A 6.4 Mb Duplication of the α-Synuclein Locus Causing Frontotemporal Dementia and Parkinsonism

Abstract

IMPORTANCE α-Synuclein (SNCA) locus duplications are associated with variable clinical features and reduced penetrance but the reasons underlying this variability are unknown.OBJECTIVES To report a novel family carrying a heterozygous 6.4 Mb duplication of the SNCA locus with an atypical clinical presentation strongly reminiscent of frontotemporal dementia and late-onset pallidopyramidal syndromes and study phenotype-genotype correlations in SNCA locus duplications. DESIGN, SETTING, AND PARTICIPANTSWe report the clinical and neuropathologic features of a family carrying a 6.4 Mb duplication of the SNCA locus. To identify candidate disease modifiers, we completed a genetic analysis of the family and conducted statistical analysis on previously published cases carrying SNCA locus duplications using regression modeling with robust standard errors to account for clustering at the family level. MAIN OUTCOMES AND MEASURESWe assessed whether length of the SNCA locus duplication influences disease penetrance and severity and whether extraduplication factors have a disease-modifying role. RESULTSWe identified a large 6.4 Mb duplication of the SNCA locus in this family. Neuropathological analysis showed extensive α-synuclein pathology with minimal phospho-tau pathology. Genetic analysis showed an increased burden of Parkinson disease-related risk factors and the disease-predisposing H1/H1 microtubule-associated protein tau haplotype. Statistical analysis of previously published cases suggested there is a trend toward increasing disease severity and disease penetrance with increasing duplication size. The corresponding odds ratios from the univariable analyses were 1.17 (95% CI, 0.81-1.68) and 1.34 (95% CI, 0.78-2.31), respectively. Sex was significantly associated with both disease risk and severity; men compared with women had increased disease risk and severity and the corresponding odds ratios from the univariable analyses were 8.36 (95% CI, 1.97-35.42) and 5.55 (95% CI, 1.39-22.22), respectively.CONCLUSIONS AND RELEVANCE These findings further expand the phenotypic spectrum of SNCA locus duplications. Increased dosage of genes located within the duplicated region probably cannot increase disease risk and disease severity without the contribution of additional risk factors. Identification of disease modifiers accounting for the substantial phenotypic heterogeneity of patients with SNCA locus duplications could provide insight into molecular events involved in α-synuclein aggregation.

Mutations in LRRK2 impair NF-κB pathway in iPSC-derived neurons

“…Indeed, missense mutations and multiplications in SNCA [32–35] cause familial autosomal dominant forms of PD. α-synuclein is also the main component of the proteinaceous inclusions (Lewy bodies and neurites) considered the pathological hallmark of PD [2, 36].…”

Autosomal dominant Parkinson's disease caused by SNCA duplications

“…Neuropathological examinations were conducted on four Japanese patients and one British patient with SNCA duplication (Table 2) [9, 16–21]. Three of the Japanese cases (II-4, III-1, IV-1) were from the same family.…”

“…The British case presented with hallucinations that began in childhood; this patient also suffered from anxiety and panic disorder that began at age eight years. The parkinsonism associated with this case appeared at age 38 years [21]. …”

The Protein Complex of Neurodegeneration-related Phosphoinositide Phosphatase Sac3 and ArPIKfyve Binds the Lewy Body-associated Synphilin-1, Preventing Its Aggregation

“…Although FIG4/SAC3 gene amplification or gain-of-function polymorphism in PD has not yet been reported, excessive accumulation of Sac3 protein has been observed recently in triple negative breast cancer cell types (58). These data, together with the evidence that some forms of PD pathology are triggered by multiplication of the SNCA gene and/or elevated expression of ␣-Syn, which increase ␣-Syn propensity to aggregate (53,59,60), make the FIG4/SAC3 genome-wide association study in the PD cases an important objective. The neuropathology in patients with familial Parkinsonism, in addition to a nigral neuronal loss and the presence of widespread Lewy bodies in the brainstem or cerebral cortex, is characterized by vacuolation within the temporal lobe and lower neurons (61)(62)(63).…”