One-carbon metabolism in children with marasmus and kwashiorkor

Abstract

Background Kwashiorkor is a childhood syndrome of edematous malnutrition. Its precise nutritional precipitants remain uncertain despite nine decades of study. Remarkably, kwashiorkor's disturbances resemble the effects of experimental diets that are deficient in one-carbon nutrients. This similarity suggests that kwashiorkor may represent a nutritionally mediated syndrome of acute one-carbon metabolism dysfunction. Here we report findings from a cross-sectional exploration of serum one-carbon metabolites in Malawian children.Methods Blood was collected from children aged 12À60 months before nutritional rehabilitation: kwashiorkor (N = 94), marasmic-kwashiorkor (N = 43) marasmus (N = 118), moderate acute malnutrition (N = 56) and controls (N = 46). Serum concentrations of 16 one-carbon metabolites were quantified using LC/MS techniques, and then compared across participant groups.Findings Twelve of 16 measured one-carbon metabolites differed significantly between participant groups. Measured outputs of one-carbon metabolism, asymmetric dimethylarginine (ADMA) and cysteine, were lower in marasmic-kwashiorkor (median µmol/L ( § SD): 0¢549 ( § 0¢217) P = 0¢00045 & 90 ( § 40) P < 0¢0001, respectively) and kwashiorkor (0¢557 ( § 0¢195) P < 0¢0001 & 115 ( § 50) P < 0¢0001), relative to marasmus (0¢698 ( § 0¢212) & 153 ( § 42)). ADMA and cysteine were well correlated with methionine in both kwashiorkor and marasmic-kwashiorkor.Interpretation Kwashiorkor and marasmic-kwashiorkor were distinguished by evidence of one-carbon metabolism dysfunction. Correlative observations suggest that methionine deficiency drives this dysfunction, which is implicated in the syndrome's pathogenesis. The hypothesis that kwashiorkor can be prevented by fortifying low quality diets with methionine, along with nutrients that support efficient methionine use, such as choline, requires further investigation.

Is There Enough Choline for Children in Food Aid?

“…These include anemia, fatty liver disease, growth stunting, and immune dysfunction. A similar pattern of disturbances is often evident in malnourished children, many of whom exhibit evidence of choline deficiency in serum …”

“…These include growth stunting, anemia, and immune dysfunction. A similar pattern of disturbances is evident in malnourished children, many of whom exhibit serum evidence of choline deficiency . Choline’s diverse effects stem from its 2 primary metabolic identities.…”

“…A similar pattern of disturbances is often evident in malnourished children, many of whom exhibit evidence of choline deficiency in serum. 4 Choline's diverse effects stem from its 2 primary metabolic identities. It is a precursor for phosphatidylcholine synthesis through the cytidine diphosphocholine-choline pathway and an essential methyl donor.…”

Biallelic variation in the choline and ethanolamine transporterFLVCR1underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders

“…Maternal choline deficiency impairs hippocampal development as well as neuronal progenitor cell and retinal progenitor cell expansion and differentiation in mouse embryos 43,44 . Choline deficiency also causes anemia, liver disease, growth retardation, and immune deficiency [45][46][47] . Neurodevelopment is also disrupted by defective choline uptake 48 Finally, the protein encoded by closely related gene FLVCR2 is expressed at the blood-brain barrier and transports choline and ethanolamine 16,52 .…”

One Carbon Metabolism and S-Adenosylmethionine in Non-Alcoholic Fatty Liver Disease Pathogenesis and Subtypes

“…That is, 1CM functions as a nutrient sensor and integrator of cellular metabolism [ 25 ]. This concept is evidenced in Kwashiorkor, a syndrome seen in children continuously fed poor-quality diets, where the development of hepatic steatosis and reduced plasma TG is associated with low levels of serum methionine and related 1CM metabolites, such as choline and homocysteine, and byproducts of the transmethylation (asymmetric dimethylarginine) and transsulfuration (cysteine and GSH) pathways [ 26 ]. The importance of 1CM is also underlined by the fact that antifolate chemotherapy is widely used since its discovery in 1948 [ 27 ], which further points to the importance to maintain the right balance between methylneogenesis and SAMe-dependent methylations.…”