Familial atypical parkinsonism with rare variant in VPS35 and FBXO7 genes: A case report

Abstract

Background: A higher prevalence of parkinsonism was recently identified in southeastern Moravia (Czech Republic). Further research confirmed 3 large pedigrees with familial autosomal-dominant parkinsonism spanning 5 generations.

Methods: This case report concerns a patient belonging to one of these 3 pedigrees, in whom motor and oculomotor symptoms were accompanied by frontal-type dementia, who finally developed a clinical phenotype of progressive supranuclear palsy. Molecular genetic examinations were performed due to the positive family history.

Results: No previously described causal mutation was found. After filtering against common variants (minor allele frequency (MAF) < 0.01), 2 noncoding and 1 synonymous rare mutation potentially associable with parkinsonism were identified: GIGYF2-GRB10 Interacting GYF Protein 2, PARK11 (c.*2030G > A, rs115669549); VPS35 gene-vacuolar protein sorting 35, PARK17 (c.102 + 33G > A, rs192115886); and FBXO7-F-box only protein 7 gene, PARK15 (c.540A > G, rs41311141).

Conclusion: As to the changes in the FBXO7 and VPS35 genes (despite phylogenetic conservation in primates), probably neither the FBXO7 nor the VPS35 variants will be direct causal mutations. Both described variants, and possibly the influence of their combination, could increase the risk of the disease.

Figure 1

Part of the pedigree in which the familiar atypical parkinsonism has been identified (see Ref. ^[3]). The patient is indicated by the arrow.

Figure 2

Horizontal FLAIR MRI sequence showing diffuse brain atrophy with postischemic hyperintensities in white matter bilaterally and nonhomogeneous signal and blurred contours of the basal ganglia (A). Sagittal T1-weighted MRI showing regular configuration of the brainstem without noticeable atrophy (B). FLAIR = fluid-attenuated inversion recovery, MRI = magnetic resonance imaging.

Figure 3

Visualization of vacuolar protein sorting 35 gene variant (NM_018206.4:c.102 + 33G > A, rs192115886) in integrative genomics viewer. The variant T (complementary to the reverse base A) is shown under the blue/red column.

Figure 4

Visualization of F-box only protein 7 gene variant (NM_012179.3:c.540A > G,NP_001028196.1:p.Pro101=, rs41311141) in integrative genomics viewer. The variant G is shown under the blue/red column.