This study aims to evaluate whole-brain structural organization in RDP patients compared to other phenotypically overlapping movement disorders and healthy controls.

RDP is an autosomal dominant movement disorder linked to ATP1A3 mutations. Previous studies identified decreased thalamic blood flow in RDP without focal gray matter volume (GMV) differences, but structural gray matter changes beyond the thalamus remain poorly understood.

Structural MRI data from 17 ATP1A3(+) RDP patients were compared with 20 patients each from isolated focal dystonia, Parkinson Disease (PD), and healthy control cohorts. Two-sample t-tests were performed controlling for age, sex and intracranial volume. Clinical correlations between GMV and RDP clinical characteristics were also assessed.

RDP patients exhibited greater left prefrontal cortical volume compared to all other cohorts. Compared to controls, RDP patients showed additional GMV increases in the bilateral prefrontal cortices, right inferior temporal cortex, and right fusiform gyrus. Compared to dystonia patients, RDP patients showed GMV increases in the right prefrontal cortex, inferior parietal cortex, and superior/inferior temporal cortex and decreases in the left thalamus. Compared to PD patients, RDP patients exhibited GMV increases in the left prefrontal cortex and decreases in the left cerebellum. Overall, there were negative correlations between RDP duration and GMV in the right prefrontal cortex and bilateral caudate nucleus.

Our data suggests that structural alterations in RDP extend beyond the thalamus and basal ganglia, involving sensorimotor and executive brain regions. Volumetric increases in the prefrontal cortex in RPD patients compared to controls may suggest greater frontal circuitry dysfunction than previously studied. Additionally, understanding structural alterations in RDP compared to those found in more common movement disorders are imperative as we seek to find treatments for RDP. Overall, these findings underscore the importance of combining structural and functional imaging to better understand the genotype-phenotype relationships in ATP1A3-related disorders.