CDKL5 gene status in female patients with epilepsy and Rett-like features: two new mutations in the catalytic domain

Hiart Maortua,María-Teresa Calvo,María-Isabel Tejada,Maria-Rosario Domingo,María-Jesús Martínez,Cristina Martínez-Bouzas,Ainhoa García-Ribes,María-Asunción López-Aríztegui,Izaskun Rubio,Feliciano Ramos,Nerea Puente

doi:10.1186/1471-2350-13-68

Abstract

BackgroundMutations in the cyclin-dependent kinase-like 5 gene (CDKL5) located in the Xp22 region have been shown to cause a subset of atypical Rett syndrome with infantile spasms or early seizures starting in the first postnatal months.MethodsWe performed mutation screening of CDKL5 in 60 female patients who had been identified as negative for the methyl CpG-binding protein 2 gene (MECP2) mutations, but who had current or past epilepsy, regardless of the age of onset, type, and severity. All the exons in the CDKL5 gene and their neighbouring sequences were examined, and CDKL5 rearrangements were studied by multiplex ligation-dependent probe amplification (MLPA).ResultsSix previously unidentified DNA changes were detected, two of which were disease-causing mutations in the catalytic domain: a frameshift mutation (c.509_510insGT; p.Glu170GlyfsX36) and a complete deletion of exon 10. Both were found in patients with seizures that started in the first month of life.ConclusionsThis study demonstrated the importance of CDKL5 mutations as etiological factors in neurodevelopmental disorders, and indicated that a thorough analysis of the CDKL5 gene sequence and its rearrangements should be considered in females with Rett syndrome-like phenotypes, severe encephalopathy and epilepsy with onset before 5 months of age. This study also confirmed the usefulness of MLPA as a diagnostic screening method for use in clinical practice.

Highlights

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) located in the Xp22 region have been shown to cause a subset of atypical Rett syndrome with infantile spasms or early seizures starting in the first postnatal months
The results of this study confirm that CDKL5 mutations are a potentially important etiological factor in neurodevelopmental disorders
Females with Rett Syndrome (RTT)-like phenotypes, severe encephalopathy, and very early-onset epilepsy may benefit from a complete analysis of the CDKL5 gene, in terms of both its sequence and its rearrangements

Summary

Introduction

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) located in the Xp22 region have been shown to cause a subset of atypical Rett syndrome with infantile spasms or early seizures starting in the first postnatal months. The cyclin-dependent kinase-like 5 gene (CDKL5) is located in the Xp22 region and has been found to be associated with atypical RTT with infantile spasms or early seizures starting in the first postnatal months (Hanefeld variant) [4,5]. The clinical overlap between patients with mutations in CDKL5 and patients with RTT caused by mutations in MECP2 reflects the fact that these genes belong to the same pathway [7,8]. The present study investigated mutations in CDKL5 in a cohort of patients with epilepsy and RTT or other RTT-like phenotypes to improve the diagnostic criteria for these patients and to clarify the pathological mechanisms of CDKL5 mutations

Methods

Results

Discussion

Conclusion