One-carbon metabolism in children with marasmus and kwashiorkor

Authors: MAY, THADDAEUS - Children'S Nutrition Research Center (CNRC); DE LA HAYE, BETHANY - University Of Malawi; NORD, GABRIELLE - Stanford University School Of Medicine; KLATT, KEVIN - Children'S Nutrition Research Center (CNRC); STEPHENSON, KEVIN - Washington University School Of Medicine; ADAMS, SARA - Path; BOLLINGER, LUCY - Washington University School Of Medicine; HANCHARD, NEIL - National Institutes Of Health (NIH); ARNING, ERLAND - Baylor University Medical Center; BOTTIGLIERI, TEODORO - Baylor University Medical Center; MALETA, KENNETH - University Of Malawi; MANARY, MARK - Children'S Nutrition Research Center (CNRC); JAHOOR, FAROOK - Children'S Nutrition Research Center (CNRC)

Submitted to: EBioMedicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/16/2021
Publication Date: 1/11/2022
Citation: May, T., De La Haye, B., Nord, G., Klatt, K., Stephenson, K., Adams, S., Bollinger, L., Hanchard, N., Arning, E., Bottiglieri, T., Maleta, K., Manary, M., Jahoor, F. 2022. One-carbon metabolism in children with marasmus and kwashiorkor. EBioMedicine. 75. Article 103791. https://doi.org/10.1016/j.ebiom.2021.103791.
DOI: https://doi.org/10.1016/j.ebiom.2021.103791

Interpretive Summary: Kwashiorkor is a form of macronutrient malnutrition displayed by swelling and its nutritional cause remains uncertain. Blood was collected from severely and moderately malnourished Malawian children and blood levels of 16 one-carbon metabolites were measured and compared. Twelve of 16 measured one-carbon metabolites differed between children with kwashiorkor and with other types of macronutrient malnutrition, specifically, a sulfur containing protein components methionine deficiency. The findings of this study are relevant for considering the pathogenesis of kwashiorkor, a poorly understood and often lethal syndrome of childhood malnutrition.

Technical Abstract: 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. Blood was collected from children aged 12-60 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. 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 (+ or - SD): 0.549 (+ or - 0.217) P = 0.00045 & 90 (+ or - 40) P < 0.0001, respectively) and kwashiorkor (0.557 (+ or - 0.195) P < 0.0001 & 115 (+ or - 50) P < 0.0001), relative to marasmus (0.698 (+ or - 0.212) & 153 (+ or - 42)). ADMA and cysteine were well correlated with methionine in both kwashiorkor and marasmic-kwashiorkor. 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.