DMGDH (dimethylglycine dehydrogenase) is a mitochondrial matrix flavoprotein that catalyzes the oxidative demethylation of N,N-dimethylglycine to sarcosine, playing a crucial role in choline catabolism and one-carbon metabolism 12. The enzyme contains covalently bound FAD and utilizes tetrahydrofolate (THF) as a cofactor to capture formaldehyde produced during the reaction, forming 5,10-methylenetetrahydrofolate and preventing formaldehyde toxicity 34. DMGDH deficiency, caused by mutations such as H109R, results in a rare inborn error of metabolism characterized by fish-like body odor 15. Beyond metabolic function, DMGDH has clinical significance as a tumor suppressor in hepatocellular carcinoma, where decreased expression correlates with increased metastasis through Akt signaling pathway modulation 6. Genetic variants in DMGDH are associated with diabetes risk, with certain alleles linked to lower DMG levels and increased insulin resistance 7. Additionally, DMGDH variants show significant gene-gene interactions with BHMT in non-syndromic cleft lip/palate risk 8. The enzyme's central role in folate metabolism suggests broader implications for epigenetic regulation and disease susceptibility.