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Review Multiple System Atrophy
Understanding Multiple System Atrophy—
Could Genetics Lead the Way?
Miriam Sklerov, Cheryl Waters
Division of Movement Disorders, Department of Neurology, Columbia University Medical Center, New York, US
M ultiple system atrophy (MSA) is a progressive, adult-onset, neurodegenerative disorder characterized by parkinsonism, cerebellar
ataxia, autonomic failure, and corticospinal tract dysfunction. It is considered a rare disease, similar in frequency to the more
well-known neurodegenerative disease amyotrophic lateral sclerosis or Lou Gehrig’s disease. Though MSA has not traditionally been
considered a genetic disease, new evidence is emerging supporting some genetic predisposition in many patients. In this short review, we will
discuss advances in the knowledge of genetics in MSA and how this has furthered our understanding of the pathophysiology of the disease.
There is still much unknown about this disease, but some of the recent advances made in MSA genetics may give important clues to understanding
the pathogenesis and treatment of this disease.
Keywords Multiple System Atrophy, Genetics, Parkinsonism
Disclosure: Miriam Sklerov was supported by NIH/NINDS
T32 NS07153, under funding. Cheryl Waters has nothing to
disclose in relation to this article. No funding was received
for the publication of this article. This article involves a
review of the literature and did not involve any studies
with human or animal subjects performed by any of
Open Access: This article is published under the
Creative Commons Attribution Noncommercial License,
which permits any noncommercial use, distribution,
adaptation, and reproduction provided the original
author(s) and source are given appropriate credit.
Received: June 21, 2016
Accepted: September 13, 2016
Citation: US Neurology, 2016;12(2):110–2
Corresponding Author: Cheryl Waters,
710 West 168th street, 3rd floor, New York, NY 10032.
Multiple system atrophy (MSA) is a is an adult-onset, sporadic, progressive neurodegenerative
disease characterized by a varying combination of parkinsonism, cerebellar ataxia, autonomic failure,
and corticospinal dysfunction. Patients either have a predominance of parkinsonian symptoms
(MSA-P) such that they are often misdiagnosed with Parkinson’s disease, or a predominance
of cerebellar ataxia (MSA-C). Onset is usually in the 6th and 7th decades of life. The prevalence of
MSA is roughly 3–4 per 100,000 in the US. 1 The disease progression tends to be faster than that
of Parkinson’s disease, with an average disease duration of 8–10 years from onset of symptoms
to demise. MSA is neurologically devastating and quickly leaves patients unable walk, speak, and
take care of themselves. Patients suffering from MSA often suffer from orthostatic hypotension
that can be debilitating, urinary retention requiring catheterization, and various breathing problems.
The cause of death in MSA is usually related to dysphagia, respiratory problems, or cardiovascular
complications of dysautonomia. There is a very limited arsenal of medications that can be used
to treat this disease. Currently available treatments are symptomatic, and include medications to
treat parkinsonian symptoms, orthostatic hypotension, urinary symptoms, and sexual dysfunction.
Patients typically get brief and modest responses to these medications. There are no treatments
available to slow down or stop the progression of MSA.
There are no objective, quantitative tests to reliably make or confirm this diagnosis in living patients.
The diagnosis in this disease, as in many movement disorders, is clinical – i.e., it is made based on history,
examination, sometimes using supplementary information such as the results of a magnetic resonance
image (MRI) of the brain, iodine-123-metaiodobenzylguanidine (MIBG) nuclear medicine scan, 2,3 serum
norepinephrine levels, or testing of the autonomic nervous system. 4 The only certain diagnosis is
made with brain autopsy, which shows accumulation of the protein α-synuclein within glial cells
in the brain and degeneration in the striatum and substantia nigra, and/or degeneration in the olivo-
ponto-cerebellar regions of the brain. The lack of highly sensitive and specific confirmatory tests for
the diagnosis of MSA, in addition to the rarity of the disease, have been major factors that have made
research in MSA difficult.
More recently there have been some advances in laboratory and translational research in MSA. In
particular, genetics of MSA has been a recent topic of interest, and is opening new doors in the
understanding of the pathogenesis of MSA. In this short review, we will discuss several past and
recent advances in the knowledge of genetics in MSA and how this has furthered our understanding
of the pathophysiology of the disease and paved the way for novel therapeutic options.
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