MTHFR and LC, CFS, POTS, MCAS, SIBO, EDS: Methylating the Alphabet

Long Covid (LC), Chronic Fatigue Syndrome (CFS), Postural Orthostatic Tachycardia Syndrome (POTS), Mast Cell Activation Syndrome (MCAS), Small Intestine Bacterial Overgrowth (SIBO), and Ehlers-Danlos Syndrome (EDS) are all loosely connected, some poorly defined, some with overlapping symptoms. The female preponderance, the prominence of fatigue and chronic inflammation, and methylenetetrahydrofolate reductase (MTHFR) abnormalities may connect them all. Indeed differential methylation may lie at the root. Two - EDS and MTHFR - are genetic. But epigenetic factors may ultimately determine their phenotypic expression. Oxidative stress, overloaded mitochondria, an antioxidant and nutrient shortfall, and suboptimal gut microbiome appear to be the primary determinants. A deep dive into the folate and methionine cycles is undertaken in an attempt to connect these syndromes. The active forms of vitamin D and vitamins B2,3,6,9,12 are shown to be biochemically integral to optimal methylation and control of the epigenome. Their status largely determines the symptoms of abnormal MTHFR in all its phenotypes. The wider implications for aging, cancer, cardiovascular disease, neurodegenerative disease, and autoimmune disease are briefly explored.