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Multiple system atrophy
Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic failure (cardiovascular and/or urinary), parkinsonism, cerebellar impairment and corticospinal signs with a median survival of 6-9 years.
ORPHA:102Classification level: Disorder
Prevalence ranges from 1/50,000-1/20,000. MSA-parkinsonian type (MSA-p) predominates in the Western Hemisphere and MSA-cerebellar type (MSA-c) predominates in the Eastern Hemisphere. Genders are equally distributed.
MSA is an adult-onset disorder (>30 years, mean age 55-60 years). Clinical manifestations include autonomic failure (orthostatic hypotension, syncope, respiratory disturbances (sleep apnea, stridor and inspiratory sighs), constipation, bladder dysfunction (early urinary incontinence), erectile dysfunction in males and Raynaud syndrome). In some cases, pyramidal signs (generalized hyperreflexia and positive Babinski sign) are observed. MSA-p, a form of MSA with predominant parkinsonian features, comprises bradykinesia, rigidity, irregular jerky postural tremor and abnormal postures (camptocormia, Pisa syndrome and disproportionate antecollis). Patients with MSA-p may develop levodopa-induced orofacial and craniocervical dystonia. Classic pill-rolling rest tremor is uncommon. MSA-c is a form of MSA with predominant cerebellar features such as gait and limb ataxia, oculomotor dysfunction and dysarthria. The predominant motor feature can change with time and patients with cerebellar ataxia can develop increasingly severe parkinsonian features which dominate the clinical presentation. Neuropsychiatric features, oculomotor dysfunction and sleep disturbances are also observed in MSA and include apathy, anxiety, depression, rapid eye movement sleep behavior disorder and periodic limb movements in sleep.
Etiology of MSA is unknown but presence of cytoplasmic aggregates of α-synuclein, primarily in oligodendroglia, in combination with neurodegeneration in striatonigral and olivopontocerebellar structures are the pathological hallmark features. Mutations in COQ2 (4q21.23) (encoding an enzyme involved in biosynthesis of coenzyme Q10) have been shown in multiplex families with MSA, while some variants were associated with an increased risk for sporadic MSA.
Diagnosis of ''probable'' MSA requires presence of parkinsonism with poor levodopa response or cerebellar signs together with severe autonomic failure (otherwise unexplained urinary incontinence or an orthostatic decrease of blood pressure within 3 min of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic). MRI findings include atrophy of putamen and middle cerebellar peduncles, as well as putaminal and cerebellar hypometabolism on [18F]-fluorodeoxyglucose positron emission tomography. ''Definite'' MSA requires post-mortem demonstration of α-synuclein positive glial cytoplasmic inclusions with neurodegeneration of striatonigral and olivopontocerebellar structures.
Differential diagnosis of MSA-p includes Parkinson's disease and other atypical parkinsonian disorders (progressive supranuclear palsy, corticobasal syndrome). Differential diagnosis of MSA-c includes dominantly inherited spinocerebellar ataxias (SCAs 1, 2, 3, 6, and 7), fragile X-associated tremor/ataxia syndrome (FXTAS) and mitochondriopathies (POLG1 gene mutations).
MSA occurs sporadically. However, some familial cases have been described.
Management and treatment
Therapy mainly targets parkinsonism and autonomic failure. Levodopa may transiently improve parkinsonism (20-30% of patients). No effective neuroprotective therapy is available.
MSA is rapidly progressive and is associated with wheelchair dependence, unintelligible speech, intermittent urinary catheterization, disabling orthostatic hypotension, and cognitive impairment (executive dysfunction). Disease progression is assessed using the unified MSA rating scale (UMSARS), which rates activities of daily life, autonomic and motor impairment, as well as overall disability. Prognosis is poor with a median survival of 6-9 years.
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