To characterize the neuropathological findings of two affected individuals in a multi-incident US kindred with RAB39B-related Parkinson’s disease (PD)

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Tissue sections were obtained from the cortical lobes, brainstem, and basal ganglia. Immunohistochemical assessments included stains for α-synuclein, phospho-tau, phospho-TDP-43, and amyloid ß. The younger brother had Lewy body pathology in a neocortical distribution as expected, but also had an unusual pattern and burden of tau pathology that included neocortical neurofibrillary tangles, pretangles, and neurites in the absence of amyloid pathology. The older brother’s brain, while showing a similar pattern of tau pathology, was notable for a lack of α-synuclein pathology. Both cases showed marked pallor of the substantia nigra and severe loss of pigmented neurons with associated gliosis.

The pathology underlying monogenic forms of parkinsonism can include α-synuclein, tau, or other proteotoxic proteins, but the pathological findings are typically consistent within each disorder.  In contrast, these two cases displayed striking pathologic heterogeneity which suggests that the molecular processes underlying RAB39B-related neurodegeneration might be variable and complex.