vitamin-b-12 and Metabolism--Inborn-Errors

The haematological and neurological consequences of cobalamin deficiency define the essential role of this vitamin in key metabolic reactions. The identification of cubilin-amnionless as the receptors for intestinal absorption of intrinsic factor-bound cobalamin and the plasma membrane receptor for cellular uptake of transcobalamin bound cobalamin have provided a clearer understanding of the absorption and cellular uptake of this vitamin. As the genes involved in the intracellular processing of cobalamins and genetic defects of these pathways are identified, the metabolic disposition of cobalamins and the proteins involved are being recognized. The synthesis of methylcobalamin and 5'-deoxyadenosylcobalamin, their utilization in conjunction with methionine synthase and methylmalonylCoA mutase, respectively, and the metabolic consequences of defects in these pathways could provide insights into the clinical presentation of cobalamin deficiency.

Topics: Biological Transport, Active; Humans; Intestinal Absorption; Intrinsic Factor; Metabolism, Inborn Errors; Receptors, Cell Surface; Transcobalamins; Vitamin B 12; Vitamin B 12 Deficiency

Vitamin B(12) (cobalamin) is essential in animals and humans for metabolism of methylmalonic acid, for the remethylation of homocysteine to methionine and, consequently, for all S-adenosylmethionine-dependent methylation reactions, including DNA synthesis. In man, cobalamin deficiency leads to anemia and neurologic and cognitive impairment. In the cblF inborn error of vitamin B(12) metabolism, free vitamin accumulates in lysosomes and cannot be converted to cofactors for mitochondrial methylmalonyl-CoA mutase and cytosolic methionine synthase. Recent work has shown that this defect is caused by mutations in the lysosomal membrane protein LMBD1, which shows significant homology to lipocalin membrane receptors, thereby indicating that LMBD1 is a lysosomal membrane exporter for cobalamin.

Topics: Amino Acid Sequence; Animals; Humans; Lysosomal Membrane Proteins; Lysosomes; Metabolism, Inborn Errors; Molecular Sequence Data; Nucleocytoplasmic Transport Proteins; Sequence Alignment; Vitamin B 12

Topics: Biological Transport; Folic Acid; Humans; Hyperhomocysteinemia; Intrinsic Factor; Metabolism, Inborn Errors; Methylenetetrahydrofolate Reductase (NADPH2); Vitamin B 12; Vitamin B 12 Deficiency

Disorders of cobalamin metabolism include defects of absorption, transport and intracellular metabolism of cobalamin. Most of the patients present in the first years of life with haematological abnormalities and feeding difficulties but some of them have later onset form and can present with pure neurological manifestations.. The suggestive clinical picture is a subacute neurological disorder similar to those observed in case of insufficient B12 intake or Biermer disease. In this frame, additional diagnosis clues could be associated megaloblastic anemia, previous history of venous thrombosis, association with psychiatric disturbances, involvement of both central and peripheral nervous system. The key investigations are measurement of plasma amino acid levels and urinary organic acid, which allow to detect abnormalities consistent with intracellular cobalamin deficiency. Treatment depends on the metabolic defect but usually consist in intramuscular cobalamin supplementation. It results in stabilization or improvement in most cases.. Because this treatable condition can lead to death or irreversible neurological damage, we recommend that disorder of the cobalamin metabolism should be consider in all young adults with unexplained consistent neurological manifestations.

Topics: Adult; Animals; Humans; Metabolism, Inborn Errors; Nervous System Diseases; Prognosis; Vitamin B 12

Cobalamin deficiency in the newborn usually results from cobalamin deficiency in the mother. Megaloblastic anaemia, pancytopenia and failure to thrive can be present, accompanied by neurological deficits if the diagnosis is delayed. Most cases of spina bifida and other neural tube defects result from maternal folate and/or cobalamin insufficiency in the periconceptual period. Polymorphisms in a number of genes involved in folate and cobalamin metabolism exacerbate the risk. Inborn errors of cobalamin metabolism affect its absorption, (intrinsic factor deficiency, Imerslund-Gräsbeck syndrome) and transport (transcobalamin deficiency) as well as its intracellular metabolism affecting adenosylcobalamin synthesis (cblA and cblB), methionine synthase function (cblE and cblG) or both (cblC, cblD and cblF). Inborn errors of folate metabolism include congenital folate malabsorption, severe methylenetetrahydrofolate reductase deficiency and formiminotransferase deficiency. The identification of disease-causing mutations in specific genes has improved our ability to diagnose many of these conditions, both before and after birth.

Topics: Diet; Folic Acid; Folic Acid Deficiency; Humans; Infant, Newborn; Metabolism, Inborn Errors; Neural Tube Defects; Vitamin B 12; Vitamin B 12 Deficiency

Three topics affecting cobalamin, folate, and homocysteine that have generated interest, activity, and advances in recent years are discussed. These are: (I). the application of an expanded variety of tools to the diagnosis of cobalamin deficiency, and how these affect and are affected by our current understanding of deficiency; (II). the nature of the interaction between homocysteine and vascular disease, and how the relationship is affected by vitamins; and (III). the improved understanding of relevant genetic disorders and common genetic polymorphisms, and how these interact with environmental influences. The diagnostic approach to cobalamin deficiency now allows better diagnosis of difficult and atypical cases and more confident rejection of the diagnosis when deficiency does not exist. However, the process has also become a complex and sometimes vexing undertaking. Part of the difficulty derives from the lack of a diagnostic gold standard among the many available tests, part from the overwhelming numerical preponderance of patients with subclinical deficiency (in which isolated biochemical findings exist without clinical signs or symptoms) among the cobalamin deficiency states, and part from the decreased availability of reliable tests to identify the causes of a patient's cobalamin deficiency and thus a growing deemphasis of that important part of the diagnostic process. In Section I, Dr. Carmel discusses the tests, the diagnostic issues, and possible approaches to the clinical evaluation. It is suggested no single algorithm fits all cases, some of which require more biochemical proof than others, and that differentiating between subclinical and clinical deficiency, despite their overlap, may be a helpful and practical point of departure in the evaluation of patients encountered in clinical practice. The arguments for and against a suggested expansion of the cobalamin reference range are also weighed. The epidemiologic data suggest that homocysteine elevation is a risk factor for vascular and thrombotic disease. In Section II, Dr. Green notes that the interactions of metabolism and clinical risk are not well understood and a causative relationship remains unproven despite new reports that lowering homocysteine levels may reduce vascular complications. Genetic and acquired influences may interact in important ways that are still being sorted out. The use of vitamins, especially folate, often reduces homocysteine levels but also carries potential disa

Topics: Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Metabolism, Inborn Errors; Polymorphism, Genetic; Vascular Diseases; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Biotin; Diagnosis, Differential; Folic Acid; Humans; Metabolism, Inborn Errors; Nervous System Diseases; Prognosis; Pyridoxine; Syndrome; Thiamine; Vitamin B 12; Vitamin D; Vitamin E Deficiency

Topics: Bone Marrow; Folic Acid; Humans; Metabolism, Inborn Errors; Vitamin B 12

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Complement Factor H; Complement System Proteins; Genes, Dominant; Genes, Recessive; Genetic Diseases, Inborn; Hemolytic-Uremic Syndrome; Humans; Metabolism, Inborn Errors; Mutation; Vitamin B 12

Topics: Anemia, Megaloblastic; Diagnosis, Differential; Humans; Immune System Diseases; Metabolism, Inborn Errors; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Neutropenia; Prognosis; Vitamin B 12

The main remethylation defects include disorders which all have defective methionine synthesis in common. Methylenetetrahydrofolate reductase deficiency impairs methyltetrahydrofolate synthesis, defects in cytosolic reduction of hydroxocobalamin (CblC/D) impair the synthesis of both methyl- and adenosyl cobalamin and deficiencies of methionine synthase (CblE/G) are associated with defective methyl cobalamin synthesis. The clinical presentation is characterized by acute neurological distress in early infancy. In childhood, patients present with progressive encephalopathy with an end-stage which has many signs in common with the adult onset form. In fact, both have more or less severe signs of subacute degeneration of the cord. Cobalamin defective patients must be treated with parenteral supplementation of hydroxocobalamin (1-2 mg per dose). Some methylenetetrahydrofolate patients could be folate responsive and must have a high-dosage folate trial. In addition, oral betaine supplementation (2-9 g per day depending on age) appears an effective means to prevent further neurological deterioration.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Adult; Betaine; Child, Preschool; Folic Acid; Homocysteine; Humans; Hydroxocobalamin; Infant; Infant, Newborn; Metabolism, Inborn Errors; Methionine; Methylation; Methylenetetrahydrofolate Reductase (NADPH2); Methylmalonic Acid; Oxidoreductases Acting on CH-NH Group Donors; Practice Guidelines as Topic; Vitamin B 12

Topics: Cobamides; Diagnosis, Differential; Humans; Metabolism, Inborn Errors; Methylmalonic Acid; Prognosis; Vitamin B 12

Cobalamins are essential biological compounds structurally related to haemoglobin and the cytochromes. Although the basic cobalamin molecule is only synthesized by micro-organisms, all mammalian cells can convert this into the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). AdoCbl is the major form in cellular tissues, where it is retained in the mitochondria. MeCbl predominates in blood plasma and certain other body fluids such as breast milk; in cells MeCbl is found in the cytosol. Inherited disorders of cobalamin metabolism are single gene defects, transmitted as recessive traits. They affect absorption, transport or intracellular metabolism of cobalamin. At least 12 different mutations are known, including defects or deficiencies of IF, IF-receptor and TCII, MM-CoA mutase and of the various reductases and synthases required for synthesis of AdoCbl and MeCbl. These have been designated cblA to cblG. Abnormalities are detectable by urine and plasma assays of methylmalonic acid and homocysteine, and plasma and erythrocyte analysis of cobalamin coenzymes, which can reveal deficiencies of MeCbl or AdoCbl. Fibroblast studies discriminate between closely similar defects. In man, AdoCbl is required in only two reactions: the catabolic isomerization of MM-CoA to succinyl-CoA and interconversion of alpha- and beta-leucine. MeCbl is required in the anabolic transmethylation of homocysteine to methionine. Intestinal absorption of cobalamin requires the glycoproteins TCI and IF from the stomach and IF-cobalamin receptors in the ileum. Cobalamin is transported to cells bound to a polypeptide, TCII, is captured by surface receptors and absorbed by endocytosis. The complex is then split in the lysosomes, cobalamin is released and the coenzymes are synthesized. In plasma, 80-90% of the cobalamin is bound to TCI, whose function is uncertain. Megaloblastic anaemia at birth or in the first few weeks of life is a rare but serious event. Myelopathy and developmental delay, with or without seizures may also occur without anaemia. If urine and light-protected blood samples are collected and sent to an appropriate metabolic unit, an inborn error of cobalamin metabolism, including TCII deficiency in which the serum B12 may be normal, can quickly be diagnosed. IF deficiency or Imerslund-Gräsbeck disease usually presents with signs of cobalamin deficiency within the first year of life and can be diagnosed by absorption studies. Current treatment involves dietar

Topics: Humans; Metabolism, Inborn Errors; Vitamin B 12

All of vitamin B12 in nature is of microbial origin. Cobalamin, as vitamin B12 should correctly be termed, is a large polar molecule that must be bound to specialized transport proteins to gain entry into cells. Entry from the lumen of the intestine under physiological conditions occurs only in the ileum and only when bound to intrinsic factor. It is transported into all other cells only when bound to another transport protein, transcobalamin II. Congenital absence or defective synthesis of intrinsic factor or transcobalamin II result in megaloblastic anemia. The Immerslund-Graesbeck syndrome, a congenital defect in the transcellular transport of cobalamin through the ileal cell during absorption, also presents with megaloblastic anemia, but with accompanying albuminuria. In most bacteria and in all mammals, cobalamin regulates DNA synthesis indirectly through its effect on a step in folate metabolism, the conversion of N5-methyltetrahydrofolate to tetrahydrofolate, which in turn is linked to the conversion of homocysteine to methionine. This reaction occurs in the cytoplasm, and it is catalyzed by methionine synthase, which requires methyl cobalamin (MeCbl), one of the two coenzyme forms of the vitamin, as a cofactor. Defects in the generation of MeCbl (cobalamin E and G diseases) result in homocystinuria; affected infants present with megaloblastic anemia, retardation, and neurological and ocular defects. 5'-Deoxyadenosyl cobalamin (AdoCbl), the other coenzyme form of cobalamin, is present within mitochondria, and it is an essential cofactor for the enzyme Methylmalonyl-CoA mutase, which converts L-methylmalonyl CoA to succinyl CoA. This reaction is in the pathway for the metabolism of odd chain fatty acids via propionic acid, as well as that of the amino acids isoleucine, methionine, threonine, and valine. Impaired synthesis of AdoCbl (cobalamin A or B disease) results in infants with methylmalonic aciduria who are mentally retarded, hypotonic, and who present with metabolic acidosis, hypoglycemia, ketonemia, hyperglycinemia, and hyperammonemia. Megaloblastic anemia does not develop in these children because adequate amounts of MeCbl are present, but the effect of methylmalonic acid on marrow stem cells may give rise to pancytopenia. Congenital absence of reductases in the cytoplasm, which normally reduce the cobalt atom in cobalamin from its oxidized to its reduced state (cobalamin C and D diseases), results in impaired synthesis of both MeCbl and Ado

Topics: Biological Transport; Humans; Intestinal Absorption; Metabolism, Inborn Errors; Vitamin B 12; Vitamin B 12 Deficiency

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Animals; Bacterial Proteins; Biological Evolution; Biological Transport; Cells, Cultured; Child; Cobamides; Female; Fibroblasts; Genes; Genetic Complementation Test; Homocystinuria; Humans; Incidence; Infant, Newborn; Intestinal Absorption; Intrinsic Factor; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Mice; Transcobalamins; Vitamin B 12; Vitamin B Deficiency

In humans, subacute combined degeneration of the spinal cord and brain, a primary demyelinating disease, is caused by cobalamin or methyltetrahydrofolate deficiency. Experimental studies into its pathogenesis suggest that dysfunction of the methyl-transfer pathway may be the cause. Compelling evidence for this comes from the study of inborn errors of cobalamin metabolism where deficiency of methylcobalamin, but not deoxyadenosylcobalamin, is associated with demyelination. Recent studies have focused upon inborn errors of the methyl-transfer pathway. Cerebrospinal fluid concentrations of metabolites of the methyl-transfer pathway have been measured in humans with sequential errors of the pathway and correlated with demyelination demonstrated on magnetic resonance imaging of the brain. This has provided new data suggesting that deficiency of S-adenosylmethionine is critical to the development of demyelination in cobalamin deficiency.

Topics: Brain Diseases; Demyelinating Diseases; Humans; Metabolism, Inborn Errors; Methylation; Nerve Degeneration; Spinal Cord Diseases; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Cobamides; Humans; Lysosomes; Metabolism, Inborn Errors; Methylmalonic Acid; NADH, NADPH Oxidoreductases; Vitamin B 12

Evidence for cobalamin (vitamin B12) deficiency usually involves some combination of low serum cobalamin levels, clinical abnormalities (classically, megaloblastic anemia and neurologic defects), metabolic abnormalities, and response to therapy. However, cobalamin deficiency may often display few of the expected clinical findings. Identification of the underlying cause is also important in the diagnosis of deficiency, and its value may be particularly great when the expression of deficiency is subtle. The cause of cobalamin deficiency is usually malabsorptive, but may sometimes be limited to malabsorption of food cobalamin while free cobalamin is absorbed normally. Nongastroenterologic entities may sometimes also be found. All of these considerations allow the proposal of four patterns of cobalamin deficiency. The first type is classical deficiency; typical megaloblastic anemia with or without neurologic dysfunction occurs because of classical cobalamin malabsorption such as lack of intrinsic factor (pernicious anemia). The second type consists of classical cobalamin malabsorption in which the cobalamin deficiency is expressed subtly rather than in classical fashion. There is no megaloblastic anemia and sometimes the only evidence of deficiency may be metabolic. In the third type, cobalamin deficiency is expressed classically but is attributable to a subtle or atypical cause, such as food-cobalamin malabsorption. In the fourth type, deficiency is both expressed subtly and arises from subtle or atypical causes. Such presentations require further investigation but are a challenging expansion of our understanding and recognition of cobalamin deficiency.

Topics: Diagnosis, Differential; Humans; Malabsorption Syndromes; Metabolism, Inborn Errors; Vitamin B 12; Vitamin B 12 Deficiency

Inborn errors of vitamin B12 (cobalamin) metabolism are associated with homocystinuria and methylmalonic aciduria, either alone or in combination. A number of these disorders have provided the first evidence for the existence of important steps in the transport or metabolism of cobalamin in eukaryotic cells. Eight complementation classes have been defined on the basis of somatic cell hybridization studies. Although the majority of patients present in infancy or early childhood, some are not diagnosed until adolescence or later. For some of these disorders, prenatal diagnosis and therapy with cobalamin during pregnancy has been attempted. Although only males have been described with cblE disease, all of these disorders are presumed to be autosomal recessive in inheritance. The clinical and laboratory aspects of the different complementation classes (cblA-cblG) are reviewed here.

Topics: Cells, Cultured; Humans; Infant; Metabolism, Inborn Errors; Models, Biological; Vitamin B 12

Reduction of circulating homocysteine levels by folic acid suggests an additional approach to the prophylaxis of certain forms of vascular disease related to atherogenic amino acids.

Topics: Arterial Occlusive Diseases; Arteriosclerosis; Folic Acid; Folic Acid Deficiency; Homocysteine; Humans; Metabolism, Inborn Errors; Vascular Diseases; Vitamin B 12; Vitamin B 12 Deficiency

Inherited disorders of vitamin B12 include those which involve the inability of the vitamin to be absorbed from the gut and transported to the appropriate tissues, and those in which the vitamin is not utilised by target cells. The former include intrinsic factor abnormalities, selective malabsorption of vitamin B12 with proteinuria, and deficiencies of transcobalamin I and transcobalamin II. The latter include a defect in the release of free vitamin B12 from lysosomes (cblF), and defects in the formation of both vitamin B12 cofactors (cblC, cblD) or of adenosyl-B12 (cblA, cblB) or methyl-B12 alone (cblE, CblE variant). This article reviews the major clinical manifestations of these diseases, and provides an approach to the diagnosis of transcobalamin II deficiency and the cbl mutations using cultured cells.

