Hypomethylation of SNCA in Idiopathic REM Sleep Behavior Disorder Associated With Phenoconversion

Background Hypomethylation of intron 1 of the alpha-synuclein (SNCA) gene has been extensively reported in the blood of patients with alpha-synucleinopathies. Idiopathic rapid eye movement sleep behavior disorder represents a prodromal stage of alpha-synucleinopathies. Methylation of alpha-synuclein intron 1 in idiopathic rapid eye movement sleep behavior disorder patients is largely unexplored. The objective of the current study was to assess blood alpha-synuclein intron 1 methylation in patients and to explore it as a potential biomarker to predict phenoconversion and monitor disease progression. Methods Seventy-eight polysomnography-confirmed patients and 74 healthy controls were enrolled. After an average of 3.75 years of follow up, 16 patients converted to neurodegenerative diseases (converters), whereas 59 did not (nonconverters). Blood DNA was obtained at baseline from all participants, as well as at the follow-up visit for 27 patients. DNA methylation levels were determined using bisulfite pyrosequencing methods and were compared between patients and healthy controls, converters and nonconverters, and baseline and follow-up visits. Results Hypomethylation at cytosine-phosphate-guanine 10, 11, 12, 13, and 17 was found in patients compared with healthy controls. Hypomethylation at cytosine-phosphate-guanine 17 was associated with an increased risk of clinical phenoconversion, which was further enhanced with the presence of subtle motor abnormalities. In addition, it appeared that later reduction in methylation levels at cytosine-phosphate-guanine 14, 15, and 16 was associated with disease progression. Conclusions Peripheral blood alpha-synuclein intron 1 was hypomethylated in idiopathic rapid eye movement sleep behavior disorder patients. alpha-Synuclein methylation levels may be useful biomarkers to screen patients, predict phenoconversion, and monitor disease progression. (c) 2020 International Parkinson and Movement Disorder Society