BackgroundMembrane Protein Palmitoylated 5 (MPP5) is a highly conserved apical complex protein, essential for cell polarity. Defects in neuronal cell polarity are associated with neurologic disorders. Only three patients with heterozygous MPP5 de novo variants have been reported so far, with global developmental delay, behavioral changes and in only one case epileptic seizures. ObjectiveTo describe a new patient with a novel truncating de novo mutation in MPP5 and to characterize in detail the epileptic phenotype and electroencephalographic features of the encephalopathy. MethodsWe identified a novel truncating de novo mutation in MPP5 in a 44 year old patient by exome sequencing (p.Ser498Phefs*15). We retrospectively analyzed his clinical and instrumental data along a thirty-year follow up. ResultOur patient presents with generalized tonic-clonic seizures, myoclonic and clonic seizures, non-epileptic myoclonus, tremor, severe intellectual disability, mild face dysmorphic traits, and psychosis. Discussion and conclusionWe present a case of a childhood onset developmental encephalopathy with a likely-pathogenic variant in the MPP5 gene.. This represents the first complete description of the epileptic syndrome associated with the MPP5 gene.