Objective: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching branching, spine development, and synapse formation in layer II-III neurons of the cerebral cortex. Abnormal dendrites and synapses in Cux2(−/−) mice correlate correlate with reduced synaptic function and defects in working memory. A de novo CUX2 p.Glu590Lys variant was reported in two patients involved in large-scale scale whole-exome sequencing (WES) studies on intellectual disability and epileptic epileptic encephalopathies. We report on clinical data of six patients carrying t the de novo p.Glu590Lys variant. Methods: We reviewed clinical, MRI and EEG data from 6 patients, including 2 previously reported reported and 4 additional cases. The p.Glu590Lys variant was identified by WES in 3 and through a targeted gene panel in three. It had occurred de novo in all of them. Results: There were 4 males and 2 females. Mean age at inclusion was 13.6 years [8–21]. Epilepsy occurred in all patients. Age at onset of seizures ranged from 2 months to 1 year [mean = 6.6 months]. Seizure types at onset were myoclonic seizures, atypical absence with myoclonic component, and focal seizures. Seizures were drug-resistant in all patients but one. EEG initially showed generalized polyspikes and waves (4) or multifocal epileptiform discharges (2). Two patients are seizure-free under treatment whereas the others still have persistent seizures. Cognitive regression was noticed in childhood at least for two patients, at 8 and 12 years, respectively. All patients had severe cognitive impairment and autistic features were present in 4. Two patients had ataxic gait. Brain MRI only showed minor and non-specific anomalies. Conclusions: This study shows that patients carrying the p.Glu590Lys variant of CUX2 display a relatively homogeneous clinical presentation with infantile-onset epilepsy epilepsy frequently including myoclonic jerks with polyspikes and waves or multifocal epileptiform discharges. Patients have severe cognitive impairment sometimes associated with psychomotor regression in childhood.