Clinical Autonomic Research

, Volume 25, Issue 1, pp 19–36 | Cite as

Multiple system atrophy: the application of genetics in understanding etiology

  • Monica Federoff
  • Lucia V. Schottlaender
  • Henry Houlden
  • Andrew Singleton
Review Article
First Online:
Received:
Accepted:

Abstract

Classically defined phenotypically by a triad of cerebellar ataxia, parkinsonism, and autonomic dysfunction in conjunction with pyramidal signs, multiple system atrophy (MSA) is a rare and progressive neurodegenerative disease affecting an estimated 3–4 per every 100,000 individuals among adults 50–99 years of age. With a pathological hallmark of alpha-synuclein-immunoreactive glial cytoplasmic inclusions (GCIs; Papp–Lantos inclusions), MSA patients exhibit marked neurodegenerative changes in the striatonigral and/or olivopontocerebellar structures of the brain. As a member of the alpha-synucleinopathy family, which is defined by its well-demarcated alpha-synuclein-immunoreactive inclusions and aggregation, MSA’s clinical presentation exhibits several overlapping features with other members including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Given the extensive fund of knowledge regarding the genetic etiology of PD revealed within the past several years, a genetic investigation of MSA is warranted. While a current genome-wide association study is underway for MSA to further clarify the role of associated genetic loci and single-nucleotide polymorphisms, several cases have presented solid preliminary evidence of a genetic etiology. Naturally, genes and variants manifesting known associations with PD (and other phenotypically similar neurodegenerative disorders), including SNCA and MAPT, have been comprehensively investigated in MSA patient cohorts. More recently variants in COQ2 have been linked to MSA in the Japanese population although this finding awaits replication. Nonetheless, significant positive associations with subsequent independent replication studies have been scarce. With very limited information regarding genetic mutations or alterations in gene dosage as a cause of MSA, the search for novel risk genes, which may be in the form of common variants or rare variants, is the logical nexus for MSA research. We believe that the application of next generation genetic methods to MSA will provide valuable insight into the underlying causes of this disease, and will be central to the identification of etiologic-based therapies.

Keywords

Genome-wide association Linkage analysis Genetic risk Mutation 
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Notes

Acknowledgments

The authors work is supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project ZO1 AG000958.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Monica Federoff
    • 1
    • 2
  • Lucia V. Schottlaender
    • 2
  • Henry Houlden
    • 2
  • Andrew Singleton
    • 1
  1. 1.Laboratory of Neurogenetics, National Institute on AgingNational Institutes of HealthBethesdaUSA
  2. 2.Department of Molecular NeuroscienceUCL Institute of NeurologyLondonUK

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