vitamin-b-12 and Abnormalities--Multiple

Methylmalonic acid (MMA) is a by-product of propionic acid metabolism through the vitamin B12 (cobalamin)-dependent enzyme methylmalonyl CoA mutase. Elevated MMA concentrations are a hallmark of several inborn errors of metabolism and indicators of cobalamin deficiency in older persons. In a genome-wide analysis of 2,210 healthy young Irish adults (median age 22 years) we identified a strong association of plasma MMA with SNPs in 3-hydroxyisobutyryl-CoA hydrolase (HIBCH, p = 8.42 × 10(-89)) and acyl-CoA synthetase family member 3 (ACSF3, p = 3.48 × 10(-19)). These loci accounted for 12% of the variance in MMA concentration. The most strongly associated SNP (HIBCH rs291466; c:2T>C) causes a missense change of the initiator methionine codon (minor-allele frequency = 0.43) to threonine. Surprisingly, the resulting variant, p.Met1?, is associated with increased expression of HIBCH mRNA and encoded protein. These homozygotes had, on average, 46% higher MMA concentrations than methionine-encoding homozygotes in young adults with generally low MMA concentrations (0.17 [0.14-0.21] μmol/L; median [25(th)-75(th) quartile]). The association between MMA levels and HIBCH rs291466 was highly significant in a replication cohort of 1,481 older individuals (median age 79 years) with elevated plasma MMA concentrations (0.34 [0.24-0.51] μmol/L; p = 4.0 × 10(-26)). In a longitudinal study of 185 pregnant women and their newborns, the association of this SNP remained significant across the gestational trimesters and in newborns. HIBCH is unique to valine catabolism. Studies evaluating flux through the valine catabolic pathway in humans should account for these variants. Furthermore, this SNP could help resolve equivocal clinical tests where plasma MMA values have been used to diagnose cobalamin deficiency.

Topics: Abnormalities, Multiple; Adolescent; Adult; Aged; Amino Acid Metabolism, Inborn Errors; Case-Control Studies; Female; Homozygote; Humans; Infant, Newborn; Longitudinal Studies; Male; Methylmalonic Acid; Middle Aged; Polymorphism, Genetic; Pregnancy; Thiolester Hydrolases; Vitamin B 12; White People; Young Adult

The cobalamin type C deficiency is a rare condition that results from impaired biosynthesis of both methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). Hemizygous mutations of the HCFC1 gene explain the majority of clinically and biologically compatible cblC patients without MMACHC mutations (OMIM 309541). We report a family with two maternal half-brothers with multiple congenital anomalies and HCFC1 gene mutation in the second Kelch domain. Both presented with dysmorphic features (flat profile, cleft lip for one), increased nuchal translucency, prenatal onset microcephaly and hypospadias. Additionally to early onset intractable epilepsy and profound neurocognitive impairment, this familial observation suggests that HCFC1 gene should be considered in boys with midline malformations, even without proven cobalamin C deficiency.

Topics: Abnormalities, Multiple; Carrier Proteins; Child, Preschool; Cleft Lip; Cobamides; Comparative Genomic Hybridization; Genetic Testing; Host Cell Factor C1; Humans; Karyotyping; Male; Mutation; Oxidoreductases; Vitamin B 12; Vitamin B 12 Deficiency

Inherited disorders of vitamin B12 (cobalamin) have provided important clues to how this vitamin, which is essential for hematological and neurological function, is transported and metabolized. We describe a new disease that results in failure to release vitamin B12 from lysosomes, which mimics the cblF defect caused by LMBRD1 mutations. Using microcell-mediated chromosome transfer and exome sequencing, we identified causal mutations in ABCD4, a gene that codes for an ABC transporter, which was previously thought to have peroxisomal localization and function. Our results show that ABCD4 colocalizes with the lysosomal proteins LAMP1 and LMBD1, the latter of which is deficient in the cblF defect. Furthermore, we show that mutations altering the putative ATPase domain of ABCD4 affect its function, suggesting that the ATPase activity of ABCD4 may be involved in intracellular processing of vitamin B12.

