Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by tremors, slow movement, muscle rigidity, postural instability (collectively known as parkinsonism), autonomic dysfunction and ataxia. This is caused by progressive degeneration of neurons in several parts of the brain including the basal ganglia, inferior olivary nucleus, and cerebellum. MSA was first described in 1960 by Milton Shy and Glen Drager and is also known as Shy–Drager syndrome.
Many people affected by MSA experience dysfunction of the autonomic nervous system, which commonly manifests as orthostatic hypotension, impotence, loss of sweating, dry mouth, urinary retention and incontinence. Palsy of the vocal cords is an important and sometimes initial clinical manifestation of the disorder.
A prion of the alpha-synuclein protein within affected neurons may cause MSA. About 55% of MSA cases occur in men, with those affected first showing symptoms at the age of 50–60 years. MSA often presents with some of the same symptoms as Parkinson's disease. However, those with MSA generally show little response to the dopamine agonists used to treat Parkinson's disease and only about 9% of MSA patients with tremor exhibit a true parkinsonian pill-rolling tremor (an involuntary, rhythmic movement of the thumb and index finger suggesting the rolling of a pill between them).
MSA is distinct from multisystem proteinopathy, a more common muscle-wasting syndrome. MSA is also different from multiple organ dysfunction syndrome, sometimes referred to as multiple organ failure, and from multiple organ system failures, an often-fatal complication of septic shock and other severe illnesses or injuries.
Signs and symptoms MSA is characterized by autonomic dysfunction and at least one motor abnormality (clinically established MSA criteria 2022): autonomic dysfunction: Post-void urinary residual volume ≥100 mL (usually by ultrasound); unexplained urinary urge incontinence; or neurogenic orthostatic hypotension (≥20/10 mmHg blood pressure drop) within 3 minutes (usually by head‐up tilt) parkinsonism (muscle rigidity +/ tremor and slow movement: MSA-P) cerebellar ataxia (Poor coordination/unsteady walking: MSA-C)
A variant with combined features of MSA and dementia with Lewy bodies may also exist. There have also been occasional instances of frontotemporal lobar degeneration associated with MSA.
Initial presentation The most common first sign of MSA is the appearance of an "akinetic-rigid syndrome" (i.e. slowness of initiation of movement resembling Parkinson's disease) found in 62% at first presentation. Other common signs at onset include problems with balance (cerebellar ataxia) found in 22% at first presentation, followed by genito-urinary symptoms (9%); both men and women often experience urgency, increased frequency, incomplete bladder emptying, or an inability to pass urine (retention). About 1 in 5 MSA patients experience a fall in their first year of disease.
For men, the first sign can be erectile dysfunction. Women have also reported reduced genital sensitivity.
Progression As the disease progresses, one of three groups of symptoms predominates. These are: Parkinsonism – slow, stiff movement, writing becomes small and spidery Cerebellar dysfunction – difficulty coordinating movement and balance Autonomic nervous system dysfunction – impaired automatic body functions, including one, some, or all of the following: postural or orthostatic hypotension, resulting in dizziness or fainting upon standing up urinary incontinence or urinary retention impotence constipation vocal cord paralysis dry mouth and skin trouble regulating body temperature due to sweating deficiency in all parts of the body loud snoring, abnormal breathing or inspiratory stridor during sleep other sleep disorders including sleep apnea, REM behavior disorder double vision muscle twitches cognitive impairment
Genetics Variations in the gene that encodes alpha-synuclein may play a role in MSA.
One study found a correlation between the deletion of genes in a specific genetic region and the development of MSA in a group of Japanese patients. The region in question includes the SHC2 gene which, in mice and rats, appears to have some function in the nervous system. The authors of this study hypothesized that there may be a link between the deletion of the SHC2 and the development of MSA.
A follow-up study was unable to replicate this finding in American MSA patients. The authors of the study concluded that "Our results indicate that SHC2 gene deletions underlie few, if any, cases of well-characterized MSA in the US population. This is in contrast to the Japanese experience reported by Sasaki et al., likely reflecting heterogeneity of the disease in different genetic backgrounds."
Another study investigated the frequency of RFC1 intronic repeat expansions, a phenomenon implicated in CANVAS (a disease with a diagnostic overlap with MSA). The study concluded that these repeats were absent in pathologically confirmed MSA, suggesting an alternative genetic cause.
Pathophysiology
The defining pathologic feature of multiple system atrophy is the presence of inclusion bodies (known as glial cytoplasmic inclusions or Papp-Lantos bodies) consisting of alpha-synuclein in oligodendrocytes. In addition, neurons are lost in several regions of the nervous system, particularly in the basal ganglia, inferior olivary nuclei, cerebellum, pons, and spinal cord. Reactive astrocytes and microglia are prominent in damaged areas of the central nervous system, especially in regions with abundant oligodendroglial inclusions. Neuronal cytoplasmic inclusions also are present in MSA, although these are much less numerous than are oligodendroglial inclusions. Inclusions sometimes occur in the cell nucleus of neurons and oligodendrocytes. Outside of the central nervous system, alpha‐synuclein inclusions may be found in Schwann cells of cranial, spinal and autonomic nerves and in the enteric nervous system.
