Study objectives to describe early diagnostic clues in Cyclin-dependent kinase-like 5 (CDKL5) refractory encephalopathy, to improve treatment strategies. Methods we retrospectively studied 35 patients (25 females, 10 males) with CDKL5 gene mutations or deletion, focusing on their early seizure semiology, the electroencephalogram pattern, the effect of treatment and developmental outcome. Results the first seizures were recognizable and consisted of tonic, then clonic and spasms phases, occurring in sleep at a median age of 6 weeks. Clusters of spasms were observed in quiet sleep (QS) or slow wave sleep (SWS), with screaming, staring and arms’ extension that mimicked sleep terror in 28 of 35 patients (80%). Programmed awakening prevented these spasms in nine of 16 patients and small doses of clonazepam given at night improved epilepsy in 14 of 23 patients. Conclusion peculiar seizures with spasms starting in SWS are an early diagnostic clue in infants with CDKL5 encephalopathy. Sleep video-EEG polygraphy is an easy tool to disclose these early seizures and epileptic spasms in infants during first months of life while polysomnography is unlikely to give contribution at that early age. While conventional antiepileptic treatment and corticosteroids are poorly, transiently or not efficient, therapeutic strategy used for sleep terror could help, although the mechanism of spasms generation in SWS needs to be elucidated.

Angelman syndrome is a rare neurogenetic disease caused by the loss of the function of the maternal allele of the UBE3A gene on chromosome 15 (site 15q11.2–q13) and is characterized by severe mental retardation, lack of speech, epilepsy, microcephaly and a characteristic facial phenotype with a unique behavior in the form of frequent laughter. The combination of microcephaly, epilepsy, speechlessness and mental retardation poses a problem for differential diagnosis with many genetic diseases presenting with similar symptoms. Epileptic encephalopathy due to CDKL5 gene mutation and Rett syndrome have the greatest similarity. The hallmark of Angelman syndrome are laughter attacks and specific EEG changes. The authors have presented a table of the differential diagnosis of Angelman syndrome with some phenotypically similar genetic syndromes, indicating the most significant distinguishing features, which should facilitate for the pediatrician and neurologist the diagnostic path of establishing the correct diagnosis.