Abstract Details

Parkinson’s disease (PD) is the most common cause of parkinsonism in older adults. However, up to 15% of individuals initially diagnosed with PD have normal DAT scans; these cases are termed scans without evidence of dopaminergic deficits (SWEDD). While it is understood that the etiology of parkinsonism in individuals with SWEDD is not due to PD, the causes of parkinsonism in SWEDDs are still unclear. One area of interest is the extent to which genetic causes of parkinsonism can mimic PD. We aimed to identify whether variants in dystonia-parkinsonism-related genes are possible etiologies of parkinsonism in SWEDDs.

To determine if there are genetic etiologies for dystonia-parkinsonism among individuals diagnosed with parkinsonism with normal dopamine transporter (DAT) SPECT scans.

Data were from the Parkinson Progression Markers Initiative (PPMI), a multisite, observational study of early PD and healthy controls (HC). Cohorts included: PD (PD) (n=423), parkinsonism with SWEDD (n=64), and healthy controls (HC) (n=196). Whole genome sequencing data were screened for rare, predicted functional variants in dystonia-parkinsonism genes. Comparison of genotype prevalence in SWEDD, PD, and HC groups, minor allele frequency, and reported and predicted function were used to determine the potential significance of variants. For each case with a reported pathogenic variant or one predicted to be functionally relevant, clinical, and imaging data were reviewed.

Eight out of 64 SWEDD patients had a likely deleterious variant in the following genes: PRKRA, SGCE, GLB1, ADCY5, SLC6A3, and GCDH. Average age of symptoms onset was 55.08 (SD=8.64) years, 87.5% were female, and average MDS-UPDRS-3 (motor) score was 11.5 (SD=6.61). 

Genetic abnormalities in dystonia-parkinsonism genes occur in 12.5% individuals with parkinsonism and normal DAT scans (SWEDDs). It is important to consider genetic dystonic disorders as a possible etiology in SWEDD patients for appropriate clinical diagnosis and management.