Topics: Humans; Metabolism, Inborn Errors; Vitamin B 12

Topics: Female; Humans; Infant; Metabolism, Inborn Errors; Pregnancy; Transcobalamins; Vitamin B 12; Vitamin B 12 Deficiency

This monograph on the clinical chemistry of vitamin B12 reviews the literature on daily requirements, methods for measurement, the effects of drugs on vitamin B12 metabolism absorption, pregnancy, clinical conditions associated with vitamin B12 deficiency, errors of metabolism, and reactions to vitamin therapy. Although only very small quantities of vitamin B12 are required to satisfy the daily requirement, a sufficient supply is stored in the liver to meet normal requirements for at least a 3-year period. A number of drugs are known to affect the absorption of vitamin B12, including neomycin, potassium chloride, p-aminosalicylic acid, and colchicine. Significantly reduced serum concentrations of vitamin B12 have been noted in users of oral contraceptives (OCs), although concentrations still remain within the limits of normal. It appears that the vitamin B12 level in OC users reestablishes itself at a different and somewhat lower level. Vitamin B12 binding protein appears to remain unchanged. A vitamin B12 deficiency is unusual in pregnant women who consume a normal, varied diet. On the other hand, lactating women whose diets are low in animal protein and dairy products may have problems providing enough vitamin B12 to meet their own and their infant's needs; supplementary oral vitamins should be considered.

Topics: Absorption; Adult; Alcoholism; Anemia, Pernicious; Ascorbic Acid; Autoantibodies; Biguanides; Biological Transport; Chemical Phenomena; Chemistry; Chlorpromazine; Contraceptives, Oral; Diet; Female; Gastrectomy; Gastritis; Humans; Intrinsic Factor; Malabsorption Syndromes; Male; Metabolism, Inborn Errors; Middle Aged; Neoplasms; Nervous System Diseases; Nitrous Oxide; Nutritional Requirements; Pancreatic Diseases; Parasitic Diseases; Pregnancy; Pregnancy Complications; Transcobalamins; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Acetyl-CoA Carboxylase; Acidosis; Amino Acid Metabolism, Inborn Errors; Animals; Biotin; Folic Acid; Glutaryl-CoA Dehydrogenase; Humans; Intestinal Absorption; Maple Syrup Urine Disease; Metabolism, Inborn Errors; Methemoglobinemia; Methylmalonic Acid; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Propionates; Pyridoxine; Pyruvate Carboxylase Deficiency Disease; Pyruvate Kinase; Riboflavin; Tetrahydrofolate Dehydrogenase; Thiamine; Transcobalamins; Vitamin B 12; Vitamins

Topics: 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); Apoenzymes; Cystathionine beta-Synthase; Genetic Diseases, Inborn; Humans; Ileum; Intrinsic Factor; Ketone Oxidoreductases; Metabolism, Inborn Errors; Multienzyme Complexes; Pyridoxal Phosphate; Pyridoxine; Transcobalamins; Vitamin B 12; Vitamin B Complex; Vitamins

Topics: Child, Preschool; Diagnosis, Differential; Female; Folic Acid Deficiency; Homocystinuria; Humans; Infant; Intestinal Absorption; Metabolism, Inborn Errors; Methylmalonic Acid; Transcobalamins; Vitamin B 12; Vitamin B 12 Deficiency

Several vitamins have been demonstrated to interfere with the pathogenesis of some metabolic diseases, mainly by three different mechanisms: 1) vitamin malabsorption, 2) errors in vitamin metabolism, 3) vitamin dependent syndromes. The latter is due to a deficiency of the apoenzyme whose coenzyme is the vitamin itself. In this case pharmacological, instead of nutritional doses of the vitamin may be needed. The vitamins which interfere with inborn metabolic errors are reviewed; for each vitamin the corresponding diseases which may be treated are indicated. The vitamins are: 1) thiamine (leucinosis); b) nicotinic acid (hyperlipoproteinemia); c) biotin (beta-methyl-crotonyl-glycinuria, propionic aciduria); d) pyridoxine (infantile convulsions, familial pyridoxine responsive anemia, homocystinuria, cystathioninuria, xanthurenicaciduria); e) cobalamins (congenital intrinsic factor deficiency, cobalamin malabsorption, transcobalamin deficiency, methylmalonic aciduria) f) folic acid (congenital folic acid malabsorption, formimino-transferase deficiency, methylenetetrahydrofolic reductase deficiency, Lesch-Nyhan syndrome); g) vitamin D (phosphatic diabetes, Prader's type rickets, Albright's syndrome; essential hereditary hypophosphatemia, etc). It is noteworthy that the vitamin therapy of these diseases, not only corrects the metabolic errors, but can also promote the healing or the amelioration of the psycho-physical growth, of central nervous system alterations and of other lesions.

Topics: Biotin; Dose-Response Relationship, Drug; Folic Acid; Humans; Metabolism, Inborn Errors; Niacin; Nicotinic Acids; Pyridoxine; Thiamine; Vitamin B 12; Vitamin D; Vitamins

Topics: Amino Acids; Biotin; Coenzymes; Enzymes; Folic Acid; Humans; Metabolism, Inborn Errors; Orthomolecular Therapy; Pyridoxine; Thiamine; Vitamin B 12

Topics: Animals; Clone Cells; Cobamides; Genetic Complementation Test; Humans; Hybrid Cells; Leukocytes; Malonates; Metabolism, Inborn Errors; Methylmalonic Acid; Mice; Mitochondria; Mutation; Phenotype; Propionates; Vitamin B 12

Topics: Adolescent; Amino Acid Metabolism, Inborn Errors; Anemia, Megaloblastic; Child; Female; Folic Acid; Galactosemias; Glutamate Decarboxylase; Homocystinuria; Humans; Infant; Infant, Newborn; Lactose Intolerance; Maple Syrup Urine Disease; Metabolism, Inborn Errors; Methylmalonic Acid; Phenylketonurias; Pregnancy; Vitamin B 12

Topics: Adolescent; Adult; Anemia, Hemolytic; Anemia, Macrocytic; Anemia, Megaloblastic; Anemia, Pernicious; Biological Transport; Bone Marrow; Bone Marrow Cells; Child; Child, Preschool; Female; Folic Acid; Folic Acid Deficiency; Homocystinuria; Humans; Infant; Intrinsic Factor; Malabsorption Syndromes; Male; Metabolism, Inborn Errors; Methionine; Methionine Adenosyltransferase; Orotic Acid; Phenylketonurias; Tetrahydrofolate Dehydrogenase; Transcobalamins; Vitamin B 12

Topics: Adult; Aged; Anemia, Megaloblastic; Anticonvulsants; Blood-Brain Barrier; Brain; Brain Diseases; Child; Epilepsy; Erythrocytes; Female; Folic Acid; Folic Acid Deficiency; Formiminoglutamic Acid; Humans; Intellectual Disability; Male; Mental Disorders; Metabolism, Inborn Errors; Methotrexate; Middle Aged; Nervous System Diseases; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Avitaminosis; Biological Transport, Active; Humans; Metabolism, Inborn Errors; Pyridoxine; Thiamine; Thiamine Deficiency; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B 6 Deficiency; Vitamins

Topics: Adult; Animals; Bone Marrow; Bone Marrow Cells; DNA; Fibroblasts; Folic Acid; Folic Acid Deficiency; Humans; Liver; Metabolism, Inborn Errors; Methionine; Methyltransferases; Rats; Skin; Tetrahydrofolate Dehydrogenase; Vitamin B 12; Vitamin B 12 Deficiency

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Adolescent; Adult; Alcohol Oxidoreductases; Amino Acid Metabolism, Inborn Errors; Child; Female; Folic Acid; Formates; Glutamates; Glycine; Humans; Hydrolases; Imines; Infant; Malabsorption Syndromes; Male; Metabolism, Inborn Errors; Methionine Adenosyltransferase; Methylenetetrahydrofolate Dehydrogenase (NADP); Phenylketonurias; Tetrahydrofolate Dehydrogenase; Tetrahydrofolates; Transferases; Vitamin B 12

Literature relevant to drugs reported as affecting or not affecting nutrient metabolism and diet for developmentally disabled persons was summarized. Many investigators have found side effects of anticonvulsant drugs on vitamin D, calcium, folid acid, and vitamin B12 metabolism. Growth-retarding effects of certain central nervous system stimulants have also been reported. It has beed found that tranquilizers and antidepressant therapy show no effects on nutrient metabolism. Vitamins used in pharmacologic doses are considered as drugs; their therapeutic use was briefly reviewed here. The need for more research on biochemical interaction of drugs and nutrients was recommended.

Topics: Anticonvulsants; Antidepressive Agents; Appetite; Dextroamphetamine; Drug-Related Side Effects and Adverse Reactions; Folic Acid; Growth; Humans; Hyperkinesis; Intellectual Disability; Metabolism, Inborn Errors; Methylphenidate; Nutritional Physiological Phenomena; Pyridoxine; Tranquilizing Agents; Vitamin B 12; Vitamin D; Vitamins

Topics: Adrenal Insufficiency; Amino Acid Metabolism, Inborn Errors; Amino Acids, Sulfur; Ammonia; Anemia, Sickle Cell; Anencephaly; Carbohydrate Metabolism, Inborn Errors; Fabry Disease; Female; Fetal Diseases; Fetus; Gangliosides; Gaucher Disease; Humans; Karyotyping; Lipid Metabolism, Inborn Errors; Lipidoses; Lysine; Metabolism, Inborn Errors; Mucopolysaccharidoses; Polyploidy; Pregnancy; Propionates; Sphingolipidoses; Turner Syndrome; Vitamin B 12

Topics: Adult; Amino Acid Metabolism, Inborn Errors; Biotin; Carboxylic Acids; Chromatography, Gas; Coenzyme A; Crotonates; Female; Gestational Age; Humans; Hydroxy Acids; Hydroxybutyrates; Infant; Infant, Newborn; Isomerases; Leucine; Male; Malonates; Metabolism, Inborn Errors; Pedigree; Pregnancy; Prenatal Diagnosis; Propionates; Pyrrolidonecarboxylic Acid; Valerates; Vitamin B 12

Topics: Coenzymes; Genotype; Homocysteine; Humans; Metabolism, Inborn Errors; Methionine; Molecular Biology; Mutation; Neurologic Manifestations; Phenotype; Pyridoxine; Vitamin B 12; Vitamins

Topics: Abetalipoproteinemia; Acrodermatitis; Acute Disease; Age Factors; Amino Acid Metabolism, Inborn Errors; Animals; Celiac Disease; Child; Chlorides; Cystic Fibrosis; Diarrhea; Diet Therapy; Endopeptidases; Enteritis; Food Hypersensitivity; Humans; Lactose Intolerance; Malabsorption Syndromes; Metabolism, Inborn Errors; Milk; Vitamin B 12

Topics: Age Factors; Diet; Female; Folic Acid; Folic Acid Deficiency; Gastrointestinal Diseases; Humans; Infant; Intrinsic Factor; Malabsorption Syndromes; Metabolic Diseases; Metabolism, Inborn Errors; Nutrition Disorders; Nutritional Physiological Phenomena; Nutritional Requirements; Pregnancy; Time Factors; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Amino Acids; Animals; Coenzymes; Homocysteine; Humans; Malonates; Metabolism, Inborn Errors; Propionates; Vitamin B 12; Vitamin B 12 Deficiency

Combined methylmalonic aciduria and homocystinuria cobalamin C type (cobalamin C disease) is an inborn metabolic disorder consisting of an impaired intracellular synthesis of the 2 active forms of vitamin B12 (cobalamin), namely, adenosylcobalamin and methylcobalamin, that results in increased levels of methylmalonic acid and homocysteine in the blood and urine. Most patients present in the first year of life with systemic, hematological, and neurological abnormalities. Late-onset forms are rare and had not been comprehensively characterized. They could be easily misdiagnosed.. To describe clinical and biochemical features of the disease in 2 siblings affected with presumed late-onset cobalamin C disease.. Case report and review of the literature.. Neurological intensive care unit of a university hospital.. We describe 2 patients with neurological deterioration due to presumed cobalamin C disease. A 16-year-old girl was initially seen with psychosis and severe progressive neuropathy requiring mechanical ventilatory support and her 24-year-old sister had a 2-year disease course of subacute combined degeneration of the spinal cord. A metabolic workup displayed increased methylmalonic acid levels, severe hyperhomocysteinemia, and low plasma methionine levels. The diagnosis was then confirmed by demonstration of impaired synthesis of adenosylcobalamin and methylcobalamin in cultured skin fibroblasts and Epstein-Barr virus-infected lymphocytes. Under specific treatment the younger sister's condition dramatically improved.. Although complementation studies have not been conducted, it is most likely these patients had cobalamin C disease. This study emphasizes the possibility of late-onset disease with purely neurological manifestations. Left untreated, this treatable condition can lead to death or irreversible damage to the nervous system. Screening for intracellular vitamin B12 dysmetabolism should, therefore, be considered in the investigation of adults with unexplained neurological disease, particularly when they are initially seen with a clinical picture suggestive of vitamin B12 deficiency.

Topics: Adolescent; Adult; Brain; Cobamides; Female; Fibroblasts; Homocysteine; Humans; Mental Disorders; Metabolism, Inborn Errors; Methylmalonic Acid; Nervous System Diseases; Sural Nerve; Vitamin B 12

Elevated total plasma homocysteine (hyperhomocysteinemia) is a marker of cardiovascular, thrombotic, and neuropsychological disease. It has multiple causes, including the common nutritional vitamin B12 or folate deficiency. However, some rare but treatable, inborn errors of metabolism (IEM) characterized by hyperhomocysteinemia can be missed due to variable presentations and the lack of awareness. The aim of this study is to identify undiagnosed IEM in adults with significantly elevated homocysteine using key existing clinical data points, then IEM specific treatment can be offered to improve outcome. We conducted a retrospective study with data mining and chart review of patients with plasma total homocysteine >30 μmol/L over a two-year period. We offer biochemical and genetic testing to patients with significant hyperhomocysteinemia without a clear explanation to diagnose IEM. We identified 22 subjects with significant hyperhomocysteinemia but no clear explanation. Subsequently, we offered genetic testing to seven patients and diagnosed one patient with classic homocystinuria due to cystathionine beta-synthase deficiency. With treatment, she lowered her plasma homocysteine and improved her health. This study stresses the importance of a thorough investigation of hyperhomocysteinemia in adults to identify rare but treatable IEM. We propose a metabolic evaluation algorithm for elevated homocysteine levels.

Topics: Adult; Female; Folic Acid; Homocysteine; Homocystinuria; Humans; Hyperhomocysteinemia; Metabolism, Inborn Errors; Retrospective Studies; Vitamin B 12

Methionine synthase deficiency (cblG complementation group) is a rare inborn error of metabolism affecting the homocysteine re-methylation pathway. It leads to a biochemical phenotype of hyperhomocysteinemia and hypomethioninemia. The clinical presentation of cblG is variable, ranging from seizures, encephalopathy, macrocytic anemia, hypotonia, and feeding difficulties in the neonatal period to onset of psychiatric symptoms or acute neurologic changes in adolescence or adulthood. Given the variable and nonspecific symptoms seen in cblG, the diagnosis of affected patients is often delayed. Medical management of cblG includes the use of hydroxocobalamin, betaine, folinic acid, and in some cases methionine supplementation. Treatment has been shown to lead to improvement in the biochemical profile of affected patients, with lowering of total homocysteine levels and increasing methionine levels. However, the published literature contains differing conclusions on whether treatment is effective in changing the natural history of the disease. Herein, we present five patients with cblG who have shown substantial clinical benefit from treatment with objective improvement in their neurologic outcomes. We demonstrate more favorable outcomes in our patients who were treated early in life, especially those who were treated before neurologic symptoms manifested. Given improved outcomes from treatment of presymptomatic patients, cblG warrants inclusion in newborn screening.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Adult; Amino Acid Metabolism, Inborn Errors; Early Diagnosis; Homocysteine; Humans; Metabolism, Inborn Errors; Methionine; Vitamin B 12

Long-term outcome is postulated to be different in isolated methylmalonic aciduria caused by mutations in the MMAA gene (cblA type) compared with methylmalonyl-CoA mutase deficiency (mut), but case definition was previously difficult.. Cross-sectional analysis of data from the European Registry and Network for Intoxication type Metabolic Diseases (Chafea no. December 1, 2010).. Data from 28 cblA and 95 mut patients in most cases confirmed by mutation analysis (including 4 new mutations for cblA and 19 new mutations for mut). Metabolic crisis is the predominant symptom leading to diagnosis in both groups. Biochemical disturbances during the first crisis were similar in both groups, as well as the age at diagnosis. Z scores of body height and body weight were similar in both groups at birth, but were significantly lower in the mut group at the time of last visit. Glomerular filtration rate was significantly higher in cblA; and as a consequence, chronic renal failure and related complications were significantly less frequent and renal function could be preserved even in older patients. Neurological complications were predominantly found in the mut subgroup. Methylmalonic acidemia (MMA) levels in urine and plasma were significantly lower in cblA. 27/28 cblA patients were reported to be responsive to cobalamin, only 86% of cblA patients were treated with i.m. hydroxocobalamin. In total, 73% of cblA and 98% of mut patients followed a calculated diet with amino acid supplements in 27% (cblA) and 69% (mut). During the study interval, six patients from the mut group died, while all cblA patients survived.. Although similar at first, cblA patients respond to hydroxocobalamin treatment, subsequently show significantly lower levels of MMA and a milder course than mut patients.

