Clinical manifestations of Parkinson's disease harboring VPS35 retromer complex component p.D620N with long-term follow-up

Abstract

IntroductionTo identify and investigate patients with Parkinson's disease (PD) harboring VPS35 variants in Japan. MethodsUsing targeted gene panel screening, we analyzed 393 familial, 294 young-onset, and 52 late-onset sporadic PD patients derived from the Juntendo PD DNA bank, and obtained clinical information from the medical records on each patient in whom we found VPS35 p.D620N variants. ResultsWe identified VPS35 p.D620N in three new patients: two patients with familial PD and one patient with sporadic PD. Additionally, we newly confirmed p.D620 from a patient of a family reported previously. The prevalence of familial PD was 0.7% (2/307), young-onset sporadic PD was 0.3% (1/294), and late-onset sporadic PD was 0% (0/52) in our cohort. Combining four patients with p.D620N from our previous reports, haplotype analysis indicated at least two founders in our cohort. Patients commonly showed a slow progression of parkinsonism with onset in middle or late age and mild parkinsonism with good response to levodopa and little cognitive decline even for more than 10 years of disease duration. Psychosis was occurred in two patients. One-half of patients required device-aided therapies such as deep brain stimulation or levodopa-carbidopa intestinal gel. Brain magnetic resonance imaging mostly showed normal findings, even at more than 10 years after onset. 123I-metaiodobenzylguanidine myocardial scintigraphy indicated normal heart-to-mediastinum ratio values among three of four patients. Conclusions: Patients with VPS35 p.D620N showed distinctive symptoms and neuroimaging. Our findings expand the clinical findings of patients with VPS35 variants.