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.
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