Objective: To analyze candidate genes in a cohort of 87 patients with a clinical diagnosis of probable MSA.

Background: Multiple System Atrophy (MSA) is a rare adult-onset neurodegenerative disorder that leads to severe motor disability and death after few years from symptom-onset. The pathological hallmarks comprise widespread α-synuclein glial cytoplasmic inclusions (GCIs), striatonigral and olivopontocerebellar degeneration. Although MSA has been considered to be a non-genetic disorder, several groups have described affected members belonging to the same families. Genes involved in Parkinson’s disease and other neurodegenerative disorders, including SNCA and GBA, have been screened in MSA cohorts without conclusive evidences of a causative role. Recently, the identification of rare variants in the COQ2 gene in familial and sporadic MSA Japanese patients has broadened the spectrum of genes possibly involved in the etiology of MSA.

Methods: Clinical diagnosis was performed according to current consensus criteria. After written informed consent, blood samples were collected. DNA was blood-extracted according standard procedures. Coding sequences of COQ2, GBA and SNCA were directly sequenced by Sanger approach. Copy number variation of SNCA locus was also assessed by quantitative PCR. Genetic loci associated with some dominant SCA presentations were investigated for aberrant repeat expansions by fragment Gene Scan analysis and RP-PCR protocols.

Results: We performed a genetic analysis in 87 patients diagnosed with probable MSA, including GBA, SNCA and COQ2 genes. Moreover, several candidate genes involved in genetic form of cerebellar ataxia have been studied in the subset of MSA-C patients (n=36), including SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12 and SCA17. No mutations were identified in SNCA. GBA variants had the same frequencies of controls. No expansions in the pathological range were detected at SCA loci. Novel heterozygous variants (p.N180S and p.H303P) in the COQ2 gene were found in two patients diagnosed with sporadic MSA-C, but their pathogenic role is still uncertain.

Conclusions: The analysis of candidate genes in our cohort of MSA patients did not detect pathogenic mutations. An additional effort is required to identify genes associated with MSA and to clarify the pathogenesis of this rare disorder.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-analysis-of-eighty-seven-multiple-system-atrophy-patients/