Researchers at the Mayo Clinic, Rochester, MN performed retrospective chart reviews of 6 children with epilepsy and CDKL5 mutations. Four were girls and 2 boys. All developed infantile spasms after the majority (4/6, 67%) presented with partial-onset seizures. Five had dysphagia, profound in 4. The EEG revealed hypsarrhythmia in 3 children and modified hypsarrhythmia in 2. Mean age of seizure onset was 1.8 months (range, 1-3 months). Four had hypotonia, and all had developmental delay and cortical visual impairment. Topiramate, vigabatrin, and the ketogenic diet were of most benefit, but all had refractory seizures at follow-up. Steroids or ACTH were used in 4 patients, without complete seizure control. Boys and girls were affected equally, despite the X-linked mutation involved. Screening for CDKL5 mutations is recommended in children with epileptic encephalopathies of unknown origin and infantile spasms. [1]

COMMENT. The authors list several genetic defects that predispose children to early-onset epileptic encephalopathies and infantile spasms, previously considered cryptogenic. The CDKL5 mutations are thought to influence brain development via a similar molecular pathway to MECP2, the mutation that causes the majority of Rett syndrome cases. However, none of the authors' CDKL5 cases demonstrate the typical Rett syndrome-like phenotype with hand stereotypies, and only 1 has a characteristic microcephaly. Seizures with CDKL5 mutations are refractory to treatment including the ketogenic diet, whereas the majority (56%) of children with Rett syndrome and MECP2 mutations have treatment-responsive seizures [2]. The authors' suggestion that acidosis is a possible mechanism of the ketogenic diet is contrary to earlier research conducted at the Mayo Clinic [3, 4].

KCNQ2 Encephalopathy, an emerging phenotype of a neonatal epileptic encephalopathy is reported in 8 patients with early onset intractable seizures (first week of life) with prominent tonic component [5]. Seizures resolved by 3 years but residual intellectual disability and motor impairment were severe. EEG at onset showed a burst-suppression pattern or multifocal epileptiform activity. Early brain MRI showed hyperintensities in basal ganglia and thalamus that later resolved. KCNQ2 screening should be considered in the workup of refractory neonatal seizures of unknown origin.