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

TL;DR

This paper shows that a genetic mutation in DNM1 causes progressive retinal dysfunction in a rare neurological disorder, with visual testing revealing inner retinal issues.

Contribution

The study is the first to report progressive cone-rod synaptic dysfunction in humans with DNM1-related encephalopathy.

Findings

Serial ERG testing showed progressive inner retinal dysfunction affecting rod and cone pathways.

The DNM1 variant c.709C > T;p.(Arg237Trp) is linked to synaptic dysfunction in human retinas.

Retinal structure remains normal despite synaptic dysfunction, similar to mouse models.

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.

Variants in the DNM1 gene cause a progressive cone‐rod synaptic dysfunction, evidenced by the electroretinogram. This is due to retinal synaptic abnormality due to poor endocytic scission of synaptic buds at the synapse consequent on Dynamin‐1 abnormalities.

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