vitamin-b-12 and Cardiomyopathies

Vitamin B12 and folate (methyl donors) deficiency is frequent during pregnancy. Experimental rat models with methyl donor deficit during pregnancy and lactation (Initial methyl donor deficit (iMDD)) produce impaired myocardium fatty acid oxidation and mitochondrial energy metabolism at weaning.. The consequences of iMDD on heart of rat pups under normal diet after weaning and high fat diet (HF) between day (D) 50 and D185 are investigated. iMDD/HF induces increased histological fibrosis and increased B-type natriuretic peptide blood level. Inflammation is evidenced by increased protein expression of NFkB, Caspase1, and IL1β and fibrosis by increased expression of αSMA, col1a1, and col1a2 in females, but not in males. Fibrosis is related to increased angiotensin at D50 and D185 and increased protein expression of TGFB1 and AT1 angiotensin receptors at D185. The limited fibrosis in males is consistent with increased expression of AT2, the antagonist receptor of AT1. The increased expression of GLUT4 and decreased expression of PGC1α and PPARα reflect a shift from fatty acid oxidation to glycolysis.. Developmental programming by iMDD produces cardiomyopathy in female offspring exposed to HF. The cardiomyopathy is linked to inflammation and fibrosis through angiotensin-AT2 and TGFB1 pathways and alteration of energy metabolism.

Topics: Animals; Cardiomyopathies; Diet, High-Fat; Energy Metabolism; Female; Fetal Development; Folic Acid; Folic Acid Deficiency; Lactation; Lipid Metabolism; Male; Maternal Nutritional Physiological Phenomena; Myocardium; Pregnancy; Rats; Rats, Wistar; Receptor, Angiotensin, Type 2; Transforming Growth Factor beta1; Ventricular Function, Left; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adaptor Proteins, Signal Transducing; Animals; Cardiomyopathies; Diabetes Mellitus, Type 1; DNA-Cytosine Methylases; Female; Insulin-Like Growth Factor I; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Signal Transduction; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling 3 Protein; Vitamin B 12

Folate and vitamin B(12) metabolism are essential for de novo purine synthesis, and several defects in these pathways have been associated with immunodeficiency. Here we describe the occurrence of severe combined immunodeficiency (SCID) with megaloblastic anemia, leukopenia, atypical hemolytic uremic syndrome, and neurologic abnormalities in which hydroxocobalamin and folate therapy provided partial immune reconstitution. Whole exome sequencing identified compound heterozygous mutations in the MTHFD1 gene, which encodes a trifunctional protein essential for processing of single-carbon folate derivatives. We now report the immunologic details of this novel genetic cause of SCID and the response to targeted metabolic supplementation therapies. This finding expands the known metabolic causes of SCID and presents an important diagnostic consideration given the positive impact of therapy.

Topics: 3-Hydroxyacyl CoA Dehydrogenases; Anemia, Megaloblastic; Bone Marrow Examination; Cardiomyopathies; Combined Modality Therapy; DNA Mutational Analysis; Drug Combinations; Drug Therapy, Combination; Exome; Female; Genetic Carrier Screening; Humans; Hydroxocobalamin; Immunization, Passive; Infant; Infant, Newborn; Leukopenia; Lipid Metabolism, Inborn Errors; Methylenetetrahydrofolate Dehydrogenase (NADP); Minor Histocompatibility Antigens; Mitochondrial Myopathies; Mitochondrial Trifunctional Protein; Nervous System Diseases; Opportunistic Infections; Peripheral Nervous System Diseases; Pneumonia, Pneumocystis; Retinitis Pigmentosa; Rhabdomyolysis; Sequence Analysis, DNA; Severe Combined Immunodeficiency; Sulfadoxine; Trimethoprim; Vitamin B 12

Topics: Animals; Cardiomyopathies; Chlorides; Disease Models, Animal; Electrocardiography; Immobilization; Magnesium; Methods; Myocardium; Necrosis; Potassium Chloride; Rabbits; Vitamin B 12

Topics: Animals; Cardiomyopathies; Diphtheria; Diphtheria Toxin; Heart; Myocarditis; Myocardium; Protein Hydrolysates; Rabbits; Regeneration; RNA; Vitamin B 12

Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Aortic Valve Stenosis; Cardiomegaly; Cardiomyopathies; DNA; Dogs; Folic Acid; Humans; Hypertrophy; Methionine; Muscle Proteins; Myocardium; Nucleic Acids; Nucleosides; Orotic Acid; Pharmacology; Rabbits; Rats; Research; Strophanthins; Vitamin B 12