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
