Original Research ARTICLE
A meta-analysis of α-Synuclein multiplication in familial parkinsonism
- 1Centre for Applied Neurogenetics (CAN), Canada
- 2INSERM U1127 Institut du Cerveau et de la Moelle épinière, France
- 3Département de Génétique, Hôpitaux Universitaires Pitié Salpêtrière, France
- 4Sorbonne Universités, France
- 5Department of Neurology, School of Medicine, Juntendo University, Japan
- 6Department of Neurology, Seoul National University Hospital, South Korea
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±2.45Mb) nor the number of genes included (range 1 to 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, Duplications, triplications, parkinsonism, Dementia, clinical phenotype
Received: 23 Aug 2018;
Accepted: 13 Nov 2018.
Edited by:Clara Van Karnebeek, University Medical Center Amsterdam, Netherlands
Reviewed by:Jordi Clarimon, Sant Pau Institute for Biomedical Research, Spain
Georgios Koutsis, National and Kapodistrian University of Athens Medical School, Greece
Copyright: © 2018 Book, Guella, Candido, Brice, Hattori, Jeon and Farrer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Matthew J. Farrer, Centre for Applied Neurogenetics (CAN), Vancouver, British Columbia, Canada, firstname.lastname@example.org