Topics: Amino Acid Metabolism, Inborn Errors; Child; Cross-Sectional Studies; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Mitochondrial Membrane Transport Proteins; Mutation; Vitamin B 12

The association of moderate hyperhomocysteinemia (HHcy) (15-30 μmol/L) with cardiovascular diseases (CVD) has been challenged by the lack of benefit of vitamin supplementation to lowering homocysteine. Consequently, the results of interventional studies have confused the debate regarding the management of patients with intermediate/severe HHcy.. We sought to evaluate the association of intermediate (30-100 μmol/L) and severe (>100 μmol/L) HHcy related to vitamin deficiencies and/or inherited disorders with CVD outcomes.. We performed a retrospective cross-sectional study on consecutive patients who underwent a homocysteine assay in a French University Regional Hospital Center. Patients with CVD outcomes were assessed for vitamin B12, folate, Hcy, methylmalonic acid, and next-generation clinical exome sequencing.. We evaluated 165 patients hospitalized for thromboembolic and other cardiovascular (CV) manifestations among 1006 patients consecutively recruited. Among them, 84% (138/165) had Hcy >30 μmol/L, 27% Hcy >50 μmol/L (44/165) and 3% Hcy >100 μmol/L (5/165). HHcy was related to vitamin B12 and/or folate deficiency in 55% (87/165), mutations in one or more genes of one-carbon and/or vitamin B12 metabolisms in 11% (19/165), and severe renal failure in 15% (21/141) of the studied patients. HHcy was the single vascular risk retrieved in almost 9% (15/165) of patients. Sixty % (101/165) of patients received a supplementation to treat HHcy, with a significant decrease in median Hcy from 41 to 17 µmol/L (IQR: 33.6-60.4 compared with 12.1-28). No recurrence of thromboembolic manifestations was observed after supplementation and antithrombotic treatment of patients who had HHcy as a single risk, after ∼4 y of follow-up.. The high frequency of intermediate/severe HHcy differs from the frequent moderate HHcy reported in previous observational studies of patients with pre-existing CVD. Our study points out the importance of diagnosing and treating nutritional deficiencies and inherited disorders to reverse intermediate/severe HHcy associated with CVD outcomes.

Topics: Adult; Cardiovascular Diseases; Child, Preschool; Cross-Sectional Studies; Female; Folic Acid; Folic Acid Deficiency; Homocysteine; Humans; Hyperhomocysteinemia; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Middle Aged; Retrospective Studies; Vitamin B 12

The role of epigenetics in inborn errors of metabolism (IEMs) is poorly investigated. Epigenetic changes can contribute to clinical heterogeneity of affected patients but could also be underestimated determining factors in the occurrence of IEMs. An epigenetic cause of IEMs has been recently described for the autosomal recessive methylmalonic aciduria and homocystinuria, cblC type (cblC disease), and it has been named epi-cblC. Epi-cblC has been reported in association with compound heterozygosity for a genetic variant and an epimutation at the MMACHC locus, which is secondary to a splicing variant (c.515-1G > T or c.515-2A > T) at the adjacent PRDX1 gene. Both these variants cause aberrant antisense transcription and cis-hypermethylation of the MMACHC gene promotor with subsequent silencing. Until now, only nine epi-cblC patients have been reported.. We report clinical/biochemical assessment, MMACHC/PRDX1 gene sequencing and genome-wide DNA methylation profiling in 11 cblC patients who had an inconclusive MMACHC gene testing. We also compare clinical phenotype of epi-cblC patients with that of canonical cblC patients.. All patients turned out to have the epi-cblC disease. One patient had a bi-allelic MMACHC epimutation due to the homozygous PRDX1:c.515-1G > T variant transmitted by both parents. We found that the bi-allelic epimutation produces the complete silencing of MMACHC in the patient's fibroblasts. The remaining ten patients had a mono-allelic MMACHC epimutation, due to the heterozygous PRDX1:c.515-1G > T, in association with a mono-allelic MMACHC genetic variant. Epi-cblC disease has accounted for about 13% of cblC cases diagnosed by newborn screening in the Tuscany and Umbria regions since November 2001. Comparative analysis showed that clinical phenotype of epi-cblC patients is similar to that of canonical cblC patients.. We provide evidence that epi-cblC is an underestimated cause of inborn errors of cobalamin metabolism and describe the first instance of epi-cblC due to a bi-allelic MMACHC epimutation. MMACHC epimutation/PRDX1 mutation analyses should be part of routine genetic testing for all patients presenting with a metabolic phenotype that combines methylmalonic aciduria and homocystinuria.

Topics: DNA Methylation; Female; Humans; Infant, Newborn; Male; Metabolism, Inborn Errors; Neonatal Screening; Oxidoreductases; Peroxiredoxins; Vitamin B 12

Transcobalamin (TC) deficiency is a rare autosomal recessive inborn error of cobalamin transport which clinically manifests in early infancy. We describe a child with TC deficiency who presented with classical clinical and lab stigmata of inborn error of vitamin B

Topics: Child; Exons; Genetic Testing; Homozygote; Humans; Injections, Intramuscular; Male; Metabolism, Inborn Errors; Transcobalamins; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

The molecular consequences of inborn errors of vitamin B12 or cobalamin metabolism are far from being understood. Moreover, innovative therapeutic strategies are needed for the treatment of neurological outcomes that are usually resistant to conventional treatments. Our previous findings suggest a link between SIRT1, cellular stress and RNA binding proteins (RBP) mislocalization in the pathological mechanisms triggered by impaired vitamin B12 metabolism.. The goal of this study was to investigate the effects of the pharmacological activation of SIRT1 using SRT1720 on the molecular mechanisms triggered by impaired methionine synthase activity. Experiments were performed in vitro with fibroblasts from patients with the cblG and cblC inherited defects of vitamin B12 metabolism and in vivo with an original transgenic mouse model of methionine synthase deficiency specific to neuronal cells. Subcellular localization of the RBPs HuR, HnRNPA1, RBM10, SRSF1 and Y14 was investigated by immunostaining and confocal microscopy in patient fibroblasts. RBPs methylation and phosphorylation were studied by co-immunoprecipitation and proximity ligation assay. Cognitive performance of the transgenic mice treated with SRT1720 was measured with an aquatic maze.. Patient fibroblasts with cblC and cblG defects of vitamin B12 metabolism presented with endoplasmic reticulum stress, altered methylation, phosphorylation and subcellular localization of HuR, HnRNPA1 and RBM10, global mRNA mislocalization and increased HnRNPA1-dependent skipping of IRF3 exons. Incubation of fibroblasts with cobalamin, S-adenosyl methionine and okadaic acid rescued the localization of the RBPs and mRNA. The SIRT1 activating compound SRT1720 inhibited ER stress and rescued RBP and mRNA mislocalization and IRF3 splicing. Treatment with this SIRT1 agonist prevented all these hallmarks in patient fibroblasts but it also improved the deficient hippocampo-dependent learning ability of methionine synthase conditional knock-out mice.. By unraveling the molecular mechanisms triggered by inborn errors of cbl metabolism associating ER stress, RBP mislocalization and mRNA trafficking, our study opens novel therapeutic perspectives for the treatment of inborn errors of vitamin B12 metabolism.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Animals; Cells, Cultured; Cognitive Dysfunction; Endoplasmic Reticulum Stress; Fibroblasts; Humans; Metabolism, Inborn Errors; Mice; Mice, Knockout; RNA-Binding Proteins; RNA, Messenger; Sirtuin 1; Vitamin B 12; Vitamin B 12 Deficiency

Vitamin B

Topics: Adult; Aged; Aged, 80 and over; Alkyl and Aryl Transferases; Biomarkers; Energy Metabolism; Female; Ferredoxin-NADP Reductase; Genome-Wide Association Study; Homocysteine; Humans; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Middle Aged; Mitochondria; Molecular Epidemiology; Polymorphism, Single Nucleotide; Thiolester Hydrolases; Transcobalamins; Valine; Vitamin B 12

To date, epimutations reported in man have been somatic and erased in germlines. Here, we identify a cause of the autosomal recessive cblC class of inborn errors of vitamin B

Topics: Alleles; Azacitidine; Base Sequence; Carrier Proteins; Enzyme Inhibitors; Epistasis, Genetic; Family Health; Female; Fibroblasts; Heterozygote; Humans; Male; Metabolism, Inborn Errors; Mutation; Oxidoreductases; Pedigree; Peroxiredoxins; Vitamin B 12; Whole Genome Sequencing

Vitamin B

Topics: Amino Acid Metabolism, Inborn Errors; Amino Acid Substitution; ATP-Binding Cassette Transporters; Catalytic Domain; Cell Line, Transformed; Cells, Cultured; HeLa Cells; Humans; Luminescent Proteins; Lysosomes; Metabolism, Inborn Errors; Models, Molecular; Molecular Docking Simulation; Mutation; Nucleocytoplasmic Transport Proteins; Protein Conformation; Protein Interaction Domains and Motifs; Protein Multimerization; Protein Transport; Recombinant Fusion Proteins; Structural Homology, Protein; Vitamin B 12

Objective Birth prevalence of Cobalamin (Cbl) C or D defects in Portugal is an estimated 1:85,000, one of the highest worldwide. We compared the genotype/phenotype of patients identified with CblC or CblD before and after the implementation of expanded newborn screening. Methods Twenty-five Portuguese CblC/D patients, 14 symptomatic and 11 identified through screening, were diagnosed using gas chromatography or tandem mass spectrometry. Molecular characterization was performed through the study of MMACHC and MMADHC genes. Results The most common MMACHC mutation, c.271dupA, was present in 100% of MMACHC alleles of all CblC screened patients, in contrast with the 61% identified before expanded newborn screening. All studied cases (except one, who presented a CblD deficiency) presented a CblC defect. More CblC late-onset patients were diagnosed before the introduction of newborn screening than in the post newborn screening era, probably because some early onset patients died without a definitive diagnosis. Conclusion The molecular data found in this cohort contribute to the improvement of screening and diagnosis of Cbl defects and would enable a confirmatory diagnosis of these patients, reducing the need for complex, costly, laborious, and time-consuming biochemical/enzymatic tests.

Topics: Carrier Proteins; Ethnicity; Female; Humans; Infant, Newborn; Intracellular Signaling Peptides and Proteins; Male; Metabolism, Inborn Errors; Mitochondrial Membrane Transport Proteins; Mutation; Neonatal Screening; Oxidoreductases; Portugal; Prevalence; Quality Improvement; Vitamin B 12

Inborn errors of cobalamin (Cbl) metabolism form a large group of rare diseases. One of these, Cbl deficiency type C (CblC), is a well-known cause of thrombotic microangiopathy (TMA), especially in infants. However, there has only been a single published case of TMA associated to Cbl deficiency type G (CblG), also known as methionine synthase deficiency (MSD).. A 21-month-old boy presented with pallor and oral ulcers during episodes of upper respiratory infection (URI). Further examination revealed signs of TMA, and the patient progressed to acute renal failure (ARF). Renal biopsy showed TMA. Evaluation for infection and autoantibodies were negative. The C3 and C4 complement fractions were normal. Analysis of the bone marrow aspirate suggested megaloblastic anemia and signs of hematopoiesis activation (secondary to peripheral hemolysis). Although the serum vitamin B12 level was normal, the patient was treated with cyanocobalamin, with no improvement. The ARF and hematologic parameters improved with conservative treatment. A severe relapse occurred during the follow-up, with normal ADAMTS13 activity. The presumed diagnosis was atypical hemolytic uremic syndrome, and the patient was started on eculizumab, but his response was poor, even when the dosage was increased. At this point it was also recognized that his developmental speech was delayed. Based on these findings, whole exome sequencing was performed, leading to the detection of two novel deleterious variants in the gene coding for methionine synthase, confirming the diagnosis of MSD. Subsequent treatment consisted of elevating the patient's serum homocysteine level and starting him on hydroxicobalamin, with normalization of all hematologic parameters although the microalbuminuria remained.. Methionine synthase deficiency is very rare and characterized by megaloblastic anemia and neurological symptoms. We report the second case of MSD associated to TMA previously diagnosed as aHUS in which the patient had a poor response to eculizumab.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Acute Kidney Injury; ADAMTS13 Protein; Anemia, Megaloblastic; Antibodies, Monoclonal, Humanized; Atypical Hemolytic Uremic Syndrome; Biopsy; Bone Marrow; Exome Sequencing; Humans; Hydroxocobalamin; Hyperhomocysteinemia; Infant; Kidney; Language Development Disorders; Male; Metabolism, Inborn Errors; Recurrence; Thrombotic Microangiopathies; Vitamin B 12; Vitamin B Complex

Next generation sequencing (NGS) based gene panel testing is increasingly available as a molecular diagnostic approach for inborn errors of metabolism. Over the past 40 years patients have been referred to the Vitamin B12 Clinical Research Laboratory at McGill University for diagnosis of inborn errors of cobalamin metabolism by functional studies in cultured fibroblasts. DNA samples from patients in which no diagnosis was made by these studies were tested by a NGS gene panel to determine whether any molecular diagnoses could be made. 131 DNA samples from patients with elevated methylmalonic acid and no diagnosis following functional studies of cobalamin metabolism were analyzed using the 24 gene extended cobalamin metabolism NGS based panel developed by Baylor Miraca Genetics Laboratories. Gene panel testing identified two or more variants in a single gene in 16/131 patients. Eight patients had pathogenic findings, one had a finding of uncertain significance, and seven had benign findings. Of the patients with pathogenic findings, five had mutations in ACSF3, two in SUCLG1 and one in TCN2. Thus, the NGS gene panel allowed for the presumptive diagnosis of 8 additional patients for which a diagnosis was not made by the functional assays.

Topics: Amino Acid Metabolism, Inborn Errors; Child, Preschool; Coenzyme A Ligases; Female; Genetic Testing; Genetic Variation; Genotype; Heterozygote; High-Throughput Nucleotide Sequencing; Humans; Infant; Infant, Newborn; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Molecular Diagnostic Techniques; Mutation; Phenotype; Succinate-CoA Ligases; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

Vitamin B12 (cobalamin, Cbl) cofactors adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) are required for the activity of the enzymes methylmalonyl-CoA mutase (MCM) and methionine synthase (MS). Inborn errors of Cbl metabolism are rare Mendelian disorders associated with hematological and neurological manifestations, and elevations of methylmalonic acid and/or homocysteine in the blood and urine. We describe a patient whose fibroblasts had decreased functional activity of MCM and MS and decreased synthesis of AdoCbl and MeCbl (3.4% and 1.0% of cellular Cbl, respectively). The defect in cultured patient fibroblasts complemented those from all known complementation groups. Patient cells accumulated transcobalamin-bound-Cbl, a complex which usually dissociates in the lysosome to release free Cbl. Whole-exome sequencing identified putative disease-causing variants c.851T>G (p.L284*) and c.1019C>T (p.T340I) in transcription factor ZNF143. Proximity biotinylation analysis confirmed the interaction between ZNF143 and HCFC1, a protein that regulates expression of the Cbl trafficking enzyme MMACHC. qRT-PCR analysis revealed low MMACHC expression levels both in patient fibroblasts, and in control fibroblasts incubated with ZNF143 siRNA.

Topics: Carrier Proteins; Cells, Cultured; Cytoplasm; Fibroblasts; Humans; Infant; Male; Metabolism, Inborn Errors; Mutation; Oxidoreductases; Pedigree; Trans-Activators; Transcobalamins; Vitamin B 12

The physiology of human skin pigmentation is varied and complex, with an extensive melanogenic paracrine network involving mesenchymal and epithelial cells, contributing to the regulation of melanocyte survival and proliferation and melanogenesis. Mutations in several genes, involving predominantly the KIT ligand/c-Kit and Ras/mitogen-activated protein kinase signalling pathways, have been implicated in a spectrum of diseases in which there is hyperpigmentation, hypopigmentation or both. Here, we report on a 12-year-old girl from Taiwan with a 6-year history of diffuse progressive skin hyperpigmentation resulting from a different aetiology: an inborn metabolic disorder of vitamin B12 (cobalamin), designated cblJ. Using whole-exome sequencing we identified a homozygous mutation in ABCD4 (c.423C>G; p.Asn141Lys), which encodes an ATP-binding cassette transporter with a role in the intracellular processing of cobalamin. The patient had biochemical and haematological evidence of cobalamin deficiency but no other clinical abnormalities apart from a slight lightening of her previously black hair. Of note, she had no neurological symptoms or signs. Treatment with oral cobalamin (3 mg daily) led to metabolic correction and some reduction in the skin hyperpigmentation at the 3-month follow-up. This case demonstrates that defects or deficiencies of cobalamin should be remembered in the differential diagnosis of diffuse hyperpigmentary skin disorders.

Topics: ATP-Binding Cassette Transporters; Child; Female; Homozygote; Humans; Hyperpigmentation; Metabolism, Inborn Errors; Mutation; Polymorphism, Single Nucleotide; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

Combined methylmalonic acidemia and homocystinuria is an inborn error of metabolism of vitamin B12 or cobalamin. It's a rare autosomal recessive disease in which there are several variants depending on the pathogenesis of the metabolic disorder (cblC, cblD, cblF and cblJ). The more frequent and more severe is the cblC variant, which usually manifests in the first months of life, although some cases have been reported at the beginning of adulthood. A proper diagnosis and effective therapeutic approach is fundamental. We report the case of a patient of 18 years with a history of epilepsy who consults for acute renal failure requiring renal replacement therapy and diagnosed with combined methylmalonic acidemia and homocystinuria cblC variant.. La combinación de homocistinuria con acidemia metilmalónica es un error congénito del metabolismo de la vitamina B12 o cobalamina. Es una patología poco frecuente de herencia autosómica recesiva en la que existen diversas variantes en función de la patogenia del trastorno metabólico (cblC, cblD, cblF y cblJ). La más frecuente y más grave es la variante cblC, que suele manifestarse en los primeros meses de vida, aunque se han reportado casos al inicio de la edad adulta. Se hace fundamental un correcto diagnóstico y un abordaje terapéutico eficaz. Presentamos el caso clínico de una paciente de 18 años con antecedentes personales de epilepsia que acude por fracaso renal agudo con necesidad de terapia renal sustitutiva diagnosticándose de homocistinuria con acidemia metilmalónica variante cblC.

