AbstractObjectiveST3GAL3‐related developmental and epileptic encephalopathy (DEE‐15) is an autosomal recessive condition characterized by intellectual disability, language and motor impairments, behavioral difficulties, stereotypies, and epilepsy. Only a few cases have been reported, and the epilepsy phenotype is not fully elucidated.MethodsA retrospective chart review of two siblings withST3GAL3‐related DEE was completed. In addition, we reviewed all published cases ofST3GAL3‐related congenital disorder of glycosylation.ResultsTwo brothers presented with global developmental delay, motor and language impairment, hypotonia, and childhood‐onset seizures. Seizures started between 2.5 and 5 years and had tonic components. Both siblings had prolonged periods of seizure freedom on carbamazepine. Tremor was present in the younger sibling. Whole exome sequencing revealed two novel pathogenic variants inST3GAL3, (a) c.302del, p.Phe102Serfs*34 and (b) c.781C>T, p.Arg261*, which were inheritedin trans. Magnetic resonance imaging showed T2 hyperintensities and restricted diffusion in the brainstem and middle cerebellar peduncle in the older sibling, also described in two reported cases. A review of the literature revealed 24 cases ofST3GAL3‐related CDG. Twelve cases had information about seizures, and epilepsy was diagnosed in 8 (67%). The median age of seizure onset was 5.5 months. Epileptic spasms were most common (67%). Four children were diagnosed with Infantile Epileptic Spasms syndrome and Lennox Gastaut syndrome (57%). Most children (n = 6, 75%) had seizures despite anti‐seizure medication treatment.SignificanceSeizures related toST3GAL3‐related DEE often occur in infancy and may present as epileptic spasms. However, seizure onset may also occur outside of infancy with mixed seizure types and show good response to treatment with prolonged seizure freedom. Tremor may also be uniquely observed in this condition.