Abstracts

Rationale: De novo mutations in DNM1 encoding the presynaptic protein Dynamin 1 are an emerging cause of severe epileptic encephalopathies. We aim to define the phenotypic spectrum of DNM1 encephalopathy by reviewing the clinical features of patients carrying de novo mutations in the DNM1 gene.Methods: We reviewed phenotypic data of patients with DNM1 mutations including previously published and newly identified patients. We compared available mutation data to known functional data on the fitful mouse, an epilepsy mouse model with a spontaneous heterozygous mutation in the mouse Dnm1 gene and undertook biomolecular modeling studies to assess the effect of the DNM1 mutations on protein function.Results: In total, we identified 12 patients with de novo mutations in DNM1 including 4 new patients and 8 previously reported patients. In addition, we include one patient with a mutation of unknown inheritance. Of the 12 patients with de novo mutations, 4 patients carried a recurrent mutation (p.R237W). The phenotype of patients with DNM1 encephalopathy included global developmental delay and infantile spasms starting between 2 and 6 months transitioning to Lennox-Gastaut-Syndrome with very frequent seizures and characteristic EEG features. All patients with de novo DNM1 mutations had severe intellectual disability and hypotonia. The epilepsy was intractable to a broad range of antiepileptic medications in all patients. Comparison to existing functional mouse data suggested that many recurrent and non-recurrent mutations have a dominant negative effect on Dynamin function and cluster within the GTPase or middle domain of the protein.Conclusions: DNM1 alterations may result in a unique epileptic encephalopathy characterized by infantile spasms with progression to Lennox-Gastaut-Syndrome with frequent, intractable seizures and persisting high amplitude slow spike wave discharges. Up to 30% of patients with DNM1 encephalopathy carry a recurrent p.R237W mutation and computational modeling data suggest a dominant negative effect on Dynamin function.