Table 1.

Frequent causes of C1 metabolic disorders.

Cellular deficiency in one or more of the vitamins B6, B12 and folate:

(a) Insufficient intake via food: Vitamin B12 deficiency in vegetarians and vegans, who do not supplement vitamin B12 [18,19]. All three vitamins in elderly subjects, especially in nursing homes [18,20]. Pronounced folic acid deficiency in industrialized countries around the world [21,22]. It is the main reason for folic acid supplementation in more than 70 countries [23]. (b)Loss due to inadequate preparation, especially for folic acid [24]. (c)Increased need during pregnancy, lactation and hemodialysis. (d)Insufficient intestinal absorption: unspecific in celiac disease, inflammatory bowel diseases and resections, specific for B12 with intrinsic factor deficiency or auto-antibodies against parietal cells [25,26]. (e)Intracellular, metabolic causes, e.g., accumulation of 5-methyl-THF in the case of pronounced B12 deficiency (“folic acid trap”), leading to a deficiency of THF-dependent C1 compounds, despite adequate folic acid intake [6,7]. (f)Side effects of pharmaceuticals on absorption or metabolism of particular vitamins, e.g., anticonvulsant drugs, levodopa, metformin [27].

Common genetic variants in C1 metabolism:

(a)MTHFR: C677T point mutation in homozygous form (TT) in 12–15% of the European population, which can be compensated by adequate folic acid intake [28]. Combined occurrence of the heterozygous form (CT) with the heterozygous form (AC) of another point mutation—A1298C—is relatively common (approximately 25%) and can be associated with various disturbances [29,30]. (b)CBS: About 230 known mutations that are rarely homozygous. In the heterozygous form, they potentially occur in around 1% of the European population [31].

Lifestyle factors (the underlying mechanisms are often not clear or multifactorial and usually linked to their effect on plasma HCys level):

(a)Acquired reductions in the activity of enzymes, e.g., methionine synthase due to acetaldehyde in alcoholics [32]. (b)Cigarette smoking appears as an independent determinant of HCys levels, with an increase in approx. 1% per cigarette smoked [33]. (c)Relatively large amounts of coffee consumption are necessary to increase HCys [34].

Oxidative stress:

Particularly nitric oxide inhibits methionine synthase directly, as well as by binding cobalamin [35]. Consequently, increase in plasma HCys is accompanied by that of markers of NO formation, e.g., citrulline. In addition, methylmalonic acid strongly increases as NO inhibits cobalamin transport from cytosol into mitochondria [36].