Affiliations: Department of Child Neurology, Sant Joan de Deu Children's Hospital, Barcelona, Spain | Molecular Genetics Laboratory, Sant Joan de Deu Children's Hospital, Barcelona, Spain
Note:  Corresponding author: Ana Roche Martínez, Department of Child Neurology, Sant Joan de Deu Children's Hospital, Passeig de Sant Joan, 2, 08950 Esplugues, Barcelona, Spain. Tel.: +34 932804000; Fax: +34 932033959; E-mail: firstname.lastname@example.org.
Abstract: Mutations in cyclin-dependent kinase-like 5 (CDKL5) have been observed in patients with epileptic encephalopathies and atypical variants of Rett syndrome (RTT) associated with early epilepsy. Determination of the type and location of CDKL5 mutations may provide molecular diagnosis and prognostic information and aid in genetic counseling for the family. Molecular analysis of CDKL5 and X-chromosome inactivation pattern in 53 Spanish RTT girls (without identifiable methyl-CpG-binding-protein 2) and nine boys with epileptic encephalopathy was performed. De novo CDKL5 mutations were identified in eight atypical RTT patients: one late regression; one preserved speech, one congenital variant with epilepsy onset at 3 years of age, and five patients. An additional five patients with early-onset epilepsy. Seizure types and CDKL5 mutations were identified. Seizures types included infantile spasms or tonic seizures, and developing polymorphic seizures that were resistant to antiepileptic drugs. Electroencephalography records were abnormal, without characteristic pathologic pattern. Epilepsy control (total or partial) was achieved with valproate (four patients) or carbamazepine (three patients). Long-term outcome was variable, depending on type of mutation and epilepsy control. These are the first eight girls from Spain with CDKL5 mutations. Mutations were identified in early epilepsy variants with early hypotonia, but also in other atypical variants without a molecular diagnosis. This study highlights the importance of CDKL5 analysis in all atypical RTT patients without an identifiable methyl-CpG-binding-protein 2 mutation. Type and location of CDKL5 mutation and the resultant effect on protein appear to determine the severity of epilepsy.
Keywords: Cyclin-dependent kinase-like 5, drug-resistant epileptic encephalopathy, early epilepsy RTT variant, phenotype-genotype, Rett syndrome