Topics: Adolescent; Amino Acid Metabolism, Inborn Errors; Female; Homocystinuria; Humans; Hydroxocobalamin; Kidney; Metabolism, Inborn Errors; Vitamin B 12; Vitamins

Human CblC catalyzes the elimination of the upper axial ligand in cobalamin or B12 derivatives entering the cell from circulation. This processing step is critical for assimilation of dietary cobalamin into the active cofactor forms that support the B12-dependent enzymes, methionine synthase and methylmalonyl-CoA mutase. Using a modified nitroreductase scaffold tailored to bind cobalamin and glutathione, CblC exhibits versatility in the mechanism by which it removes cyano versus alkyl ligands in cobalamin. In this study, we have characterized the effects of two pathogenic missense mutations at the same residue, R161G and R161Q, which are associated with early and late onset of the CblC disorder, respectively. We find that the R161Q and R161G CblC mutants display lower protein stability and decreased dealkylation but not decyanation activity, suggesting that cyanocobalamin might be therapeutically useful for patients carrying mutations at Arg-161. The mutant proteins also exhibit impaired glutathione binding. In the presence of physiologically relevant glutathione concentrations, stabilization of the cob(II)alamin derivative is observed, which occurs at the expense of increased oxidation of glutathione. Futile redox cycling, which is suppressed in wild-type human CblC, explains the reported increase in oxidative stress levels associated with the CblC disorder.

Topics: Alkylation; Arginine; Biocatalysis; Glutathione; Humans; Metabolism, Inborn Errors; Models, Molecular; Molecular Chaperones; Mutation, Missense; Nitriles; Oxidation-Reduction; Protein Stability; Protein Structure, Tertiary; Proto-Oncogene Proteins c-cbl; Reactive Oxygen Species; Vitamin B 12

The cblC defect is the most common inborn error of vitamin B12 metabolism. Despite therapeutic measures, the long-term outcome is often unsatisfactory. This retrospective multicentre study evaluates clinical, biochemical and genetic findings in 88 cblC patients. The questionnaire designed for the study evaluates clinical and biochemical features at both initial presentation and during follow up. Also the development of severity scores allows investigation of individual disease load, statistical evaluation of parameters between the different age of presentation groups, as well as a search for correlations between clinical endpoints and potential modifying factors.. No major differences were found between neonatal and early onset patients so that these groups were combined as an infantile-onset group representing 88 % of all cases. Hypotonia, lethargy, feeding problems and developmental delay were predominant in this group, while late-onset patients frequently presented with psychiatric/behaviour problems and myelopathy. Plasma total homocysteine was higher and methionine lower in infantile-onset patients. Plasma methionine levels correlated with "overall impression" as judged by treating physicians. Physician's impression of patient's well-being correlated with assessed disease load. We confirmed the association between homozygosity for the c.271dupA mutation and infantile-onset but not between homozygosity for c.394C>T and late-onset. Patients were treated with parenteral hydroxocobalamin, betaine, folate/folinic acid and carnitine resulting in improvement of biochemical abnormalities, non-neurological signs and mortality. However the long-term neurological and ophthalmological outcome is not significantly influenced. In summary the survey points to the need for prospective studies in a large cohort using agreed treatment modalities and monitoring criteria.

Topics: Age of Onset; Brain; Carrier Proteins; Child; Child, Preschool; Disease Progression; Ethnicity; Female; Humans; Infant; Infant, Newborn; Male; Metabolism, Inborn Errors; Oxidoreductases; Prognosis; Proto-Oncogene Proteins c-cbl; Surveys and Questionnaires; Vitamin B 12

Methylmalonic aciduria and homocystinuria, cobalamin C (CblC) disease (OMIM 277400), is the most frequent inborn error of vitamin B12 (cobalamin, Cbl) metabolism and is caused by an inability of the cell to convert Cbl to its active forms (MeCbl and AdoCbl). More than 75 mutations have been identified in the MMACHC gene which is responsible for CblC disease. We present a case with CblC disease and pulmonary arterial hypertension (PAH) as the main symptom. The patient improved dramatically with parenteral hydroxocobalamin treatment. Most cases of CblC disease have a multisystemic disease with failure to thrive, developmental delay, hypotonia, visual impairment, and hematologic manifestations. This patient had isolated pulmonary hypertension and hyperhomocysteinemia which is thought to be an important factor in the pathogenesis of PAH. Genetic analysis identified a novel homozygous mutation (c.484G > T; p.Gly162Trp) in the MMACHC gene.. CblC disease should be considered in the differential diagnosis of pulmonary hypertension.

Topics: Carrier Proteins; DNA; DNA Mutational Analysis; Echocardiography; Female; Humans; Hypertension, Pulmonary; Infant; Metabolism, Inborn Errors; Mutation; Oxidoreductases; Pulmonary Wedge Pressure; Vitamin B 12

Classical (or isolated) methylmalonic acidemia (MMA) is a heterogeneous inborn error of metabolism most typically caused by mutations in the vitamin B12-dependent enzyme methylmalonyl-CoA mutase (MUT). With the improved survival of individuals with MMA, chronic kidney disease has become recognized as part of the disorder. The precise description of renal pathology in MMA remains uncertain.. Light microscopy, histochemical, and ultrastructural studies were performed on the native kidney obtained from a 19-year-old patient with mut MMA who developed end stage renal disease and underwent a combined liver-kidney transplantation.. The light microscopy study of the renal parenchyma in the MMA kidney revealed extensive interstitial fibrosis, chronic inflammation, and tubular atrophy. Intact proximal tubules were distinguished by the widespread formation of large, circular, pale mitochondria with diminished cristae. Histochemical preparations showed a reduction of cytochrome c oxidase and NADH activities, and the electron microscopy analysis demonstrated loss of cytochrome c enzyme activity in these enlarged mitochondria.. Our results demonstrate that the renal pathology of MMA is characterized by megamitochondria formation in the proximal tubules in concert with electron transport chain dysfunction. Our findings suggest therapies that target mitochondrial function as a treatment for the chronic kidney disease of MMA.

Topics: Amino Acid Metabolism, Inborn Errors; Atrophy; Diet, Protein-Restricted; Female; Humans; Kidney; Kidney Diseases; Kidney Tubules, Proximal; Metabolism, Inborn Errors; Methylmalonyl-CoA Mutase; Mitochondria; Mitochondrial Diseases; Nephritis; Vitamin B 12; Young Adult

Vitamin B12 (B12, cobalamin (Cbl)) is a water-soluble vitamin that requires complex mechanisms for its assimilation, blood transport and intracellular metabolism. Three proteins, intrinsic factor (IF), haptocorrin (HC), and transcobalamin (TC), and their specific receptors are involved in B12 absorption and transport. Acquired and inherited deficiencies can result in megaloblastic anemia and neurological manifestations. Several genetic diseases are linked to these two steps, namely inherited deficits in FI and TC, and Imerslund-Gräsbeck disease. In mammalian cells, only two enzymes depend on vitamin B12: L-methylmalonyl-CoA mutase (EC 5.4.99.2) in mitochondria, and methionine synthase (EC 2.1.1.13) in cytoplasm. Direct metabolic consequences of impaired B12 absorption and metabolism are the accumulation of methylmalonic acid (MMA) and of homocysteine (HCy), respectively. More than a dozen genes are involved in the intracellular metabolism of B12, and their defects result in several diseases designated cblA through cblJ This article reviews the steps involved in vitamin B12 absorption, transport and intracellular metabolism, and the main related genetic defects.

Topics: Humans; Intestinal Absorption; Metabolism, Inborn Errors; Vitamin B 12; Vitamin B 12 Deficiency

Cobalamin (Cbl) is an essential B vitamin involved in the normal functioning of the nervous system, the formation of key components of blood, DNA synthesis and methylation, and energy production. Physiological levels of Cbl vary greatly within populations, although the basis for this variability remains largely unknown. We conducted a twin study to characterise the basis of variation in plasma Cbl levels and to test whether common genetic polymorphisms in genes known to cause defects in inborn errors of Cbl metabolism and transport are also associated with mean plasma Cbl levels in the general population. The present results showed that plasma levels of Cbl were heritable, with genetic and phenotypic variance increasing with age, and levels significantly correlated with age, BMI, exercise, alcohol consumption, smoking status, social class and folate levels, which collectively accounted for up to 15 % of Cbl variation. Of eight genes responsible for the defects of the Cbl metabolic pathway (cblA-G and mut), MMAA, MMACHC, MTRR and MUT harboured polymorphisms that showed evidence of association with Cbl levels. Characterisation of the heritable component of variation in Cbl levels can facilitate the early diagnosis and prognosis of Cbl insufficiency/deficiency in individuals at a higher risk of associated diseases.

Topics: Adult; Age Factors; Alcohol Drinking; Body Mass Index; Exercise; Female; Folic Acid; Genotype; Humans; Metabolism, Inborn Errors; Middle Aged; Phenotype; Polymorphism, Genetic; Smoking; Social Class; 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

Inborn errors of vitamin B(12) (cobalamin) metabolism are characterized by decreased production of active cobalamin cofactors and subsequent deficiencies in the activities of methionine synthase and methylmalonyl-CoA mutase. With the recent discovery of the cblJ defect in two patients with phenotypes mimicking the cblF defect, there are nine genes known to be involved in cobalamin metabolism. The new defect is caused by mutations in the ABCD4 gene, encoding an ABC transporter. At the moment, there is no clear distinction between the cblJ and cblF defects either clinically or biochemically, and both defects result in blocks in the transport of cobalamin from the lysosome to the cytoplasm. A patient was diagnosed with hyperhomocysteinemia and methylmalonic aciduria at the age of 8 years. Incorporations of both [(14)C]propionate and [(14)C]methyltetrahydrofolate in cultured fibroblasts were within reference ranges and thus too high to allow for complementation analysis. We observed decreased synthesis of both adenosylcobalamin and methylcobalamin and accumulation of unmetabolized cyanocobalamin. Exome sequencing was performed to identify causative mutation(s) and Sanger re-sequencing was performed to validate segregation of mutation in the family. By this approach, a homozygous mutation, c.423C>G, in the ABCD4 gene was identified. Here, we report the successful application of exome sequencing for diagnosis of a rare inborn error of vitamin B(12) metabolism in a patient whose unusual presentation precluded diagnosis using standard biochemical and genetic approaches. The patient represents only the third known patient with the cblJ disorder.

Topics: Adolescent; Age of Onset; Alleles; ATP-Binding Cassette Transporters; Base Sequence; Exome; Fibroblasts; Genotype; Humans; Male; Metabolism, Inborn Errors; Methylenetetrahydrofolate Reductase (NADPH2); Mutation; Pedigree; Vitamin B 12

Topics: Congresses as Topic; Dietary Supplements; Homocysteine; Humans; Hyperhomocysteinemia; Metabolic Diseases; Metabolic Networks and Pathways; Metabolism, Inborn Errors; Vitamin B 12

The cblF disorder, characterized by accumulation of internalized cobalamin in the lysosome, is caused by mutations in the LMBRD1 gene which encodes an integral lysosomal membrane protein. We describe novel mutations in LMBRD1 in three patients: two splice site mutations, c.916-1G>T and c.1339-1G>T, and a 6785 bp deletion encompassing exon 2, c.70-4298_246+2311del6785. The three patients are compound heterozygotes for one novel mutation and the common c.1056delG mutation.

Topics: Exons; Frameshift Mutation; Genetic Association Studies; Genetic Testing; Heterozygote; Humans; Hyperhomocysteinemia; Metabolism, Inborn Errors; Methylmalonic Acid; Nucleocytoplasmic Transport Proteins; Protein Isoforms; Sequence Deletion; Vitamin B 12

Derivatives of cobalamin (vitamin B(12)) are required for activity of two enzymes in humans. Adenosylcobalamin is required for activity of mitochondrial methylmalonylCoA mutase and methylcobalamin is required for activity of cytoplasmic methionine synthase. Deficiency in cobalamin, or inability to absorb cobalamin normally, can result in accumulation of methylmalonic acid and homocysteine in blood and urine. Methylmalonic acidemia can result in metabolic acidosis which in severe cases may be fatal. Hyperhomocysteinemia along with hypomethioninemia can result in hematologic (megaloblastic anemia, neutropenia, thrombocytopenia) and neurologic (subacute combined degeneration of the cord, dementia, psychosis) defects. Inborn errors affecting cobalamin absorption (inherited intrinsic factor deficiency, Imerslund–Gra¨ sbeck syndrome) and transport (transcobalamin deficiency) have been described. A series of inborn errors of intracellular cobalamin metabolism, designated cblA-cblG, have been differentiated by complementation analysis. These can give rise to isolated methylmalonic acidemia (cblA, cblB, cblD variant 2), isolated hyperhomocysteinemia (cblD variant 1, cblE, cblG) or combined methylmalonic acidemia and hyperhomocysteinemia (cblC, classic cblD, cblF). All these disorders are inherited as autosomal recessive traits. The genes underlying each of these disorders have been identified. Two other disorders, haptocorrin deficiency and transcobalamin receptor deficiency, have been described, but it is not clear that they have any consistent clinical phenotype.

Topics: Amino Acid Metabolism, Inborn Errors; Anemia, Megaloblastic; Cobamides; Homocysteine; Humans; Hyperhomocysteinemia; Infant, Newborn; Malabsorption Syndromes; Metabolism, Inborn Errors; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Neonatal Screening; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Combined methylmalonic aciduria and homocystinuria, cobalamin (cbl)C type (cblC disease), the most common inborn error of vitamin B(12), is a rare disorder of intracellular cbl metabolism because of mutations in the MMACHC gene located in chromosome region 1p34.1. It has become possible to establish phenotype-genotype correlations and to observe ethnicity-related trends. This article provides detailed clinical manifestations and outcomes of a Taiwanese infant boy with early-onset cblC disease, heterozygous for c.609G>A and c.567dupT mutations, although there is limited information about cases with c.609G>A or c.567dupT mutation in the literature. He had no significant clinical abnormality during his neonatal period, whereas elevated C3 level was noted at newborn screening. He presented later with life-threatening manifestations and failure to thrive, which resolved through our treatment, although delayed development was still noted at 6 months of age. To date, all reported cblC patients with the c.609G>A mutation have been East Asians. Therefore, we suggest that c.609G>A should be included in the initial mutation screening tests for a cblC patient in East Asian populations.

Topics: Carrier Proteins; Genotype; Homocystinuria; Humans; Infant, Newborn; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Mutation; Oxidoreductases; Vitamin B 12

Combined methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type, is an inherited disorder of vitamin B(12) metabolism caused by mutations in MMACHC. CblC typically presents in the neonatal period with neurological deterioration, failure to thrive, cytopenias, and multisystem pathology including renal and hepatic dysfunction. Rarely, affected individuals present in adulthood with gait ataxia and cognitive decline. Treatment with hydroxocobalamin may ameliorate the clinical features of early-onset disease and prevent clinical late-onset disease. Propionic acidemia (PA), methylmalonic acidemia (MMA), and various disorders of cobalamin metabolism are characterized by elevated propionylcarnitine (C3) on newborn screening (NBS). Distinctions can be made between these disorders with secondary analyte testing. Elevated methionine is already routinely used as a NBS marker for cystathionine beta-synthase deficiency. We propose that low methionine may be useful as a secondary analyte for specific detection of cbl disorders among a larger pool of infants with elevated C3 on NBS.. Retrospective analysis of dried blood spot (DBS) data in patients with molecularly confirmed cblC disease.. Nine out of ten patients with confirmed cblC born in New York between 2005 and 2008 had methionine below 13.4mumol/L on NBS. Elevated C3, elevated C3:C2 ratio, and low methionine were incorporated into a simple screening algorithm that can be used to improve the specificity of newborn screening programs and provide a specific and novel method of distinguishing cblC from other disorders of propionate metabolism prior to recall for confirmatory testing.. It is anticipated that this algorithm will aid in early and specific detection of cobalamin C, D, and F diseases, with no additional expense to NBS laboratories screening for organic acidemias and classical homocystinuria.

Topics: Algorithms; Carnitine; Demography; False Positive Reactions; Female; Follow-Up Studies; Genetic Association Studies; Homocystinuria; Humans; Infant, Newborn; Male; Metabolism, Inborn Errors; Methionine; Methylmalonic Acid; Neonatal Screening; New York; Propionates; Referral and Consultation; Vitamin B 12

Elevated methylmalonic acid in five asymptomatic newborns whose fibroblasts showed decreased uptake of transcobalamin-bound cobalamin (holo-TC), suggested a defect in the cellular uptake of cobalamin. Analysis of TCblR/CD320, the gene for the receptor for cellular uptake of holo-TC, identified a homozygous single codon deletion, c.262_264GAG (p.E88del), resulting in the loss of a glutamic acid residue in the low-density lipoprotein receptor type A-like domain. Inserting the codon by site-directed mutagenesis fully restored TCblR function.

Topics: Amino Acid Sequence; Antigens, CD; Base Sequence; Cells, Cultured; DNA Mutational Analysis; Female; Fibroblasts; Homocysteine; Humans; Infant; Infant, Newborn; Metabolism, Inborn Errors; Methylmalonic Acid; Molecular Sequence Data; Mutation; Neonatal Screening; Pregnancy; Receptors, Cell Surface; Transcobalamins; Vitamin B 12

To characterize enamel defects in patients with methylmalonic acidemia (MMA) and cobalamin (cbl) metabolic disorders and to examine salivary methylmalonate levels in MMA.. Teeth from patients (n = 32) were evaluated for enamel defects and compared with age- and gender-matched controls (n = 55). Complementation class (mut, cblA, cblB and cblC) and serum methylmalonate levels were examined. Primary teeth from two patients were examined by light and scanning electron microscopy and salivary methylmalonate levels from two patients were analyzed.. Enamel defects were significantly more prevalent per tooth in the affected group than the control group, across complementation types (P < 0.0001). The mut MMA subgroup had a significantly higher prevalence per individual of severe enamel defects than controls (P = 0.021), and those with enamel defects exhibited higher serum methylmalonate levels than those without (P = 0.017). Salivary methylmalonate levels were extremely elevated and were significantly higher than controls (P = 0.002). Primary teeth were free of enamel defects except for two cblC patients who exhibited severe enamel hypoplasia. One primary tooth from a cblC patient manifested markedly altered crystal microstructure.. Enamel anomalies represent a phenotypic manifestation of MMA and cbl metabolic disorders. These findings suggest an association between enamel developmental pathology and disordered metabolism.

