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Original Investigation
September 2014

A 6.4 Mb Duplication of the α-Synuclein Locus Causing Frontotemporal Dementia and Parkinsonism: Phenotype-Genotype Correlations

Author Affiliations
  • 1Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
  • 2The Queen Square Brain Bank, UCL Institute of Neurology, London, United Kingdom
  • 3Department of Clinical Neuroscience, UCL Institute of Neurology, London, United Kingdom
  • 4Department of Neurology, Frenchay Hospital, Bristol, United Kingdom
  • 5Department of Neuropathology, Frenchay Hospital, Bristol, United Kingdom
  • 6Biomedical Research Centre, UCL, London, United Kingdom
  • 7Education Unit, UCL Institute of Neurology, Queen Square, London, United Kingdom
  • 8Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland
  • 9Department of Academic Hematology, Royal Free Campus, UCL, London, United Kingdom
  • 10Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, United Kingdom
  • 11MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom
JAMA Neurol. 2014;71(9):1162-1171. doi:10.1001/jamaneurol.2014.994
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 Participants  We 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 Measures  We assessed whether length of the SNCA locus duplication influences disease penetrance and severity and whether extraduplication factors have a disease-modifying role.

Results  We 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.

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