Multiple system atrophy (MSA) is a rare neurological condition, affecting 15,000 to 50,000 Americans and 200 of every 5 million people worldwide. Like Parkinson’s disease (PD), MSA is a synucleinopathy, associated with the accumulation of misfolded alpha-synuclein. MSA is often initially erroneously diagnosed as Parkinson’s disease because patients may exhibit similar symptoms, such as rigidity, slowness, gait, and speech difficulties.1 Distinct from typical Parkinson’s disease, people with MSA may experience rapid progression within 5 to 10 years of symptom onset, as well as severe autonomic and cerebellar dysfunction. Pathologically, research indicates that alpha-synuclein accumulates in the neurons in greater quantities in people with MSA compared to PD.
Adding to the body of research focused on this condition is a study recently published in Neuron, aimed at studying genetic risk factors for MSA; in this study, researchers identified new risk loci significantly associated with MSA. 1
“Identifying genetic risk loci is at the heart of efforts to understand the pathogenesis of MSA and inform translational efforts,” note the study authors, who examined the genomes of 888 patients diagnosed with MSA and 7128 controls, all with European ancestry.
Of those with MSA, 47% had clinically probable and 53% had pathologically definite disease based on Gilman consensus criteria. The MSA cohort was 47% female and an average of 64 years old. Control subjects were sourced from the DEMENTIA-SEQ project (n=3018) and the TOPMed consortium (n=4110) and were selected based on a lack of cognitive decline and neurological deficits.
A genome-wide association study (GWAS) of approximately 9.2 million variants identified locus at chromosomes 4q31.21, pointing to the GAB1 gene which encodes a scaffolding protein regulating oligodendrocyte development. A recessive analysis identified additional locus at chromosomes 5q34, within a gene which encodes a protein involved in neuronal migration, signaling and cell adhesion, A second risk locus identified under the recessive model was located on chromosome 7q11.21; this locus may be pleomorphic in MSA with. mutations in KCTD7, known to be associated with a progressive myoclonic epilepsy syndrome linked to potassium channels, and highly expressed in the cerebellum and modulating neuronal excitability. A transcriptome-wide association study implicated USP38-DT, linked to expression of a gene necessary for α-synuclein-mediated endocytosis. GWAS further showed that variations in COQ2, MAPT, SNCA, ZIC1-ZIC4, and PLA2G4C, all previously reported to be associated with MSA, showed no association with MSA in this study sample. This lack of evidence of common genetic variation in the European and Northern American populations studied highlights the need for further genetic analyses, including the study of MSA in racially and ethnically diverse populations
The genomic resource developed by the authors “advances the understanding of MSA’s pathogenesis and paves the way for modeling the disease and developing targeted treatments,” said the authors.
References:
- Multiple system atrophy. National Institutes of Health. Updated July 19, 2024. Accessed September 27, 2024. https://www.ninds.nih.gov/health-information/disorders/multiple-system-atrophy
