Genetics of Multiple System Atrophy and Progressive Supranuclear Palsy: A Systemized Review of the Literature

Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are uncommon multifactorial atypical Parkinsonian syndromes, expressed by various clinical features. MSA and PSP are commonly considered sporadic neurodegenerative disorders; however, our understanding is improving of their genetic framework. The purpose of this study was to critically review the genetics of MSA and PSP and their involvement in the pathogenesis. A systemized literature search of PubMed and MEDLINE was performed up to 1 January 2023. Narrative synthesis of the results was undertaken. In total, 43 studies were analyzed. Although familial MSA cases have been reported, the hereditary nature could not be demonstrated. COQ2 mutations were involved in familial and sporadic MSA, without being reproduced in various clinical populations. In terms of the genetics of the cohort, synuclein alpha (SNCA) polymorphisms were correlated with an elevated likelihood of manifesting MSA in Caucasians, but a causal effect relationship could not be demonstrated. Fifteen MAPT mutations were linked with PSP. Leucine-rich repeat kinase 2 (LRRK2) is an infrequent monogenic mutation of PSP. Dynactin subunit 1 (DCTN1) mutations may imitate the PSP phenotype. GWAS have noted many risk loci of PSP (STX6 and EIF2AK3), suggesting pathogenetic mechanisms related to PSP. Despite the limited evidence, it seems that genetics influence the susceptibility to MSA and PSP. MAPT mutations result in the MSA and PSP pathologies. Further studies are crucial to elucidate the pathogeneses of MSA and PSP, which will support efforts to develop novel drug options.