Objective: To detect a neuropathological background of parkinsonism associated with rare sequence variants in the VPS35 and FBXO7 genes.

Background: A total of 23 gene loci have been identified in association with Parkinson’s disease, but the neuropathological background has been described in only a few of them [1]. We had recently studied the pathological findings in case of atypical parkinsonism with clinical picture of PSP-P which was associated with rare sequence variants in the VPS35 and FBXO7genes [2]; the neuropathology associated with variants in these genes has not yet been described.

Methods: After the patient died a detailed neuropathological examination of the brain was conducted. The 5 μm-thick sections of formalin-fixed paraffin-embedded tissue from specific regions of the brain were examined: frontal, temporal, parietal, occipital, and motor cortices, cingular gyrus, hippocampus and parahippocampal region, basal ganglia, thalamus, midbrain at the level of the substantia nigra, pons, oblongata at the level of the inferior olivary nucleus, and pons, medulla oblongata at the level of inferior olivary nucleus, and cerebellum. For immunohistochemistry the primary antibodies against the following antigens were used: phospho-PHF-tau AT8, tau 3-repeat isoform RD3, tau 4-repeat isoform RD4, α-synuclein, b-amyloid, and phospho- TDP-43.

Results: At autopsy the brain showed mild diffuse atrophy, the substantia nigra and locus coeruleus were depigmented. In hematoxilin and eosin staing, loss of neurons associated with gliosis and classical Lewy bodies were found in a number of regions. Immunohistochemical examination revealed α-synuclein positivity of varying density and range of extension. The overall pathological picture corresponded to the neocortical type of Parkinson’s disease (Braak stage VI).

Conclusions: This case provides the first description of a neuropathological correlation of parkinsonism associated with VPS35 and with FBXO7 gene mutations. The clinical picture resembling PSP-P was probably the result of the significant impairment of brainstem structures including the periaqueductal gray matter and the nucleus involved in the supranuclear control of gaze. Supported by grans: AZV- Ministry of Health of the Czech Republic Nr. 15-32715A, IGA-LF-2018-009 and MH CZ – DRO (FNOL 00098892) – 2017.

References: 1. Schneider SA, Alcalay RN. Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature. Mov Disord 2017; 32:1504-1523. 2. Bartonikova T, Mensikova K, Mikulicova L et al. Familial atypical parkinsonism with rare variant in VPS35 and FBXO7 genes. Medicine 2016; 95:e5398.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsonism-with-rare-sequence-variants-in-vps35-and-fbxo7-genes-associated-with-lewy-body-pathology/