Topics: Adolescent; Adult; Biomarkers; Case-Control Studies; Child; Dental Enamel; Dentition, Permanent; Female; Genetic Complementation Test; Humans; Male; Matched-Pair Analysis; Metabolism, Inborn Errors; Methylmalonic Acid; Reference Values; Saliva; Statistics, Nonparametric; Tooth Abnormalities; Tooth, Deciduous; Vitamin B 12; Young Adult

MMAB (methylmalonic aciduria type B) is a mitochondrial enzyme involved in the metabolism of vitamin B(12). It functions as the ATP:cob(I)alamin adenosyltransferase for the generation of adenosylcobalamin (AdoCbl), the cofactor of methylmalonyl-CoA mutase (MCM). Impaired MMAB activity leads to the inherited disorder methylmalonic aciduria and is responsible for the cblB complementation group. In this study, the effects on substrate binding of two catalytically inactive patient mutations, R190H and R186W, were investigated using intrinsic fluorescence quenching of MMAB as a measure of ligand-binding. We report the dissociation constant (K(d)) of wild-type MMAB for HOCbl is 51 microM and for ATP is 365 microM and show that cobalamin enhances the affinity of MMAB for ATP, while ATP does not show detectable effects on cobalamin binding. We confirm that residue Arg190 plays a role in the formation of the ATP-binding site as described previously [H.L. Schubert, C.P. Hill, Structure of ATP-bound human ATP:cobalamin adenosyltransferase, Biochemistry 45 (2006) 15188-15196]. Unexpectedly, mutation R186W does not disrupt the binding of HOCbl to MMAB as predicted; instead, both R190H and R186W significantly disrupt the affinity between MMAB and AdoCbl. We surmise that these two residues may be critical for the transfer of the 5'-deoxyadenosyl group from ATP to cob(I)alamin, possibly by contributing to the precise positioning of the two substrates to permit catalysis to occur. Characterization of ligand-binding by MMAB provides insight into the mechanism of cobalamin adenosylation and the effect of patient mutations in the inherited disorder.

Topics: Adenosine Triphosphate; Alkyl and Aryl Transferases; Binding Sites; Catalysis; Humans; Ligands; Metabolism, Inborn Errors; Mutation; Spectrometry, Fluorescence; Vitamin B 12

Patients with the cblC vitamin B(12) (cobalamin, cbl) disorder are defective in the intracellular synthesis of adenosylcobalamin and methylcobalamin and have combined homocystinuria and methylmalonic aciduria. While other vitamin B(12) disorders are treatable with high dose cyanocobalamin (CNCbl) or hydroxocobalamin (OHCbl), cblC patients respond well to OHCbl but not to CNCbl. Patient mutations were introduced into recombinant MMACHC (cblC) protein and the binding of CNCbl and OHCbl was examined. Three mutations were analyzed: G147D, associated with early onset, vitamin B(12) unresponsive disease; R161Q, associated with late onset disease that is highly responsive to OHCbl; and H122A, selected to test the hypothesis that H122 is central to a proposed vitamin B(12) binding motif on MMACHC. We report here that wild-type MMACHC binds both OHCbl and CNCbl with similar, tight affinity (K(d)=5.7 microM). We also report that MMACHC binds CNCbl in the base-off form, with the dimethylbenzimidazole (DMB) base of cobalamin displaced from coordination with the cobalt. In this form, wild-type MMACHC is able to reductively decyanate CNCbl to cob(II)alamin requiring only the presence of NADPH and FAD. We demonstrate that MMACHC with the G147D mutation is unable to bind either CNCbl or OHCbl, providing a straight forward explanation for the absence of response to either vitamin form. However, we show that MMACHC containing the R161Q mutation binds OHCbl with wild-type affinity, but is disturbed in binding CNCbl and has impaired decyanation. Finally, we show that H122A has reduced binding, but like R161Q, it binds OHCbl more tightly than CNCbl, suggesting that this histidine is not absolutely required for binding. These studies suggest that the ability of mutant MMACHC to respond to vitamin therapy depends on its ability to bind the vitamin with significant affinity, and for CNCbl, also on its ability to bind in the base-off form to facilitate reductive decyanation. These studies emphasize the continued use of OHCbl with cblC patients for maximum therapeutic effect.

Topics: Amino Acid Substitution; Carrier Proteins; Electrophoresis, Polyacrylamide Gel; Homocystinuria; Humans; Hydroxocobalamin; Kinetics; Metabolism, Inborn Errors; Methylmalonic Acid; Mutant Proteins; Oxidoreductases; Protein Binding; Recombinant Fusion Proteins; Spectrophotometry, Ultraviolet; Vitamin B 12

Cobalamin C (cblC) disease, an inborn error of vitamin B(12) metabolism, results in neurometabolic, neurochemical and neuroanatomical changes. Little is known of the long-term effects of the disorder on cognition and behaviour in children. Here, the complete neuropsychological profiles of two 12-year-old girls with cblC disease are presented. The two girls were tested longitudinally with standardized neuropsychological tests including intellectual ability, attention and memory, as well as executive, adaptive and behavioural function. The results indicate the presence of intellectual dysfunction, attention problems, and concerns with behavioural aspects of executive function. Both patients demonstrated a pattern of decreasing intellectual function over time, which may reflect a growing developmental gap in comparison with their same age peers. These impairments are in contrast to the relatively spared verbal expression and comprehension abilities, as well as strengths in sociability. The findings highlight a pattern of neuropsychological strengths and weaknesses that may distinguish cblC disease from other inborn errors of metabolism. Overt sociability such as observed in these two patients may actually mask underlying cognitive deficits because the patients appear to function at a more advanced level than that reflected by quantitative assessment of intellectual and cognitive functioning. This is of clinical and functional importance and suggests that accurate determination of cognitive, adaptive and social abilities necessitates an in-depth and broad evaluation. The presence of significant intellectual and cognitive deficits also underscores the need to document and monitor cognitive development in children with cblC disease and to consider remediative and adaptive learning strategies.

Topics: Adaptation, Psychological; Child; Child Behavior; Child Behavior Disorders; Child, Preschool; Cognition; Cognition Disorders; Female; Humans; Infant; Metabolism, Inborn Errors; Neuropsychological Tests; Social Behavior; Vitamin B 12

To assess and compare longitudinal visual function and retinal morphology in patients with methylmalonic aciduria with homocystinuria, cobalamin C type (cblC), and identified mutations in the MMACHC gene.. Vision function, anterior segment, and fundi were evaluated in patients with homozygous or compound heterozygous MMACHC mutations. Best-corrected visual acuity, full-field electroretinogram (ERG), refractive error, and retinopathy were assessed and compared for different genotypes and ages at onset, defined as early (<1 year of age) or late (>5 years).. We identified 7 patients (homozygous mutation: 6 of 7; compound heterozygous mutations: 1 of 7) between the ages of 3 months and 20.6 years. Six patients were reexamined after 3.2 to 11.5 years (mean, 6.5) Ocular phenotype ranged from normal to severely compromised visual function. Visual acuity was reduced from 0.2 logMAR to counting fingers and from 0.0 to 0.3 logMAR in the early- (3 of 7) and in the late-onset group (4 of 7), respectively. No retinopathy was evident in the late-onset group. Only patients with the homozygous c.547_548 delGT mutations (n = 2) demonstrated advanced retinopathy associated with cone-rod or rod-cone dysfunction. Retinopathy occurred despite systemic treatment for cblC.. Ocular phenotype in patients with cblC is variable. Ocular involvement seems to be correlated with age at onset. Patients with early-onset cblC developed generally progressive retinal disease ranging from subtle retinal nerve fiber layer loss to advanced macular and optic atrophy with "bone spicule" pigmentation. Patients with late-onset disease showed no definite evidence of retinal degeneration.

Topics: Adolescent; Age of Onset; Anterior Eye Segment; Carrier Proteins; Child; Child, Preschool; Disease Progression; Electroretinography; Eye; Female; Fundus Oculi; Genes, Recessive; Heterozygote; Homocystinuria; Humans; Infant; Longitudinal Studies; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Mutation; Oxidoreductases; Phenotype; Retina; Retinal Diseases; Visual Acuity; Vitamin B 12; Young Adult

It is unusual for inborn errors of metabolism to be considered in the investigative work-up of pancytopenia. We report a family in which the proband presented with failure to thrive at 2 months of age and subsequent bone marrow failure. A previous sibling had died at 7 months of age with suspected leukaemia. Haematological findings in the proband were significant for pancytopenia, and bone marrow aspiration showed dysplastic changes in all cell lineages. Urinary organic acid analysis revealed elevated methylmalonic acid. The synthesis of transcobalamin II (transcobalamin, TC) by cultured fibroblasts was markedly reduced, confirming the diagnosis of TC deficiency. The proband and his younger asymptomatic sister (also found to have TC deficiency) were homozygous for R399X (c.1195C>T), a novel mutation resulting in the loss of the C- terminal 29 amino acids of TC, a highly conserved region. Response to parenteral vitamin B(12) in the proband was dramatic. At 6 years 3 months of age, physical examination is normal and developmental level is age appropriate. His sister is clinically asymptomatic and is also developing normally. Propionylcarnitine concentrations were not elevated in the newborn screening cards from the proband and sister, but that was for specimens retrieved from storage after 7 years and 5 years, respectively. Inherited and acquired cobalamin disorders should both be considered in the differential diagnosis of bone marrow failure syndromes in young children. Early detection of the metabolic causes of bone marrow failure can ensure prompt recovery in some cases involving the vitamin B(12) pathway.

Topics: Biomarkers; Bone Marrow Diseases; Bone Marrow Examination; Cells, Cultured; Child; Child Development; Child, Preschool; DNA Mutational Analysis; Failure to Thrive; Female; Fibroblasts; Genetic Predisposition to Disease; Humans; Infant; Male; Metabolism, Inborn Errors; Mutation; Pancytopenia; Pedigree; Phenotype; Transcobalamins; Treatment Outcome; Vitamin B 12

Elevated propionyl C3 carnitine is the most common abnormality seen in tandem mass spectrometry newborn screening profiles, with an incidence of 0.15% seen in our South Australian newborn screening programme. The most common cause for this result in our population is vitamin B12 deficiency but differential diagnoses include the inherited disorders of propionic and methylmalonic acid metabolism and cobalamin deficiencies. An approach to confirmatory testing and subsequent management of infants with elevated propionic carnitine is presented.

Topics: Humans; Infant, Newborn; Metabolism, Inborn Errors; Neonatal Screening; Vitamin B 12

Vitamin B12 (cobalamin) is an essential cofactor in several metabolic pathways. Intracellular conversion of cobalamin to its two coenzymes, adenosylcobalamin in mitochondria and methylcobalamin in the cytoplasm, is necessary for the homeostasis of methylmalonic acid and homocysteine. Nine defects of intracellular cobalamin metabolism have been defined by means of somatic complementation analysis. One of these defects, the cblD defect, can cause isolated methylmalonic aciduria, isolated homocystinuria, or both. Affected persons present with multisystem clinical abnormalities, including developmental, hematologic, neurologic, and metabolic findings. The gene responsible for the cblD defect has not been identified.. We studied seven patients with the cblD defect, and skin fibroblasts from each were investigated in cell culture. Microcell-mediated chromosome transfer and refined genetic mapping were used to localize the responsible gene. This gene was transfected into cblD fibroblasts to test for the rescue of adenosylcobalamin and methylcobalamin synthesis.. The cblD gene was localized to human chromosome 2q23.2, and a candidate gene, designated MMADHC (methylmalonic aciduria, cblD type, and homocystinuria), was identified in this region. Transfection of wild-type MMADHC rescued the cellular phenotype, and the functional importance of mutant alleles was shown by means of transfection with mutant constructs. The predicted MMADHC protein has sequence homology with a bacterial ATP-binding cassette transporter and contains a putative cobalamin binding motif and a putative mitochondrial targeting sequence.. Mutations in a gene we designated MMADHC are responsible for the cblD defect in vitamin B12 metabolism. Various mutations are associated with each of the three biochemical phenotypes of the disorder.

Topics: Adolescent; Amino Acid Sequence; Child; Chromosomes, Human, Pair 2; DNA Mutational Analysis; Female; Homocystinuria; Humans; Infant; Infant, Newborn; Intracellular Signaling Peptides and Proteins; Male; Membrane Transport Proteins; Metabolism, Inborn Errors; Methylmalonic Acid; Mitochondrial Membrane Transport Proteins; Mitochondrial Proteins; Molecular Sequence Data; Sequence Analysis, Protein; Vitamin B 12

Inborn errors of vitamin B12 (cobalamin, Cbl) metabolism are autosomal recessive disorders and have been classified into nine distinct complementation classes (cblA-cblH and mut). Disorders affecting methylcobalamin metabolism cause megaloblastic anemia, which may be accompanied by leukopenia and thrombocytopenia, and a variety of neurological problems. Disorders affecting adenosylcobalamin cause methylmalonic acidemia and metabolic acidosis. Previous studies have shown that cobalamin binds to two enzymes in humans: methylmalonyl-CoA mutase in mitochondria and methionine synthase in the cytosol. In this study, cobalamin binding patterns were analyzed in crude mitochondrial fractions obtained from both control and patient fibroblasts that had been incubated with [57Co]cyanocobalamin. Crude mitochondrial fractions from control fibroblasts confirmed that the majority of [57Co]Cbl eluted with methylmalonyl-CoA mutase. However, in six of the nine disorders, at least one previously unidentified mitochondrial cobalamin binding protein was observed to bind [57Co]Cbl. The proportion of [57Co]Cbl that binds, is increased compared to controls when a deficiency in either adenosylcobalamin synthesis or utilization prevents binding to methylmalonyl-CoA mutase. Furthermore, unique cobalamin binding profiles emerged demonstrating how known mutations in these patients affect cobalamin binding to as yet unidentified proteins.

Topics: Case-Control Studies; Cell Line; Chromatography, Gel; Cobamides; Enzymes; Fibroblasts; Genetic Complementation Test; Humans; Metabolism, Inborn Errors; Methylmalonyl-CoA Mutase; Mitochondrial Proteins; Transcobalamins; Vitamin B 12

The methylmalonic aciduria is an organic acidemia, inherited as autosomic recessive trait, caused by a deficiency of the methylmalonyl-CoA mutase, or by defects in the biosynthesis of the cofactor adenosylcobalamin. Regarding the enzymatic defect, there are two forms: mut(o) with no detectable enzymatic activity and mut(-) with reduced activity. Its clinical presentation may vary from a severe neonatal form with acidosis and death, up to a progressive chronic form. Here we describe the case of a four year-old boy, with diagnosis of methylmalonyl-CoA mutase deficiency type mut(-) with an acute presentation. Molecular analysis of MUT gene identified two mutations c.607G>A (G203R) and c.2080C>T (R694W), later confirmed in the parents. The aim of this report is to highlight the importance of including the organic acid analysis in urine among the first line exams in acutely and severely ill children with undefined etiology. The definitive diagnosis is important because it may allow a specific treatment and a favorable evolution to prevent the secuelae.

Topics: Acidosis; Amino Acid Substitution; Child, Preschool; Coma; Diet, Protein-Restricted; Diseases in Twins; Fertilization in Vitro; Genes, Recessive; Humans; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Mutation, Missense; Point Mutation; Twins, Dizygotic; Vitamin B 12; Vomiting

Cobalamin is an essential cofactor for two mammalian enzymes: methionine synthase and methylmalonyl-CoA mutase. Patients with the cobalamin C (CblC) defect have combined methylmalonic aciduria and homocystinuria. Recently, the gene responsible for the CblC type, MMACHC, was identified, which enables molecular diagnostics. In this study, we describe two siblings, a 16-year-old girl and her 11-year-old brother, of a consanguineous family who presented with a very distinct clinical manifestation. The girl presented at the age of 13 years with macrocytic anaemia, cognitive regression and Marfanoid features such as increased arm-span, arachnodactyly, joint hyperlaxity and scoliosis. Her brother presented at the age of 10 months with developmental delay and behavioural abnormalities. Biochemical analysis showed severely increased homocysteine and methylmalonic acid levels in plasma of both siblings. In addition, plasma cysteine levels were decreased in the girl but not in her brother. The diagnosis of CblC defect was confirmed by genomic sequencing of the coding exons of the MMACHC gene. Two heterozygous mutations were identified in both siblings; the common c.271dupA p.Arg91LysfsX14 and a novel mutation, c.1A > G p.Met1?. Therapy consisting of folic acid, vitamin B6, l-carnitine and intramuscular vitamin B12 resulted in a clear improvement of biochemical parameters and, importantly, resulted in amelioration of the Marfanoid features in the girl. These data might suggest that low cysteine levels account for the Marfanoid features observed in the girl and indicate that the CblC type of combined methylmalonic aciduria and homocystinuria should be considered in the differential diagnosis of patients with Marfanoid features.

Topics: Adolescent; Carnitine; Carrier Proteins; Child; Cysteine; Diagnosis, Differential; DNA Mutational Analysis; Exons; Female; Folic Acid; Genetic Testing; Heterozygote; Homocysteine; Homocystinuria; Humans; Male; Marfan Syndrome; Metabolism, Inborn Errors; Methylmalonic Acid; Mutation; Oxidoreductases; Pedigree; Phenotype; Treatment Outcome; Vitamin B 12; Vitamin B 6; Vitamins

We report on the case of a 36-year-old Hispanic woman with a spinal cord infarct, who was subsequently diagnosed with methylmalonic aciduria and homocystinuria, cblC type (cblC). Mutation analysis revealed c.271dupA and c.482G > A mutations in the MMACHC gene. The patient had a past medical history significant for joint hypermobility, arthritis, bilateral cataracts, unilateral hearing loss, anemia, frequent urinary tract infections, and mental illness. There was no significant past history of mental retardation, failure to thrive, or seizure disorder as reported in classic cases of cblC. Prior to the thrombotic incident, the patient experienced increased paresthesia in the lower extremities, myelopathy, and impaired gait. Given her previous psychiatric history, she was misdiagnosed with malingering until hemiplegia and incontinence became apparent. The authors would like to emphasize the recognition of a neuropsychiatric presentation in late onset cblC. Ten other reported late onset cases with similar presentations are also reviewed.

