A Meta-Analysis of α-Synuclein Multiplication in Familial Parkinsonism

Abstract

Chronic alpha-synuclein (<i>SNCA</i>) overexpression is a relatively homogenous and well-defined cause of parkinsonism and dementia. Parkinson's disease (PD), PD with dementia, dementia with Lewy bodies and multiple system atrophy all manifest in <i>SNCA</i> multiplication families. Herein we summarize genealogic, clinical and genetic data from 59 families (25 not previously published) with parkinsonism caused by <i>SNCA</i> multiplications. Longitudinal clinical assessments and genealogic relationships were documented for all family members. All probands were genotyped with an Illumina MEGA high-density genotyping array to identify copy number variants (CNV) and enable <i>SNCA</i> multiplication breakpoints to be defined. Three <i>SNCA</i> short tandem repeat (STR) markers were genotyped in all available samples to validate genomic dosage and inheritance. A web-application was built as a forum for future data sharing. CNV analysis identified 49 subjects with heterozygous <i>SNCA</i> duplication (CNV3), 2 with homozygous duplication (CNV4) and 7 with a triplication mutation (CNV4). Clinical presentations varied greatly throughout the cohort. <i>SNCA</i> dosage correlates with disease onset (mean age of onset CNV3: 46.9 ± 10.5 years vs. 34.5 ± 7.4 CNV4, <i>p</i> = 0.003). Atypical or more severe clinical courses were described in several patients and dementia was noted in 50.9% of the probands. Neither the multiplication size (average 2.05 ± 2.45 Mb) nor the number of genes included (range 1-50) was associated with motor symptom onset or dementia. Families with <i>SNCA</i> multiplication are rare and globally-distributed. Nevertheless, they may both inform and benefit from the development of <i>SNCA</i> targeted therapeutic strategies relevant to the treatment of all alpha-synucleinopathies.