Progressive Cone-Rod Synaptic Dysfunction in Dynamin-1 (DNM1) Related Developmental and Epileptic Encephalopathy: A Distinct Retinal Phenotype in Human.

Abstract

Dynamin-1 is an essential enzyme involved in the recycling of synaptic vesicles, in particular in the scission of endocytic buds within the pre-synaptic terminal. Heterozygous pathogenic variants in DNM1 result in Developmental and Epileptic Encephalopathy type 31A, where patients exhibit early onset refractory epilepsy, severe-profound intellectual disability and poor visual behaviour. We present data demonstrating that this disorder progressively affects retinal synaptic function which, to our knowledge, is the first report of this phenotype in human. Clinical notes of the proband were reviewed incorporating ophthalmic phenotyping (imaging, electroretinography (ERG), pattern visual evoked potentials (PVEPs) and visual symptoms). Genetic testing was performed using trio whole genome sequencing. Genetic testing confirmed a de-novo pathogenic variant in DNM1, a recurrent heterozygous missense variant, c.709C > T;p.(Arg237Trp). Serial ERG testing at 1, 3, 9 and 12 years old indicated a progressive inner retinal dysfunction affecting both rod and cone synaptic pathways mirroring the abnormalities in the mouse model of dnm1, with normal retinal structure. DNM1 affects retinal synaptic recycling and endocytosis and our findings show likely usefulness of ERG testing in affected individuals. Further work is needed to expand our understanding of how different DNM1 variants affect retinal function.