Topics: Adult; Carrier Proteins; Female; Homocystinuria; Humans; Mental Disorders; Metabolism, Inborn Errors; Methylmalonic Acid; Mutation; Neuropsychological Tests; Oxidoreductases; Vitamin B 12

Renal tubular dysfunction and chronic renal failure are well recognised complications of methylmalonic acidaemia (MMA) and can occur even in the context of optimal medical metabolic management. Organ transplantation, such as renal and combined liver and renal transplants, have been utilised in the past for children whose disease cannot be managed by conservative medical practices and those with end stage renal disease. Our patient was diagnosed with B(12)-responsive MMA (subsequently proven to be cblA-type MMA) in the postoperative period following renal transplantation for idiopathic chronic renal failure. She remains well, with excellent graft function and metabolic control 4 years after transplantation. This patient highlights the importance of testing for the inborn errors of metabolism in patients presenting with recurrent acidosis and progressive renal impairment.

Topics: Adolescent; Cobamides; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Metabolism, Inborn Errors; Methylmalonic Acid; Vitamin B 12

Methylmalonic aciduria and homocystinuria, cblC type (OMIM 277400), is the most common inborn error of vitamin B(12) (cobalamin) metabolism, with about 250 known cases. Affected individuals have developmental, hematological, neurological, metabolic, ophthalmologic and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood. The cblC locus was mapped to chromosome region 1p by linkage analysis. We refined the chromosomal interval using homozygosity mapping and haplotype analyses and identified the MMACHC gene. In 204 individuals, 42 different mutations were identified, many consistent with a loss of function of the protein product. One mutation, 271dupA, accounted for 40% of all disease alleles. Transduction of wild-type MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. Molecular modeling predicts that the C-terminal region of the gene product folds similarly to TonB, a bacterial protein involved in energy transduction for cobalamin uptake.

Topics: Amino Acid Sequence; Bacterial Proteins; Carrier Proteins; Cell Line; Chromosome Mapping; Conserved Sequence; Fibroblasts; Haplotypes; Homocystinuria; Humans; Membrane Proteins; Metabolism, Inborn Errors; Methylmalonic Acid; Molecular Sequence Data; Mutation; Oxidoreductases; Protein Folding; Structural Homology, Protein; Vitamin B 12

Methylmalonic aciduria, cblB type (OMIM 251110) is an inborn error of vitamin B(12) metabolism that occurs due to mutations in the MMAB gene. MMAB encodes the enzyme ATP:cobalamin adenosyltransferase, which catalyzes the synthesis of the coenzyme adenosylcobalamin required for the activity of the mitochondrial enzyme methylmalonyl CoA mutase (MCM). MCM catalyzes the isomerization of methylmalonyl CoA to succinyl CoA. Deficient MCM activity results in methylmalonic aciduria and a susceptibility to life-threatening acidotic crises. The MMAB gene was sequenced from genomic DNA from a panel of 35 cblB patients, including five patients previously investigated. Nineteen MMAB mutations were identified, including 13 previously unknown mutations. These included 11 missense mutations, two duplications, one deletion, four splice-site mutations, and one nonsense mutation. None of these mutations was identified in 100 control alleles. Most of the missense mutations (9/11) were clustered in exon 7; many of these affected amino acid residues that are part of the probable active site of the enzyme. One previously described mutation, c.556C >T (p.R186W), was particularly common, accounting for 33% of pathogenic alleles. It was seen almost exclusively in patients of European background and was typically associated with presentation in the first year of life.

Topics: Alkyl and Aryl Transferases; Cells, Cultured; Child; Child, Preschool; Female; Genotype; Humans; Infant; Infant, Newborn; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Mutation; Phenotype; Vitamin B 12

ATP:cob(I)alamin adenosyltransferase (MMAB protein; methylmalonic aciduria type B) is an enzyme of vitamin B(12) metabolism that converts reduced cob(I)alamin to the adenosylcobalamin co-factor required for the functional activity of methylmalonyl-CoA mutase. Mutations in the human MMAB gene result in a block in adenosylcobalamin synthesis and are responsible for the cblB complementation group of inherited vitamin B(12) disorders. In this study, we examined the impact of several mutations, previously identified in cblB patients and clustered within a small, highly conserved region in MMAB. We confirmed mitochondrial expression of MMAB in human cells and showed that two mutations, R186W and E193K, were associated with absent protein by Western blot, while one, R191W, coupled with another point mutation, produced a protein in patient fibroblasts. Wild type MMAB and all four mutant proteins were stably expressed at high level as GST-fusion proteins, but only the R191W protein was enzymatically active. It showed an elevated K(m) of 320 microM (vs 6.8 microM for wild type enzyme) for ATP and 60 microM (vs 3.7 microM) for cob(I)alamin, with a reduction in k(cat) for both substrates. Circular dichroism spectroscopy revealed that three mutant proteins examined retained a alpha-helical structure as for the wild type protein. Characterization of MMAB will contribute to our understanding of cobalamin processing in mammalian cells and of disease mechanisms in the genetic disorders.

Topics: Alkyl and Aryl Transferases; Cell Line; Circular Dichroism; Humans; Kinetics; Metabolism, Inborn Errors; Point Mutation; Protein Structure, Secondary; Vitamin B 12

Subacute combined degeneration (SCD) of the spinal cord is a characteristic complication of vitamin B12 deficiency, but it has never been neuropathologically demonstrated in a B12-inborn error of metabolism. In this report SCD is documented in a 15-year-old boy with early-onset cobalamin C (cblC) disorder. The neuropathologic findings included multifocal demyelination and vacuolation with predilection for the dorsal and lateral columns at the mid-thoracic level of the spinal cord, confirming the similarity of SCD in cblC disorder to the classic adult SCD due to vitamin B12 deficiency. SCD developed in this boy despite treatment for cblC disorder that began at 3 months of age. There is clinical and experimental evidence to suggest that a deficiency in remethylation with concomitant reduction in brain methionine may be the cause of SCD. In this patient plasma methionine levels were low without betaine and/or l-methionine supplementation and in the normal range for only a 2-year period during compliance with therapy. In cblC disorder, a consistent increase in blood methionine to high normal or above normal levels by the use of betaine and l-methionine supplementation may be helpful in preventing SCD. This is especially important now that the presymptomatic detection of cblC disorder is possible through the expansion of newborn screening.

Topics: Adolescent; Brain; Child; Child, Preschool; Fatal Outcome; Humans; Hydroxocobalamin; Infant; Infant, Newborn; Male; Median Nerve; Metabolism, Inborn Errors; Muscle, Skeletal; Neurodegenerative Diseases; Spinal Cord; Spinal Cord Diseases; Vitamin B 12

Topics: Carrier Proteins; Cell Line; Homocystinuria; Humans; Metabolism, Inborn Errors; Methylmalonic Acid; Models, Biological; Mutation; Oxidoreductases; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Vitamin B 12

Methylmalonic aciduria and homocystinuria, cblC type (MIM 277400), is the most frequent inborn error of vitamin B12 (cobalamin, Cbl) metabolism, caused by an inability of the cell to convert Cbl to both of its active forms (MeCbl, AdoCbl). Although considered a disease of infancy, some patients develop symptoms in childhood, adolescence, or adulthood. The gene responsible for cblC, MMACHC, was recently identified. We studied phenotype-genotype correlations in 37 patients from published case-reports, representing most of the landmark descriptions of this disease. 25/37 had early-onset disease, presenting in the first 6 months of life: 17/25 were found to be either homozygous for the c.271dupA mutation (n=9) or for the c.331C>T mutation (n=3), or compound heterozygotes for these 2 mutations (n=5). 9/12 late-onset cases presented with acute neurological symptoms: 4/9 were homozygous for the c.394C>T mutation, 2/9 were compound heterozygotes for the c.271dupA and c.394C>T mutations, and 3/9, for the c.271dupA mutation and a missense mutation. Several observations on ethnic origins were noted: the c.331C>T mutation is seen in Cajun and French-Canadian patients and the c.394C>T mutation is common in the Asiatic-Indian/Pakistani/Middle Eastern populations. The recognition of phenotype-genotype correlations and the association of mutations with specific ethnicities will be useful for identification of disease-causing mutations in cblC patients, for carrier detection and prenatal diagnosis in families where mutations are known, and in setting up initial screening programs in molecular diagnostic laboratories. Further study into disease mechanism of specific mutations will help to understand phenotypic presentations and the overall pathogenesis in cblC patients.

Topics: Adolescent; Age of Onset; Carrier Proteins; Child; Ethnicity; Female; Fibroblasts; Heterozygote; Homocystinuria; Homozygote; Humans; Infant; Infant, Newborn; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Mutation; Oxidoreductases; Vitamin B 12

The patients affected by vitamin B12-unresponsive methylmalonic acidemia (MMA) on the long run develop chronic renal disease with interstitial nephropathy and progressive renal insufficiency. The mechanism of nephrotoxicity in vitamin B12-unresponsive MMA is not yet known. Chronic hyporeninemic hypoaldosteronism has been found in many cases of methylmalonic acidemia, hyperkalemia and renal tubular acidosis type 4. We report 2 patients affected by B12-unresponsive methylmalonic acidemia diagnosed at the age of 23 months and 5 years, respectively, with normal glomerular filtration and function. They showed hyporeninemic hypoaldosteronism and significant hyperkalemia requiring sodium potassium exchange resin (Kayexalate) therapy after an episode of metabolic decompensation leading to diagnosis of MMA. In both children, hyporeninemic hypoaldosteronism and hyperkalemia disappeared after 6 months of good metabolic control.

Topics: Child, Preschool; Female; Fumarates; Humans; Hyperkalemia; Hypoaldosteronism; Infant; Kidney; Male; Maleates; Metabolism, Inborn Errors; Vitamin B 12

Organic acidemias (OAs) have been detected worldwide in symptomatic patients using gas chromatography mass spectrometry. We diagnosed 188 Asian cases of OAs by analysis of urinary organic acids and investigated their clinical onset and outcome. Methylmalonic acidemia (MMA) was most common (74 cases), followed by propionic acidemia (23 cases), ornitine transcarbamylase deficiency (22 cases), and multiple carboxylase deficiency (15 cases). For these 188 patients, onset was most frequent in the neonatal period or early infancy. Approximately 30% of the patients had a family history of similar symptoms or diseases. Although the outcome of OA patients varied, patients with early onset generally had poor outcomes despite early detection. Of the 45 MMA patients whose clinical data were available, 25 were clinically vitamin B12-responsive, while the remaining 20 were non-responsive. A favorable outcome was obtained in 7 of the 25 B12-responsive patients, and in only 3 of the 20 B12-nonresponsive patients. It was suggested that even in B12-responsive MMA cases, earlier detection and B12 therapy were needed to improve the prognosis. We concluded that detection of such patients at the presymptomatic stages using newborn mass screening is essential for prognosis improvement with OAs.

Topics: Adolescent; Age of Onset; Asia; Carboxylic Acids; Child; Child, Preschool; Disease Progression; Drug Resistance; Family Health; Female; Gas Chromatography-Mass Spectrometry; Humans; Infant; Infant, Newborn; Male; Mass Screening; Metabolism, Inborn Errors; Methylmalonic Acid; Multiple Carboxylase Deficiency; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Prognosis; Propionates; Treatment Outcome; Vitamin B 12

Cobalamin C disease is a rare genetic condition resulting in methylmalonic aciduria, homocystinuria, and hematologic abnormalities. Clinical characteristics include ophthalmologic findings and neurological abnormalities, such as microcephaly, seizure, and mental retardation. The authors report on a 4-month-old patient initially diagnosed with hemophagocytic lymphohistiocytosis (HLH), who was later diagnosed with cobalamin C disease.

Topics: Diagnosis, Differential; Female; Hemolytic-Uremic Syndrome; Homocystinuria; Humans; Infant; Lymphohistiocytosis, Hemophagocytic; Metabolism, Inborn Errors; Methylmalonic Acid; Prednisone; Vitamin B 12

Methylmalonic aciduria (MMA) is divided into two groups according to cobalamin dependency, and this classification is important for treatment. Unfortunately, there has been no rapid and reliable method for the evaluation of cobalamin dependency.. [14C]-propionate incorporation into intact cells in the presence of either media alone or media containing various amounts of cobalamin was measured using a 96-well filtration plate and vacuum manifold. Incorporation of radioactivity was measured by direct microplate scintillation.. Using peripheral white blood cells from normal individuals, we obtained a linear relationship between the rate of 14C-propionate incorporation and the number of cells over a broad range (10,000 to 100,000 cells/well). 14C-propionate incorporation in cells from eight patients was 1% to 13% of parallel controls.. In this report, we describe a rapid, sensitive and reliable method for evaluating the cobalamin dependency of methylmalonic aciduria.

Topics: Age of Onset; Carbon Radioisotopes; Child, Preschool; Female; Filtration; Humans; Infant; Infant, Newborn; Leukocyte Count; Leukocytes; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Propionates; Sensitivity and Specificity; Vitamin B 12

Topics: Child Abuse; Diagnosis, Differential; Female; Hematoma; Hematoma, Subdural; Homocystinuria; Humans; Hypothermia; Hypovolemia; Infant; Metabolism, Inborn Errors; Methylmalonic Acid; Pregnancy; Premature Birth; Retinal Hemorrhage; Sleep Stages; Vitamin B 12

Mutations in the MMAA gene on human chromosome 4q31.21 result in vitamin B12-responsive methylmalonic aciduria (cblA complementation group) due to deficiency in the synthesis of adenosylcobalamin. Genomic DNA from 37 cblA patients, diagnosed on the basis of cellular adenosylcobalamin synthesis, methylmalonyl-coenzyme A (CoA) mutase function, and complementation analysis, was analyzed for deleterious mutations in the MMAA gene by DNA sequencing of exons and flanking sequences. A total of 18 novel mutations were identified, bringing the total number of mutations identified in 37 cblA patients to 22. A total of 13 mutations result in premature stop codons; three are splice site defects; and six are missense mutations that occur at highly conserved residues. Eight of these mutations were common to two or more individuals. One mutation, c.433C>T (R145X), represents 43% of pathogenic alleles and a common haplotype was identified. Restriction endonuclease or heteroduplex diagnostic tests were designed to confirm mutations. None of the sequence changes identified in cblA patients were found in 100 alleles from unrelated control individuals.

Topics: Child, Preschool; Chromosomes, Human, Pair 4; Cobamides; DNA Mutational Analysis; Exons; Female; Genetic Complementation Test; Haplotypes; Humans; Infant; Infant, Newborn; Male; Membrane Transport Proteins; Metabolism, Inborn Errors; Methylmalonic Acid; Mitochondrial Membrane Transport Proteins; Mitochondrial Proteins; Mutation; Polymorphism, Single Nucleotide; Vitamin B 12

We report the successful treatment of a woman with Cobalamin A disease with hydroxycobalamin injections during pregnancy and delivery and 3 months after delivery. Urine and plasma methylmalonic acid levels served to adjust therapy before and after delivery. The mother had no untoward metabolic complications and gave birth to a normal baby.

Topics: Cobamides; Female; Humans; Hydroxocobalamin; Metabolism, Inborn Errors; Methylmalonic Acid; Pregnancy; Pregnancy Complications; Vitamin B 12

We report on a favourable pregnancy in a woman affected by mut- methylmalonic acidaemia. Under vitamin B12 and carnitine therapy she remained symptom-free throughout pregnancy, labour, delivery and the postpartum period and gave birth to a term, healthy female newborn. At follow-up, the child shows normal somatic and neurocognitive development.

Topics: Adult; Carnitine; Female; Humans; Metabolism, Inborn Errors; Methylmalonic Acid; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Vitamin B 12

To investigate genetic heterogeneity within the cblA class of inborn error of cobalamin metabolism.. The cblA disorder is characterised by vitamin B12 (cobalamin) responsive methylmalonic aciduria and deficient synthesis of adenosylcobalamin, required for activity of the mitochondrial enzyme methylmalonyl CoA mutase. The cblA gene has not been identified or cloned. We have previously described a patient with the clinical and biochemical phenotype of the cblA disorder whose fibroblasts complemented cells from patients with all known types of inborn error of adenosylcobalamin synthesis, including cblA.. We have performed somatic cell complementation analysis of the cblA variant fibroblast line with a panel of 28 cblA lines. We have also performed detailed complementation analysis on a panel of 10 cblA fibroblast lines, not including the cblA variant line.. The cblA variant line complemented all 28 cell lines of the panel. There was evidence for interallelic complementation among the 10 cblA lines used for detailed complementation analysis; no cell line in this panel complemented all other members.. These results strongly suggest that the cblA variant represents a novel complementation class, which we have designated cblH and which represents a mutation at a distinct gene. They also suggest that the cblA gene encodes a protein that functions as a multimer, allowing for extensive interallelic complementation.

Topics: Alleles; Cell Line; Cobamides; Fibroblasts; Genetic Complementation Test; Humans; Metabolism, Inborn Errors; Methylmalonyl-CoA Mutase; Vitamin B 12

To report the association of optic atrophy with cobalamin C (cblC) disease.. Descriptive case reports on three patients, two of whom were siblings.. All three patients with cblC disease exhibited bilateral optic atrophy with decreased visual acuity. Of the two siblings, the younger sister had received cobalamin supplements from birth and the mother had been given cobalamin supplements prenatally.. These three cases confirm the association of optic atrophy with cblC disease. Early treatment with cobalamin supplements does not appear to prevent the development of optic atrophy.

