Abstract
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 α-synucleinopathy is the deposition of aberrant α-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.
Highlights
Multiple system atrophy (MSA) is a rare and fatal adult-onset neurodegenerative disease of an uncertain etiology that has a variety of clinical and pathological variants.Belonging to the group of α-synucleinopathies, it is a unique proteinopathy with a specific glioneuronal degeneration involving striatonigral, olivopontocerebellar (OPC), autonomic and peripheral neuronal systems [1]
Other studies have shown that the overexpression of αSyn by oligodendrocytes in transgenic mice does not recapitulate the fibrillary aggregation seen in glial cytoplasmic inclusions (GCIs) in a human MSA brain, which could help to establish a link between αSyn aggregation in the development of a clinical phenotype of MSA [52]
MSA is generally considered a sporadic disorder, and a family history of ataxia or parkinsonism has been defined as a non-supporting feature in the current diagnostic criteria [2], but MSA pedigrees with both autosomal-dominant and autosomal-recessive inheritance have been observed in Europe and Asia [84–88], and there are reports of autopsy-proven MSA [89]
Summary
Multiple system atrophy (MSA) is a rare and fatal adult-onset neurodegenerative disease of an uncertain etiology that has a variety of clinical and pathological variants. Cerebellar ataxia, widespread gait, uncoordinated limb movements, action tremor and spontaneous or gaze-invoked nystagmus predominate MSA-C [24] These patients usually have a shorter delay with disease duration, RBD prevalence and cognitive assessment scores being similar, while the burden of autonomic symptoms is usually higher in MSA-P patients [25]. The neuropathology of MSA-P shows frontal atrophy, severe atrophy and discoloration of the striatum, and depigmentation of the substantia nigra (SN) and locus ceruleus (LC), whereas MSA-C presents atrophy of the paleo- and neocerebellum, superior cerebellar peduncle, basis pontis and inferior olivary nucleus Both phenotypes with a similar disease severity and duration have a differential distribution of gray and white matter atrophy, but white matter impairment is more severe in MSA than previously thought [30]. GCIs and the resulting neurodegeneration show a characteristic distribution, involving the striatonigral and OPC systems, and multiple cortical regions, autonomic and motor nuclei in brainstem, as well as spinal cord autonomic nerve structures and the peripheral nervous system [1,36,37], characterizing MSA as a multi-system/-organ disorder [1,38]
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