical features of Rett syndrome as observed in the so-called Hanefeld variant of Rett syndrome.1 Hand apraxia and breathing dysfunction are common clinical features in Rett syndrome and EIEE2.2 Electroencephalographic findings appear not to be unique in patients with CDKL5 mutations.3, 4, 5, 6 Recently, however, epilepsy associated with CDKL5 mutations was identified to include three distinct sequential stages and the severity of epilepsy phenotype was shown to have correlations with the location of CDKL5 mutations.7

Mutations in the CDKL5 gene are associated with diverse phenotypes, including mild epilepsy, autism without epilepsy, and Angelman-like phenotype.8, 9 Most of the CDKL5 mutations are identified in girls2, 3, 4, 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and only a few mutations are found in boys.9, 20, 21, 22, 23, 24 Classifying CDKL5 mutations at DNA level without paying attention to the structure of the translated protein is not sufficient to predict the consequences of distinct mutations and predict genotype-phenotype correlations. Epileptic phenotype suggests that various perturbations of the CDKL5 protein due to mutations at its functional domains may give some clue to the pathogenesis of the disease. By bringing the different phenotype and genotype datasets together it may be possible to facilitate the development of the foundation for future studies aimed at understanding the pathophysiology of epileptic encephalopathies in general as well as improved diagnostics and therapeutic interventions.

Here, we describe the phenotype of EIEE2 in a female and a male patient with mutations in the CDKL5 gene. A gene deletion in the male patient indicated that the phenotype was caused by the absence of CDKL5 protein. In the female patient, a base substitution c.175C > T in the CDKL5 gene results in a truncated protein without catalytic activity suggesting that the phenotype resulted from the lack of functional protein. We review the previously described CDKL5 mutations in EIEE2 and discuss putative correlations between molecular and clinical findings.

Section snippets

Case 1

Our patient is a girl born to healthy, no consanguineous parents after uneventful twin pregnancy. At the 39th week of pregnancy, labour was induced because of a growth delay in the twin brother whose weight was 1980 g (−3.4 SD), length 43 cm (−3.9 SD), and head circumference 31 cm (−2.6 SD) at birth. Her birth weight was 3490 g (+0.5 SD), length 49 cm (+0.1 SD), and head circumference 36 cm (+1.3 SD). Apgar scores were 9 at one and 10 at five minutes. She was affected with tonic flexion seizures of

Discussion

Mutations in the CDKL5 gene have been shown to affect mainly females as shown in the Fig. 2.2, 25 The frequency of CDKL5 mutations has been estimated to be about 9% in women with early onset seizures and 28% in women with early onset seizures and infantile spasms.25 Most mutations are identified in single cases but some recurrent mutations are reported. The R59X mutation was recently described by Ricciardi et al. in a female patient with an early onset epileptic encephalopathy and mild

Acknowledgements

The study was supported by grants from Arvo and Lea Ylppö Foundation and the Health Care Foundation.

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