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

Abstract

Chronic alpha-synuclein (SNCA) 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 SNCA multiplication families. Herein we summarize genealogic, clinical and genetic data from 59 families (25 not previously published) with parkinsonism caused by SNCA 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 SNCA multiplication breakpoints to be defined. Three SNCA 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 SNCA duplication (CNV3), 2 with homozygous duplication (CNV4) and 7 with a triplication mutation (CNV4). Clinical presentations varied greatly throughout the cohort. SNCA dosage correlates with disease onset (mean age of onset CNV3: 46.9 ± 10.5 years vs. 34.5 ± 7.4 CNV4, p = 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 SNCA multiplication are rare and globally-distributed. Nevertheless, they may both inform and benefit from the development of SNCA targeted therapeutic strategies relevant to the treatment of all alpha-synucleinopathies.

Keywords: SNCA; clinical phenotype; dementia; duplication; parkinsonism; triplication.

Figure 1

Geographical distribution of SNCA multiplication families. (Top), A map of the world is shown highlighting the geographical regions harboring SNCA multiplication families Map data © 2018 Google. (Bottom), Table summarizing the SNCA Multiplication families presented in this study.

Figure 2

SNCA copy number, disease onset, symptoms, and duration. Cognitive decline and dementia in probands is plotted with respect to motor symptom onset and SNCA copy number. Each row is an individual. DLB is indicated when dementia onset occurred within 12 months of PD onset. Gradient shading is used to indicate cognitive decline of unknown onset. An “X” indicates patients are deceased.

Figure 3

SNCA genomic multiplications. A UCSC Genome Browser (http://genome.ucsc.edu/; hg19) view of the chromosomal region 4q21-14 is shown, together with Refseq genes. SNCA multiplications identified by MEGA CNV analysis are displayed as a custom track in USCS. The horizontal black/red bars represent the SNCA CNV3/4 in each proband. BELSNCA02 SNCA duplication (41.4 Mb) is not shown for scaling reasons.

Figure 4

Age-associated cumulative incidence of Parkinson's disease onset in SNCA multiplications carriers. Kaplan-Meier curves showing differences in cumulative incidence of PD over time, in SNCA duplication (CNV3) and triplication (CNV4) carriers. The shaded area represents the 95% confidence interval.