Topics: Abnormalities, Multiple; ATP-Binding Cassette Transporters; Case-Control Studies; Cells, Cultured; DNA Mutational Analysis; Fibroblasts; Gene Expression; Genes, Recessive; Genetic Association Studies; Humans; Infant, Newborn; Lysosomal Membrane Proteins; Metabolism, Inborn Errors; Mutation; Nucleocytoplasmic Transport Proteins; Protein Structure, Tertiary; Protein Transport; Vitamin B 12

Topics: Abnormalities, Multiple; Child; Child, Preschool; Face; Homocystinuria; Humans; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Vitamin B 12

The effect of administration of folinic acid, vitamin B6 + vitamin B12, and their combination on valproic acid (VPA)-induced teratogenesis was studied in NMRI mice. VPA (500 mg/kg, sc) was injected on Day 8 of gestation and the vitamins (two dose levels) were injected ip 1 hr before, immediately before, and 1 hr after VPA administration. Folinic acid significantly reduced VPA-induced resorptions (21-24%), and palate, rib, and sternebral malformations. Exencephaly and spina bifida occulta were also reduced (14 and 40%, respectively), but the difference was not statistically significant. On the other hand, vitamin B6 + vitamin B12 significantly reduced VPA-induced exencephaly (23%), spina bifida occulta (80%), palate and rib malformations, kidney abnormalities, and fetal weight retardation. A combination of the three vitamins was effective in reducing VPA-induced exencephaly (23-30%), spina bifida occulta (60%), and palate and rib malformations. The protection against VPA-induced malformations was not complete and was not always dose related, and the reduction in exencephaly rate was only significant in the absence of a reduction in resorption rate. Full-length cleft palate, sternebral malformations, and retarded sternebral and caudal ossification were, however, increased by the high dose of combined vitamin administration. The present study supports the view that VPA-induced teratogenesis may be mediated via an interaction with folate metabolism. Although folinic acid and vitamin B6 + vitamin B12 can effectively reduce VPA malformations, the protection was not complete, which may suggest the involvement of other factors. Furthermore, the dose levels should be carefully chosen since high doses of the combined vitamins can actually increase the incidence of certain defects.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Animals; Drug Interactions; Embryo, Mammalian; Female; Leucovorin; Mice; Mice, Inbred Strains; Pregnancy; Pyridoxine; Teratogens; Valproic Acid; Vitamin B 12

Hematological and histological studies of the rabbit brachydactyly mutant were made to clarify the question of the blood abnormality that had previously been implicated in the teratogenic process leading to congenital amputation. The hemoglobin of fetal and adult br/br rabbits, studied by electrophoresis and cyanmethemoglobin assay, exhibited no differences from that of controls. The br/br fetuses were polycythemic and severely macrocytic. Fetal limb vessels showed thrombosis leading to hemorrhages in the extremities. The hepatic tissue was abnormal, being particularly poor in hematopoietic cells; blood cell macrocytosis was attributed to impaired erthropoiesis. Treatment of pregnant rabbits with folic acid plus vitamin B12 or with folinic acid was able simultaneously to prevent the fetal blood cell macrocytosis and the congenital abnormalities.

Topics: Abnormalities, Multiple; Animals; Blood Cell Count; Drug Therapy, Combination; Electrophoresis, Cellulose Acetate; Erythrocytes, Abnormal; Erythropoiesis; Extremities; Female; Folic Acid; Hematologic Diseases; Hemoglobinometry; Homozygote; Inbreeding; Leucovorin; Limb Deformities, Congenital; Liver; Maternal-Fetal Exchange; Pregnancy; Rabbits; Vitamin B 12

Topics: Abetalipoproteinemia; Abnormalities, Multiple; Carbohydrate Metabolism, Inborn Errors; Dermatoglyphics; Dwarfism; Dysautonomia, Familial; Dystonia Musculorum Deformans; Facial Dermatoses; Factor XI Deficiency; Familial Mediterranean Fever; Gaucher Disease; Genetic Diseases, Inborn; Genetics, Population; Glucosephosphate Dehydrogenase Deficiency; Glycogen Storage Disease; Humans; Israel; Jaundice, Chronic Idiopathic; Jews; Lipidoses; Niemann-Pick Diseases; Pentoses; Phenylketonurias; Telangiectasis; Thalassemia; Vitamin B 12