Multiple System Atrophy (MSA)
Multiple System Atrophy (MSA) is a rare neurodegenerative disease that typically occurs in adulthood, with a mean age of onset between 55 and 60 years. It is characterized by the simultaneous involvement of multiple systems within the central nervous system. The hallmark that guides the diagnosis is autonomic nervous system dysfunction. Two main clinical subtypes have been identified: the MSA-P form, characterized by a prevalence of parkinsonian symptoms and more common in Western countries; and the MSA-C form, in which cerebellar disorders predominate, more widespread in East Asia..
The origin of MSA remains largely unknown. Unlike Parkinson’s disease, where alpha-synuclein aggregates accumulate within neurons, in MSA these aggregates deposit predominantly in oligodendrocytes, forming abnormal structures called glial cytoplasmic inclusions (or Papp-Lantos bodies). This process leads to the degeneration of key circuits such as the nigrostriatal system and the ponto-cerebellar pathways. The genetic contribution to the disease is still uncertain: the COQ2 gene, involved in coenzyme Q10 synthesis, has been associated with some familial forms of MSA, but the available data are still controversial and inconclusive.
The clinical presentation of MSA is heterogeneous and depends on the predominant subtype, but in general, significant autonomic symptoms are found, such as symptomatic orthostatic hypotension, syncope, severe constipation, and bladder function disorders. These are accompanied by neurological symptoms that may include parkinsonism poorly responsive to levodopa, cerebellar signs such as instability and dysarthria, nocturnal respiratory disorders (including typical laryngeal stridor), and signs of pyramidal system impairment.
The diagnosis of MSA is based on internationally recognized clinical criteria. To formulate a diagnosis of “probable MSA,” the presence of severe autonomic dysfunction is required—for example, urinary dysfunction or impaired blood pressure control (a decrease of at least 30 mmHg in systolic pressure or 15 mmHg in diastolic pressure after 3 minutes of standing)—associated with either atypical parkinsonism (unresponsive or poorly responsive to levodopa) or evident cerebellar signs, such as ataxia or motor incoordination. Brain imaging, particularly brain Magnetic Resonance Imaging (MRI), represents an important diagnostic support. Among the most indicative findings are atrophy of the putamen and cerebellum, the “hot-cross bun” sign in the pons, and signal alterations in the middle cerebellar peduncles. Although no single test is definitive on its own, the combination of clinical signs and neuroradiological findings can lead to a diagnosis with good accuracy.
Available therapies
Currently, there are no disease-modifying treatments capable of altering the natural course of MSA. Therapeutic management is therefore symptomatic and aims to improve the patients’ quality of life. Some individuals with the parkinsonian form (MSA-P) may initially respond to levodopa, although less markedly than in Parkinson’s disease. Furthermore, the early development of side effects, such as dyskinesias, orofacial dystonias, and a possible worsening of dysautonomia, is common. The treatment of autonomic symptoms requires a targeted and multidisciplinary approach: the management of orthostatic hypotension may include behavioral measures, pharmacological treatments (fludrocortisone, midodrine), and mechanical supports (compression stockings), while urinary and intestinal motility disorders are addressed with specific and personalized therapies. Rehabilitative care (physiotherapy, speech therapy, occupational therapy) is essential to maintain the patient’s functional autonomy for as long as possible.
Research in progress
The Movement Disorders Research Team at the “Centro Dino Ferrari” is conducting basic research to understand the pathogenic mechanisms of Multiple System Atrophy (MSA). Experimental trials to find potential new therapies for MSA have been active since 2018. Cellular projects are primarily based on the generation of striatal organoids derived from induced pluripotent stem cells (iPSCs) to evaluate the mechanisms of inclusion formation and potential therapies.
Reference laboratory
Contacts and informations
Dott. Alessio Di Fonzo
Mail: alessio.difonzo@policlinico.mi.it
Administrative Office: elena.oriani@policlinico.mi.it