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Background:   Methylation of two CpG sites related to neuronal pentraxin II protein (NPTX2) and SH2 domain containing 5 protein (SH2D5), corresponding to two neuroplasticity genes, has been associated to headache chronification. We aimed to investigate the epigenetic modification of these two genes in chronic migraine (CM).Methods:   We conducted a case–control study in which the DNA of 305 age- and sex-matched subjects classified according to the International Classification of Headache Disorders version beta (ICHD-III β) in CM (109), episodic migraine (EM; n = 98), and healthy controls (HC; 98) was analyzed. Real-time quantitative methylation-specific PCR was performed using specific methylation primers for two representative CpG sites within these genes.Results:   We found no significant differences in methylation level between CM, EM, and HC in the first exon of the NPTX2 gene nor in the 5′ upstream region of the SH2D5 gene. Methylation level in the first exon of the NPTX2 showed a low correlation with age ( r = 0.266; p &lt; 0.005).Conclusion:   We did not find methylation level differences in analyzed regions related to NPTX2 and SH2D5 in our CM sample. Despite the potential relevance of neuroplasticity genes in headache chronification, we conclude that CM is a more heterogeneous clinical diagnosis than desired and that an epigenetic marker remains elusive.

Methylation analysis of NPTX2 and SH2D5 genes in chronic migraine: A case–control study