Dystonia-Parkinsonism Gene Variants in Individuals with Parkinsonism and Brain Scans without Evidence for Dopaminergic Deficit (SWEDD)

ObjectiveTo investigate the genetic etiology of dystonia-parkinsonism among individuals with parkinsonism who have dopamine transporter (DAT) SPECT scans without evidence of dopaminergic deficits (SWEDD). MethodsData for this case-control study were from the Parkinsons Progression Markers Initiative (PPMI) cohort, a multisite observational study. The sample analyzed included participants with whole genome sequencing (WGS) who were diagnosed as Parkinsons disease (PD, n=421), SWEDD (n=64) or healthy controls (HC, n=196). WGS data were analyzed to identify rare pathogenic variants in 30 dystonia-parkinsonism genes. Rare variants were prioritized for those present in individuals with SWEDD, but not in HC, reported pathogenicity in the literature and genetic databases, and with data from programs analyzing variant conservation and effect on protein function. For each SWEDD case with predicted or reported pathogenic variant(s), demographic, clinical, and imaging data were reviewed. ResultsEight of the 64 SWEDD participants (12.5%) had a pathogenic variant in one or more dystonia-parkinsonism genes, including PRKRA, SGCE, GLB1, ADCY5, SLC6A3, and GCDH. Notably, one case had a heterozygous variant in SGCE, p.R263H, which is predicted pathogenic but currently classified as a variant of uncertain significance due to insufficient evidence. ConclusionsPathogenic variants in parkinsonism-dystonia genes occurred in more than 10% of SWEDD cases in the PPMI cohort, supporting the importance of considering dystonia disorders in the differential diagnosis of PD, particularly in the case of participants with normal DAT SPECT scans. Analysis of genetic variants in parkinsonism-dystonia genes in SWEDD cases can provide information which will improve clinical diagnosis and management. KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSIndividuals with parkinsonism with scans without evidence of dopamine deficiency (SWEDD) constitute up to 16% of subjects with early parkinsonism referred for inclusion in multicenter observational studies and randomized clinical trials; however, the majority of these individuals do not have Parkinsons disease. Dystonic disorders are high on the list of differential diagnoses for individuals with parkinsonism and SWEDD, and an increasing number of studies support genetic etiologies for dystonic disorders. What proportion of individuals with parkinsonism and SWEDD referred for research studies might carry pathogenic variants in dystonia-parkinsonism related genes is not known. What this study addsThis study identified predicted or reported pathogenic variants in dystonia-parkinsonism related genes in more than 10% of SWEDD cases in the PPMI cohort, supporting the utility of evaluating dystonia-parkinsonism related genetic etiology in SWEDD cases. How this study might affect research, practice, or policyThis study supports the importance of genetic analyses in SWEDD cases which could improve clinical diagnosis and patient management.