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Konzo, a disease characterized by sudden, irreversible spastic paraparesis, affecting up to 10% of the population in some regions of Sub-Saharan Africa during outbreaks, is strongly associated with dietary exposure to cyanogenic bitter cassava. The molecular mechanisms underlying the development of konzo remain largely unknown. Here, through an analysis of 16 individuals with konzo and matched healthy controls from the same outbreak zones, we identified 117 differentially methylated loci involved in numerous biological processes that may identify cyanogenic-sensitive regions of the genome, providing the first study of epigenomic alterations associated with a clinical phenotype of konzo., (© 2022. The Author(s).)