The major proteinaceous component of glial and neuronal inclusions in MSA is alpha-synuclein that is phosphorylated at serine residue 129. The conformation of alpha-synuclein in MSA is different from that of alpha-synuclein in Lewy bodies, indicative of variant proteopathic strains. In addition to variations in the gene for alpha-synuclein, a variety of other potential genetic and environmental risk factors have been proposed.
The origin of the alpha-synuclein that forms inclusions in oligodendrocytes is uncertain. Compared to neurons, oligodendrocytes produce little or no alpha-synuclein themselves, suggesting that these cells take up the protein that is generated by neurons. For example, it has been proposed that the α-synuclein inclusions found in oligodendrocytes result from the pruning and engulfment of diseased axonal segments containing aggregated α-synuclein, i.e., of Lewy neurites. Research has shown that the strain of the protein generated by oligodendrocytes causes a more aggressive type of disease than does the Lewy body strain. The factors in oligodendrocytes that induce the formation of especially potent alpha-synuclein seeds are not known.
Along with the primary protein alpha-synuclein, glial cytoplasmic inclusions contain several other types of protein as well as lysosomes and peroxisomes. Tau proteins (the main components of neurofibrillary tangles) have been found in some glial cytoplasmic inclusions.
Diagnosis
Clinical Clinical diagnostic criteria were defined in 1998 and updated in 2007 and in 2022. Certain signs and symptoms of MSA also occur with other disorders, such as Parkinson's disease, making the diagnosis more difficult.
Features characteristic of OPCA include progressive cerebellar ataxia, leading to clumsiness in body movements, veering from midline when walking, wide-based stance, and falls without signs of paralysis or weakness. Clinical presentation can vary greatly between patients, but mostly affects speech, balance and walking. Other possible neurological problems include spasmodic dysphonia, hypertonia, hyperreflexia, rigidity, dysarthria, dysphagia and neck dystonic posture. Dysarthria is characterized by increased pauses of irregular duration, impaired coordination of vocal pitch, prolonged syllables and an overall irregular speech rhythm. Diagnosis may be based on a thorough medical exam; the presence of signs and symptoms; imaging studies; various laboratory tests; and an evaluation of the family history.
Radiologic
Both MRI and CT scanning may show a decrease in the size of the cerebellum and pons in those with cerebellar features (MSA-C). The putamen is hypointense on T2-weighted MRI and may show an increased deposition of iron in the Parkinsonian (MSA-P) form. In MSA-C, a "hot cross bun" sign is sometimes found; it reflects atrophy of the pontocerebellar tracts that give T2 hyper intense signal intensity in the atrophic pons.
MRI changes are not required to diagnose the disease as these features are often absent, especially early in the course of the disease. Additionally, the changes can be quite subtle and are usually missed by examiners who are not experienced with MSA.
Pathologic Pathological diagnosis can only be made at autopsy by finding abundant glial cytoplasmic inclusions (GCIs) on histological specimens of the central nervous system.
Olivopontocerebellar atrophy can be used as a pathological term to describe degeneration of neurons in specific areas of the brain – the cerebellum, pons, and inferior olivary nucleus. OPCA is present in several neurodegenerative syndromes, including inherited and non-inherited forms of ataxia (such as the hereditary spinocerebellar ataxia known as Machado–Joseph disease) and MSA, with which it is primarily associated.
Contrary to most other synucleinopathies, which develop α-synuclein inclusions primarily in neuronal cell populations, MSA presents with extensive pathological α-synuclein inclusions in the cytosol of oligodendrocytes (glial cytoplasmic inclusions), with limited pathology in neurons. MSA also differs from other synucleinopathies in its regional pathological presentation, with α-synuclein positive inclusions detected predominantly in the striatum, midbrain, pons, medulla and cerebellum, rather than the brainstem, limbic and cortical regions typically effected in Lewy inclusion diseases. However, recent studies using novel, monoclonal antibodies specific for C-terminally truncated α-synuclein (αSynΔC) have now shown that neuronal α-synuclein pathology is more abundant than previously thought. One group revealed robust α-synuclein pathology in the pontine nuclei and medullary inferior olivary nucleus upon histological analysis of neurological tissue from MSA patients. Histopathological investigation on six cases of pathologically confirmed MSA, using antibodies directed at a variety of α-synuclein epitopes, revealed substantial variation in α-synuclein protein deposition across both cases and brain regions within cases, providing evidence for 'strains' of aggregated conformers that may differentially promote pathological prion-like spread.
In 2020, researchers at The University of Texas Health Science Center at Houston concluded that protein misfolding cyclic amplification could be used to distinguish between two progressive neurodegenerative diseases, Parkinson's disease and multiple system atrophy, being the first process to give an objective diagnosis of Multiple System Atrophy instead of just a differential diagnosis.
Classification MSA is one of several neurodegenerative diseases known as synucleinopathies: they have in common an abnormal accumulation of alpha-synuclein protein in various parts of the brain. Other synucleinopathies include Parkinson's disease, the Lewy body dementias, and other more rare conditions.
Old terminology