Evidence for the Causal Involvement of Homocysteine in Long COVID and ME/CFS

Long COVID (LC) and ME/CFS affect many millions of individuals, yet a satisfactory mechanistic explanation of their diverse manifestations remains elusive. Common symptoms are wide-ranging and include fatigue, post-exertional malaise, cognitive impairment (‘brain fog’), Postural Orthostatic Tachycardia Syndrome (POTS), microvascular and endothelial dysfunction, exercise intolerance, sleep disturbances, fibromyalgia, dyspnoea, small-fibre neuropathy and hearing and olfactory disorders. Homocysteine (Hcy) is a non-proteinogenic, sulphur-containing amino acid generated during methionine metabolism, that can be converted to a thiolactone that will react with the e-amino groups of protein lysine residues causing widespread dysfunction. Hyperhomocysteinaemia can arise from genetic causes or through an inadequacy of certain B vitamins. We here develop and evidence the hypothesis that raised homocysteine (Hcy), its conversion to homocysteine thiolactone (HTL), and the consequent N-homocysteinylation of proteins contribute to at least a subset of the manifestations of LC and ME/CFS. This has both testable predictions and therapeutic consequences.