Topics: Age of Onset; Child, Preschool; Consanguinity; Female; Follow-Up Studies; Homocystine; Homocystinuria; Humans; Metabolism, Inborn Errors; Methylmalonic Acid; Optic Atrophy; Vitamin B 12

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

Cobalamin C (cblC) defects result in decreased activity of both methylmalonyl-CoA mutase and N5-methyltetrahydrofolate:homocysteine methyltransferase (methionine synthase), with subsequent methylmalonic acid-uria and homocystinuria. Patients typically show failure to thrive, developmental delay and megaloblastic anaemia. Vitamin B12 therapy has been beneficial in some cases. We report a now 4-year-old Hispanic girl with cblC disease documented by complementation analysis, with progressive neurological deterioration and worsening head MRI changes while on intramuscular hydroxocobalamin begun at age 3 weeks. Oral carnitine and folic acid were added at age 1 year. Blood levels of methylmalonic acid were reduced to treatment ranges. In the absence of acute metabolic crises, she developed microcephaly, progressive hypotonia and decreased interactiveness. Funduscopic examination was normal at age 13 months. At age 19 months, she developed nystagmus, and darkly pigmented fundi and sclerotic retinal vessels were observed on examination. Her neonatal head MRI was normal. By age 1 year, the MRI showed diffuse white-matter loss with secondary third and lateral ventricle enlargement, a thin corpus callosum, and normal basal ganglia. At age 15 months, progression of the white-matter loss, as well as hyperintense globi pallidi, were present. Interval progression of both grey- and white-matter loss was seen at age 27 months. We therefore caution that progressive neurological deterioration and head MRI abnormalities may still occur in cblC disease, despite early initiation of hydroxocobalamin therapy and improvement in toxic metabolite concentrations in physiological fluids.

Topics: Brain; Child, Preschool; Disease Progression; Female; Humans; Hydroxocobalamin; Magnetic Resonance Imaging; Metabolism, Inborn Errors; Methylmalonic Acid; Neurologic Examination; Vitamin B 12

Topics: Aging; Child; Dementia; Electroencephalography; Female; Homocystinuria; Humans; Hydroxocobalamin; Leucovorin; Magnetic Resonance Imaging; Metabolism, Inborn Errors; Methylmalonic Acid; Vitamin B 12

An 18-month-old girl presented with macrocytic megaloblastic anaemia followed by haemolytic uraemic syndrome. Metabolic investigations led to the identification of an inborn error of cobalamin metabolism consisting of defective methylcobalamin biosynthesis, probably cobalamin G, since methionine synthase activity was decreased under standard reducing conditions. Despite treatment, pulmonary hypertension progressively developed and responded to oxygen therapy. Renal involvement evolved to terminal failure and haemodialysis, while pulmonary hypertension was controlled by oxygen therapy. Such clinical manifestations have never been reported in association with a defect of methylcobalamin and thus of methionine biosynthesis. A congenital abnormality of cobalamin metabolism was suspected then confirmed in the presence of typical haematological features associated with unusual clinical manifestations such as progressive renal failure and pulmonary hypertension.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Anemia, Megaloblastic; Female; Hemolytic-Uremic Syndrome; Humans; Hypertension, Pulmonary; Infant; Metabolism, Inborn Errors; Methionine; Vitamin B 12

Transcobalamin II (TC II) is a plasma protein that binds vitamin B12 (cobalamin, Cbl) and facilitates cellular Cbl uptake by receptor-mediated endocytosis. In autosomal recessive TC II deficiency, intracellular Cbl deficiency results in an early onset of megaloblastic anaemia that may be accompanied by neurological abnormalities. Inadequate treatment may lead to neurological abnormalities. We describe three sisters, the daughters of first cousins of Moroccan origin, with TC II deficiency requiring continuous and long-term vitamin B12 treatment. The diagnosis was suspected from the finding of low unsaturated vitamin B12 binding capacity and confirmed by absence of detectable TC II by radioimmunoassay and by inability of cultured fibroblasts to synthesize TC II.

Topics: Cells, Cultured; Female; Fibroblasts; Follow-Up Studies; Humans; Infant; Infant, Newborn; Ketosis; Metabolism, Inborn Errors; Methylmalonic Acid; Propionates; Transcobalamins; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency

Methylmalonic acidaemia is an inborn error of metabolism characterized by recurrent episodes of life-threatening ketoacidosis. With improved and intensive treatment, these patients are living into adulthood, but many experience late-onset disease complications such as chronic renal failure, chronic pancreatitis and osteopenia. We report the successful delivery of a healthy baby to a 20-year-old woman with vitamin B12-unresponsive methylmalonic acidaemia who has these late-onset manifestations of the disease and had plasma methylmalonic acid concentrations of 1900 mumol/L during the first trimester of pregnancy.

Topics: Acidosis; Adult; Female; Humans; Hydroxocobalamin; Infant, Newborn; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Vitamin B 12

To compare the therapeutic effectiveness of hydroxocobalamin and cyanocobalamin in patients with combined methylmalonic acidemia and homocystinuria.. Analysis of urine methylmalonic acid, plasma homocystine, and growth of two unrelated patients with cobalamin C disease who were initially receiving cyanocobalamin and were subsequently switched to hydroxocobalamin.. Each patient had a significant decrease in urine methylmalonic acid excretion while receiving cyanocobalamin, but levels remained at least 10 times normal. Cyanocobalamin treatment resulted in a decrease of plasma homocystine to near normal in one patient but had no effect on plasma homocystine in the second patient. Each patient was switched to hydroxocobalamin and urine methylmalonic acid levels decreased to the limit of detection. Plasma homocystine values while taking hydroxocobalamin remained < 5 nmol/ml in both patients. In patient 1, who continued to receive cyanocobalamin therapy for more than 1 year, growth rates (height, weight, and head circumference) were very poor. After initiation of hydroxocobalamin, growth parameters normalized with growth rates above normal.. Intramuscular cyanocobalamin treatment is inadequate in the treatment of patients with cobalamin C disease. Appropriate management of cobalamin C disease should include only the hydroxocobalamin form of cobalamin.

Topics: Child; Child, Preschool; Female; Growth; Homocystine; Homocystinuria; Humans; Hydroxocobalamin; Infant; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Vitamin B 12

Deficiency of methylenetetrahydrofolate reductase (MTHFR) is associated with a variable phenotype that includes mental retardation, gait abnormalities, and seizures. Many of the same clinical findings are also seen in patients with Angelman syndrome. We report on a patient with MTHFR deficiency who was initially diagnosed as having Angelman syndrome. This case illustrates that MTHFR deficiency can mimic the phenotype of Angelman syndrome and that MTHFR deficiency should be excluded in patients with manifestations of Angelman syndrome whose molecular studies of chromosome 15 are normal.

Topics: Angelman Syndrome; Child; Diagnosis, Differential; Homocysteine; Homocystinuria; Humans; Male; Metabolism, Inborn Errors; Methionine; Methylenetetrahydrofolate Reductase (NADPH2); Oxidoreductases Acting on CH-NH Group Donors; Phenotype; Vitamin B 12

To assess the long term outcome of patients with methylmalonic acidaemia in a cross sectional study.. All 35 patients with methylmalonic acidaemia seen at Great Ormond Street Hospital for Children in London, UK between 1970 and 1996 were studied. They were divided into cobalamin responsive (n = 6) and non-responsive (n = 29), and early and late onset groups.. There was a significant difference between cobalamin responsive and non-responsive groups in severity, survival, and incidence of neurological sequelae. Cobalamin responsive patients had mild disease, irrespective of age at presentation, their neurological complications were less severe, and they are all alive. The cobalamin non-responsive group comprised 19 early and nine late onset patients. The early onset patients had more severe disease at presentation and 14 have died; all late onset patients are alive. There was no significant difference in abnormal neurological signs, although early onset patients had a significantly reduced full scale intelligence quotient and poor cognitive outcome. In both groups, abnormal neurological signs continue to increase with age.. Cobalamin responsive patients have a better long term outcome. The outcome in the non-responsive patients, particularly the early onset group, remains poor and alternative treatments should therefore be considered early in this group.

Topics: Adolescent; Adult; Age of Onset; Child; Child, Preschool; Cognition Disorders; Dystonia; Female; Humans; Infant; Infant, Newborn; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Treatment Outcome; Vitamin B 12

Topics: Adult; Child; Female; Homocystinuria; Humans; Metabolism, Inborn Errors; Methylmalonic Acid; Vitamin B 12

Inherited defects in the gene for methylmalonyl-CoA mutase (EC 5.4.99.2) result in the mut forms of methylmalonic aciduria. mut- mutations lead to the absence of detectable mutase activity and are not corrected by excess cobalamin, whereas mut- mutations exhibit residual activity when exposed to excess cobalamin. Many of the mutations that cause methylmalonic aciduria in humans affect residues in the C-terminal region of the methylmalonyl-CoA mutase. This portion of the methylmalonyl-CoA mutase sequence can be aligned with regions in other B12 (cobalamin)-dependent enzymes, including the C-terminal portion of the cobalamin-binding region of methionine synthase. The alignments allow the mutations of human methylmalonyl-CoA mutase to be mapped onto the structure of the cobalamin-binding fragment of methionine synthase from Escherichia coli (EC 2.1.1.13), which has recently been determined by x-ray crystallography. In this structure, the dimethylbenzimidazole ligand to the cobalt in free cobalamin has been displaced by a histidine ligand, and the dimethylbenzimidazole nucleotide "tail" is thrust into a deep hydrophobic pocket in the protein. Previously identified mut0 and mut- mutations (Gly-623 --> Arg, Gly-626 --> Cys, and Gly-648 --> Asp) of the mutase are predicted to interfere with the structure and/or stability of the loop that carries His-627, the presumed lower axial ligand to the cobalt of adenosylcobalamin. Two mutants that lead to severe impairment (mut0) are Gly-630 --> Glu and Gly-703 --> Arg, which map to the binding site for the dimethylbenzimidazole nucleotide substituent of adenosylcobalamin. The substitution of larger residues for glycine is predicted to block the binding of adenosylcobalamin.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Alleles; Amino Acid Sequence; Animals; Bacteria; Binding Sites; Caenorhabditis elegans; Escherichia coli; Heterozygote; Humans; Metabolism, Inborn Errors; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Models, Molecular; Molecular Sequence Data; Nucleotides; Point Mutation; Polymorphism, Genetic; Protein Conformation; Sequence Homology, Amino Acid; Vitamin B 12

Topics: Child, Preschool; Female; Humans; Kidney; Metabolism, Inborn Errors; Methylmalonic Acid; Uremia; Vitamin B 12

The prenatal therapy is described of a patient with vitamin B12-responsive methylmalonic acidaemia during the last 10 days of gestation with oral administration of vitamin B12 (20 mg/day) given to a mother did not normalize her urinary excretion of methylmalonic acid (MMA), which was 14.5 mmol/mol creatinine at 32 weeks of gestation. Before delivery, the mother was excreting 18.9 +/- 3.3 mmol MMA/mol creatinine (mean value at 7 days after vitamin B12 therapy), as well as at 32-37 weeks of gestation with no therapy. After birth, the level of MMA in the infant's urine was remarkably elevated (500-700 mmol/mol creatinine); the level of MMA in maternal urine decreased dramatically after delivery. Compared with two previous reports, the length of administration was not sufficient to reduce maternal MMA excretion. In future, the length of the therapy, route of administration and total dose of vitamin B12 to maintain an efficient level of vitamin B12 in an affected fetus should be considered.

Topics: Female; Fetal Diseases; Humans; Metabolism, Inborn Errors; Methylmalonic Acid; Pregnancy; Prenatal Diagnosis; Vitamin B 12

Topics: Adipose Tissue; Fatty Acids; Female; Humans; Infant, Newborn; Metabolism, Inborn Errors; Methylmalonic Acid; Pregnancy; Prenatal Care; Prenatal Diagnosis; Vitamin B 12

Homocysteine and 5-CH3-tetrahydrofolate (5-CH3-THF) are converted to methionine and THF by the CH3-cobalamin (CH3-Cbl)-dependent enzyme methionine synthase. Serum homocysteine levels are elevated in more than 95% of patients with Cbl or folate deficiency and in patients with inborn errors involving the synthesis of 5-CH3-THF or CH3-Cbl. Homocysteine and betaine are converted to methionine and N,N-dimethylglycine by betaine-homocysteine methyltransferase. It requires neither Cbl nor folate, although N,N-dimethylglycine is converted to N-methylglycine and then to glycine in reactions that both involve the formation of 5,10-CH2-THF from THF. Large amounts of betaine are often given orally to patients with inborn errors, even though little is known about its metabolism in normal subjects or these patients. Thus we developed new gas chromatographic-mass spectrometric assays for serum betaine, N,N-dimethylglycine, and N-methylglycine. In 60 blood donors, we found ranges for normal serum of 17.6 to 73.3, 1.42 to 5.27, and 0.60 to 2.67 mumol/L for the three metabolites, respectively, which were normal in the majority of 50 patients with Cbl deficiency, none of whom had increased levels of N-methylglycine. In 25 patients with folate deficiency, serum betaine level was normal in most, but 76% and 60% had elevations of N,N-dimethylglycine and N-methylglycine levels that ranged as high as 343 and 43.2 mumol/L, respectively. All of seven patients on betaine therapy for inborn errors had high values for betaine (167 to 3,900 mumol/L), N,N-dimethylglycine (15.1 to 250 mumol/L), and N-methylglycine (2.93 to 49.3 mumol/L). Serum total homocysteine levels remained very high at 47.2 to 156 mumol/L (normal, 5.4 to 16.2). In patients with cbl C and cbl D mutations, methionine levels remained low or low-normal at 8.3 to 15.6 mumol/L (normal, 13.3 to 42.7) despite betaine treatment. We conclude that (1) betaine levels are maintained in most patients with Cbl and folate deficiency; (2) levels of N,N-dimethylglycine and N-methylglycine are increased in most patients with folate deficiency; and (3) betaine therapy is relatively ineffective in patients with defective synthesis of CH3-Cbl.

Topics: Adolescent; Adult; Aged; Animals; Betaine; Betaine-Homocysteine S-Methyltransferase; Chromatography; Creatinine; Cystathionine beta-Synthase; Female; Folic Acid Deficiency; Gas Chromatography-Mass Spectrometry; Homocysteine; Humans; Male; Metabolism, Inborn Errors; Methionine; Methyltransferases; Middle Aged; Rats; Rats, Sprague-Dawley; Reference Values; Renal Insufficiency; Sarcosine; Vitamin B 12; Vitamin B 12 Deficiency

Low levels of cerebrospinal S-adenosylmethionine in association with abnormal myelination in inherited disorders affecting cobalamin and folate metabolism provide new data on a possible mechanism of cobalamin neuropathy.

Topics: Child, Preschool; Folic Acid; Folic Acid Deficiency; Humans; Infant; Infant, Newborn; Metabolism, Inborn Errors; Nervous System Diseases; S-Adenosylmethionine; Vitamin B 12; Vitamin B 12 Deficiency

We describe a patient with methylmalonic aciduria and homocystinuria due to a defect in cobalamin metabolism of the Cbl-C type mutant (McKusick 277400). Our case was diagnosed within the first 2 months of life by amino acid analysis (ion-exchange chromatography) and by biochemical studies in cultured fibroblasts ([14C]propionate incorporation, methionine and serine formation). We discuss the clinical course and the biochemical evolution after 2 years of hydroxycobalamin treatment that led to an improvement in general clinical condition and neurological performance.

Topics: Amino Acids; Female; Homocystinuria; Humans; Hydroxocobalamin; Infant, Newborn; Metabolism, Inborn Errors; Methylmalonic Acid; Vitamin B 12

Several of the inborn errors of vitamin B12 (cobalamin, Cbl) metabolism (cblC, cblD, cblE, cblF, cblG) are associated with homocystinuria and hypomethioninemia due to a functional deficiency of the cytoplasmic enzyme methionine synthase which requires methylcobalamin (MeCbl) as a cofactor. We compared the growth of cultured fibroblasts from controls, from patients with a selective deficiency of MeCbl (cblE and cblG), with those with a defect in both MeCbl and adenosylcobalamin (AdoCbl) (cblC, cblD and cblF), in methionine and folic acid-free media to their growth in fully supplemented medium. Control cells were able to grow in deficient medium supplied with homocysteine, cobalamin and folate, while mutant cells were not, due to their inability to synthesize methionine from its immediate metabolic precursor, homocysteine. This differential growth is useful in screening for genetic defects of methionine biosynthesis.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Cell Division; Cell Line; Cobamides; Fibroblasts; Homocysteine; Humans; Metabolism, Inborn Errors; Methionine; Vitamin B 12; Vitamin B 12 Deficiency

Metabolic studies are described in a patient who presented at 3 weeks of age with severe anaemia, hyperbilirubinaemia and hypotonicity. Clinically, glycogen storage disease type II (Pompe disease) was suspected because of a massively enlarged heart and hepatosplenomegaly. This was confirmed biochemically by the demonstration of glycogen accumulation in skeletal muscle and undetectable acid alpha-1,4-glucosidase activity in fibroblasts. Further biochemical studies in this patient surprisingly revealed homocystinuria and methylmalonic aciduria, suggesting a defect in the uptake, transport or intracellular metabolism of vitamin B12. Studies in cultured fibroblasts from the patient revealed a low uptake of [57Co]cyanocobalamin and an impaired intracellular conversion to both 5'-deoxyadenosylcobalamin and methylcobalamin. Moreover, the incorporation of labelled propionate into proteins as well as the formation of labelled methionine from labelled 5-methyltetrahydrofolate was deficient in fibroblasts from the patient. Complementation studies revealed the presence of the cblC mutation in this patient. No treatment was initiated and the patient died at the age of 31 days. We conclude that the patient was affected by both glycogen storage disease type II and cblC disease. The remarkable combination of these two rare inborn errors can be the result of the consanguinity of the parents.

Topics: Biochemical Phenomena; Biochemistry; Consanguinity; Fibroblasts; Genetic Complementation Test; Glycogen Storage Disease Type II; Humans; Infant, Newborn; Male; Metabolism, Inborn Errors; Muscles; Mutation; Vitamin B 12

We describe a female infant with typical features of the cobalamin C form of combined methylmalonic aciduria and homocystinuria who also had the hemolytic-uremic syndrome with thrombocytopenia, microangiopathic hemolytic anemia, hypertension, and renal failure. Review of this and other described cases of the cobalamin C defect suggests that the hemolytic-uremic syndrome is part of the phenotypic spectrum of this inborn error of cobalamin metabolism.

