Heterogeneity of Multiple System Atrophy: An Update

Multiple system atrophy (MSA) is a fatal, rapidly progressing neurodegenerative disease of uncertain etiology, clinically characterized by various combinations of Levodopa unresponsive parkinsonism, cerebellar, autonomic and motor dysfunctions. The morphological hallmark of this alpha-synucleinopathy is the deposition of aberrant alpha-synuclein in both glia, mainly oligodendroglia (glial cytoplasmic inclusions /GCIs/) and neurons, associated with glioneuronal degeneration of the striatonigral, olivopontocerebellar and many other neuronal systems. Typical phenotypes are MSA with predominant parkinsonism (MSA-P) and a cerebellar variant (MSA-C) with olivocerebellar atrophy. However, MSA can present with a wider range of clinical and pathological features than previously thought. In addition to rare combined or mixed MSA, there is a broad spectrum of atypical MSA variants, such as those with a different age at onset and disease duration, minimal change or prodromal forms, MSA variants with Lewy body disease or severe hippocampal pathology, rare forms with an unusual tau pathology or spinal myoclonus, an increasing number of MSA cases with cognitive impairment/dementia, rare familial forms, and questionable conjugal MSA. These variants that do not fit into the current classification of MSA are a major challenge for the diagnosis of this unique proteinopathy. Although the clinical diagnostic accuracy and differential diagnosis of MSA have improved by using combined biomarkers, its distinction from clinically similar extrapyramidal disorders with other pathologies and etiologies may be difficult. These aspects should be taken into consideration when revising the current diagnostic criteria. This appears important given that disease-modifying treatment strategies for this hitherto incurable disorder are under investigation.

Automated summary

Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by a combination of Levodopa unresponsive parkinsonism, cerebellar, autonomic and motor dysfunctions. The deposition of aberrant alpha-synuclein in glia and neurons is a morphological hallmark of MSA, along with glioneuronal degeneration. MSA can present in different variants and its diagnosis can be challenging.