Topics: Female; Genes, Recessive; Hemolytic-Uremic Syndrome; Homocystinuria; Humans; Infant, Newborn; Metabolism, Inborn Errors; Methylmalonic Acid; Phenotype; Vitamin B 12

Human skin fibroblasts derived from patients with all seven known inborn errors of vitamin B12 metabolism have been studied for functional integrity of methylmalonyl CoA mutase and methionine synthase. Cocultivation of cblC and cblF fibroblasts in the absence of polyethylene glycol resulted in a twofold increase over the expected in both [14C]propionate and [14C]methyltetrahydrofolate incorporation into acid-precipitable material, suggesting that metabolic cooperation between cells occurs. This correction in phenotype seems to be mutant class selective since cblD fibroblasts, which are biochemically similar to cblC cells, do not cooperate metabolically when mixed with cblF cells. These observations lend further support to the division of cblC and cblD diseases into discrete classes.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Cell Division; Cells, Cultured; Fibroblasts; Humans; Kinetics; Metabolism, Inborn Errors; Methylmalonyl-CoA Mutase; Propionates; Tetrahydrofolates; Vitamin B 12

Fetuses affected with propionic acidemia incorporate great amounts of odd-numbered long-chain fatty acids (OLCFA) into their body lipids. This is due to abundant supply with precursor amino acids of propionyl-CoA throughout pregnancy. After birth, the lower provision of precursor amino acids during dietary treatment compared with fetal life results in a decline of propionyl-CoA production and therefore OLCFA synthesis. However, the observed decrease of OLCFA may also partly reflect the recovery from acute ketoacidotic episodes that the patients experienced soon after birth as long as they were undiagnosed. In a patient with vitamin B12-responsive methylmalonic aciduria treated prenatally with large doses of vitamin B12 given to the mother, the cord plasma lipids contained normal amounts of OLCFA. This indicates that prenatal therapy led to an increased flux of propionyl-CoA through the defective methylmalonyl-CoA mutase step. Thus, in addition to the quantification of a decline in methylmalonic acid in maternal urine, OLCFA in cord blood lipids might be a further parameter for evaluating prenatal treatment in patients with vitamin B12-responsive methylmalonic aciduria.

Topics: Acyl Coenzyme A; Amino Acid Metabolism, Inborn Errors; Fatty Acids; Female; Fetus; Humans; Infant, Newborn; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Pregnancy; Propionates; Vitamin B 12

Renal tubular function was assessed in seven patients with methylmalonic acidaemia not responsive to vitamin B12. Five patients failed to concentrate their urine normally and in these patients the glomerular filtration rate was also reduced. Fractional excretion of sodium was increased in four patients, fractional excretion of potassium in one patient and in three there was a decreased tubular reabsorption of phosphate. Although possibly representing primary tubular damage these findings were thought to be consistent with adaptive changes secondary to the reduced glomerular filtration rate. Two patients had evidence of a defect of urinary acidification and several had a degree of hyporeninaemic hypoaldosteronism suggesting type 4 renal tubular acidosis. In one patient with a mild variant no renal disease was detected. Decreased renal function and tubular abnormalities were common in patients with methylmalonic acidaemia. It is likely that they are linked and essentially secondary to the tubulo-interstitial nephritis that is histologically demonstrable on renal biopsy. The failure of urinary concentrating ability and the disturbed urine acidification will contribute to the metabolic derangement during episodes of decompensation.

Topics: Acidosis, Renal Tubular; Child; Child, Preschool; Glomerular Filtration Rate; Humans; Hydrogen-Ion Concentration; Kidney Concentrating Ability; Kidney Tubules; Metabolism, Inborn Errors; Methylmalonic Acid; Potassium; Sodium; Urine; Vitamin B 12

Topics: Acidosis; Amino Acids; Ammonia; Child, Preschool; Female; Fibroblasts; Humans; Ketones; Ketosis; Metabolism, Inborn Errors; Methylmalonic Acid; Oxidation-Reduction; Vitamin B 12

Cobalamin (Cbl, vitamin B12) bound to transcobalamin II (TCII) enters cultured fibroblasts by receptor-mediated endocytosis. Following degradation of the TCII, Cbl is subsequently found in either the cytoplasm bound to methionine synthase or in the mitochondria bound to methylmalonyl CoA mutase. In fibroblasts from patients belonging to the cblF complementation group, Cbl is found free in the cell and is not transferred to the above two target enzymes. Quantitative EM radioautography was utilized to visualize intracellular Cbl in fibroblasts from cblF patients and from normal subjects. In cblF cells, 60% of all silver grains were assigned to lysosomes, with only 12.6% over cytoplasm and 1.2% over mitochondria. In contrast, in control cells, only 4.7% were assigned to lysosomes, with 47% to cytoplasm and 23.4% to mitochondria. Subcellular fractionation showed that in cblF cells, the majority of label was associated with clearly recognizable lysosomes. These studies conclusively demonstrate that secondary lysosomes accumulate Cbl in cblF disease.

Topics: Autoradiography; Cells, Cultured; Humans; Lysosomes; Metabolism, Inborn Errors; Microscopy, Electron; Vitamin B 12

Creatine excretion was measured in two patients with methylmalonic aciduria and two patients with 3-hydroxy-3-methylglutaric aciduria. During periods of metabolic decompensation the creatine/creatinine ratio increased and fell during recovery. Prolonged periods of metabolic decompensation may result in the loss of a large proportion of the creatine pool. In one study, measurements of total daily urinary output of metabolites demonstrated that the absolute creatine excretion followed a similar qualitative pattern to the creatine/creatinine ratio. However, apparent fluctuations in methylmalonate excretion when expressed as methylmalonate/creatinine ratio were absent when absolute methylmalonate excretion was calculated. The increased creatine excretion during metabolic perturbations may result from loss from creatine containing tissues such as muscle and may represent an underlying defect in energy metabolism. Alternatively creatine transport may be disrupted by accompanying acidosis. The use of metabolite/creatinine ratios as a measure of metabolite excretion rates during metabolic decompensation whilst qualitatively sound may need a re-appraisal.

Topics: 3-Hydroxybutyric Acid; Carnitine; Child; Child, Preschool; Creatine; Creatinine; Female; Humans; Hydroxybutyrates; Infant; Lactates; Lactic Acid; Magnetic Resonance Spectroscopy; Male; Meglutol; Metabolism, Inborn Errors; Methylmalonic Acid; Vitamin B 12

Topics: Acidosis; Administration, Oral; Female; Humans; Metabolism, Inborn Errors; Methylmalonic Acid; Pregnancy; Pregnancy Complications; Prenatal Care; Prenatal Diagnosis; Prognosis; Vitamin B 12

A patient with infantile onset methylmalonic aciduria and homocystinuria (Cbl-C mutant) is described. Therapy with hydroxycobalamin, folate and vitamin B6 improved his condition. As hypomethioninaemia and homocystinaemia persisted, he was treated with intramuscular methylcobalamin, but without success. Treatment with betaine started at 25 months of age, normalized plasma methionine and elicited disappearance of homocystinaemia. Results of biochemical studies in cultured fibroblasts paralleled those described for other Cbl-C patients except that methylmalonyl-coenzyme A mutase activity in disrupted fibroblasts was in the normal range.

Topics: Betaine; Child, Preschool; Female; Homocystinuria; Humans; Infant; Male; Malonates; Metabolism, Inborn Errors; Methylmalonic Acid; Mutation; Vitamin B 12

Persistent hyperkalaemia was found in a patient with vitamin B12 unresponsive methylmalonic acidaemia associated with hyperuricaemia. At 3 years and 8 months of age, a serum potassium level of 6.8 mmol L-1 was found when blood gas measurement was normal. One year later azotaemia was noted. At the age of 5 years, renal function studies disclosed hyperaldosteronism, decreased creatinine clearance, reduction of the reabsorption of sodium at distal diluting segments and inadequate concentration of urine at the collecting ducts. The reduction of the reabsorption of sodium, which may have resulted in decreased potassium excretion, and the decrease in glomerular filtration rate, together with the superimposed excess intake of potassium, appeared to be responsible for the hyperkalaemia. Dietary potassium restriction was effective in suppressing the hyperkalaemia.

Topics: Child; Female; Glomerular Filtration Rate; Humans; Hyperaldosteronism; Hyperkalemia; Malonates; Metabolism, Inborn Errors; Methylmalonic Acid; Uremia; Uric Acid; Vitamin B 12

Topics: Adult; Biotin; Child; Female; Humans; Infant; Infant, Newborn; Ligases; Male; Metabolism, Inborn Errors; Middle Aged; Nervous System Diseases; Niacinamide; Orthomolecular Therapy; Pedigree; Vitamin B 12

Topics: Anemia, Megaloblastic; Homocystinuria; Humans; Infant; Male; Metabolism, Inborn Errors; Vitamin B 12; Vitamin B 12 Deficiency

An infant with vitamin B12-responsive methylmalonic aciduria and no homocystinuria or megaloblastic anemia presented with stomatitis, glossitis, convulsions, and developmental delay. Cultured fibroblasts showed defective incorporation of both [14C]5-methyltetrahydrofolate and [14C]propionate into protein by whole cells and a decrease of methionine synthase activity in cell extracts. Despite excessive incorporation of [57Co]cyano-B12 by fibroblasts from the patient, free vitamin B12 was unable to efflux from lysosomes, and, therefore, synthesis of both adenosyl-B12 and methyl-B12 was impaired.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Female; Fibroblasts; Humans; Infant, Newborn; Malonates; Metabolism, Inborn Errors; Propionates; Vitamin B 12

Topics: Adult; Child; Child, Preschool; Chromatography, Gas; Female; Folic Acid; Formiminoglutamic Acid; Humans; Hydantoins; Infant; Infant, Newborn; Male; Metabolism, Inborn Errors; Vitamin B 12

A patient has been described with methylmalonic aciduria because of an inability to release free vitamin B12 from lysosomes. Complementation analysis was performed using fibroblasts from this patient and those from patients having previously described mutations causing methylmalonic aciduria (mut, cblA, cblB, cblC, and cblD). Incorporation of label from [1-14C]propionate into acid-precipitable material was elevated in heterokaryons formed by polyethylene glycol (PEG) treatment of mixed cultures of cells from the patient and all other complementation groups as compared to the incorporation in parallel cultures not treated with PEG. These results indicate that complementation occurred in all cases and support the assignment of the patient to a new complementation group that has been designated cblF.

Topics: Genetic Complementation Test; Humans; Lysosomes; Malonates; Metabolism, Inborn Errors; Vitamin B 12

Cultured diploid fibroblasts from a patient with a previously undescribed inborn error of cobalamin metabolism accumulate unmetabolized, nonprotein-bound vitamin B12 in lysosomes. These cells are able to endocytose the transcobalamin II-B12 complex and to release B12 from transcobalamin II. The freed vitamin B12 is not released from lysosomes into the cytoplasm of the cell. This suggests that there is a specific lysosomal transport mechanism for vitamin B12 in the human.

Topics: Biological Transport; Cell Compartmentation; Cells, Cultured; Cytoplasm; Endocytosis; Female; Humans; Infant; Lysosomes; Metabolism, Inborn Errors; Vitamin B 12

Topics: Humans; Infant; Metabolism, Inborn Errors; Vitamin B 12

Topics: Adolescent; Child; Female; Homocystinuria; Humans; Hydroxocobalamin; Infant; Male; Malonates; Metabolism, Inborn Errors; Methylmalonic Acid; Mutation; Neurocognitive Disorders; Spinal Cord Diseases; Vitamin B 12

The tendency towards metabolic acidosis developing during simple infections lead to the detection of hyperglycinemia which was shown to be caused by the rare inborn error of metabolism, which was shown to be a methylmalonic acidemia, in identical twins. Under a protein restricted diet and vitamin-B12-injections once a week, all clinical symptoms disappeared so that vitamin-B12-dependency became evident. Under this therapeutic regimen methylmalonic aciduria was well under control.

Topics: Acidosis; Diseases in Twins; Glycine; Humans; Infant; Malonates; Metabolism, Inborn Errors; Methylmalonic Acid; Vitamin B 12

We studied two brothers (J.R. and M.R.) with the cobalamin D variant of congenital methylmalonic aciduria-homocystinuria, whose previously reported lack of megaloblastic anemia conflicted with current concepts of cobalamin's role in DNA synthesis and the "methyltetrahydrofolate (MTHF) trap" hypothesis. Both subjects were indeed hematologically normal, although J.R. had a mean corpuscular volume of 96 fl. However, both demonstrated abnormalities in the deoxyuridine suppression test. J.R. had an abnormal suppression value of 21.0% (normal less than 10%) that was correctable by adding hydroxocobalamin or folic acid in vitro but not MTHF. M.R. had normal suppression (8.9%), but demonstrated worsening (18.6%) when MTHF was added. J.R.'s classical deoxyuridine suppression pattern of cobalamin deficiency thus supports the trap hypothesis. However, his lack of comparable morphological changes suggests that impaired de novo thymidylate synthesis and the trap hypothesis, though valid, may not fully account for the megaloblastic maturation accompanying cobalamin deficiency. Equally noteworthy was the deleterious effect of MTHF on M.R.'s marrow, suggesting its potential usefulness as an in vitro "stress test" for latent cobalamin abnormality.

Topics: Adolescent; Adult; Anemia, Megaloblastic; Bone Marrow; Deoxyuridine; Homocystinuria; Humans; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Tetrahydrofolates; Thymidine; Vitamin B 12

Topics: Adolescent; Anemia, Macrocytic; Anemia, Megaloblastic; Child; Humans; Malabsorption Syndromes; Metabolism, Inborn Errors; Transcobalamins; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin E Deficiency

A 7 1/2-year-old girl with a rare defect in cobalamin (vitamin B12) metabolism ("cobalamin C" type) developed epileptiform ocular and eyelid movements as the major clinical manifestation of the disease. One of three other patients who have been described with congenital syndrome was similarly noted to have "fluttering" of the eyelids interpreted as epileptic discharges. The metabolic abnormality produced a defect in synthesis of cobalamin coenzymes. It is characterized biochemically by the excreation of methylmalonic acid and homocystine in the urine.

Topics: Child; Child, Preschool; Cobamides; Epilepsy; Eye Movements; Eyelid Diseases; Female; Homocystinuria; Humans; Malonates; Metabolism, Inborn Errors; Methylmalonic Acid; Syndrome; Vitamin B 12

Circulating levels of beta-leucine are elevated in the cobalamin-deficient state of pernicious anemia. Levels of leucine, on the other hand, are much lower. It is proposed that leucine 2,3-aminomutase, the cobalamin-dependent enzyme that catalyzes the interconversion of leucine and beta-leucine, is the affected enzyme in pernicious anemia and causes these results by preventing the synthesis of leucine from beta-leucine. The synthesis of leucine by human leukocytes and hair roots and by rat liver extracts has been shown to occur when either branched chain fatty acids or valine metabolites are the substances. The synthesis is dependent upon adenosylcobalamin and is inhibited by intrinsic factor.

Topics: Amino Acids, Branched-Chain; Anemia, Pernicious; Animals; Hair; Humans; Leucine; Leukocytes; Liver; Metabolism, Inborn Errors; Rats; Vitamin B 12

Biochemical investigations are reported in an infant with methylmalonic aciduria and homocystinuria who died at 4 months of age. Postmortem analysis of liver obtained 2 weeks after the child was treated with vitamin B12 revealed deficient activity of both cobalamin dependent enzymes: N5-methyltetrahydrofolate: homocysteine methyltransferase (requiring Me-Cbl), and methylmalonyl CoA mutase (requiring Ado-Cbl). MMA-CoA mutase activity could be restored to normal in vitro by added Ado-Cbl, but MeTHF-HCy transferase activity was not significantly enhanced by addition of Me-Cbl. Though the serum total cobalamin was normal, total cobalamin in liver and kidney was abnormally low. In the kidney Me-Cbl and Ado-Cbl were disproportionally decreased whereas in the liver only Ado-Cbl was significantly reduced. This suggests that at least some of the CN-Cbl administered was converted to the coenzymes in liver which would explain the reduction of MMA- and HCy-excretion during therapy. The results show 1. that this infant suffered from a congenital defect in one of the steps of intracellular cobalamin metabolism or transport common to the synthesis of both coenzymes, 2. that life-long treatment with vitamin B12 (OH-Cbl) may be of value in similar cases, particularly if given early in the course of the disease.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Amino Acids; Coenzymes; Homocystinuria; Humans; Infant; Kidney; Liver; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Vitamin B 12

Topics: Animals; Chemical Phenomena; Chemistry; Cobamides; Humans; Hydroxocobalamin; Metabolism, Inborn Errors; Vitamin B 12; Vitamin B 12 Deficiency

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Cells, Cultured; Fibroblasts; Humans; Kinetics; Metabolism, Inborn Errors; Mutation; Skin; Vitamin B 12

The case is described of an infant who suffered from progressive, severe dystrophy, hemolytic and megaloblastic anemia, hematuria, proteinuria and slight uremia. He died at 4 months of age following two acute episodes of heart failure. Abnormally increased excretion of methylmalonate and homocystine was detected by our screening program for metabolic disorders. Amino acid analyses showed that the plasma and urine levels of methionine were very low whereas those of cystathionine were raised. Vitamin B12 deficiency, malabsorption or abnormal cobalamin transport were excluded by a normal serum total cobalamin and normal transcobalamins. These findings suggested a congenital error of cobalamin metabolism. Treatment with vitamin B12 resulted in a biochemical though not a clinical response. Postmortem examination revealed severe vascular lesions with changes in the kidney characteristic of thrombotic microangiopathy supporting a diagnosis of hemolytic-uremic syndrome. It is assumed that the elevated plasma homocysteine induced the vascular lesions by causing detachment of endothelium.

Topics: Blood Vessels; Homocystinuria; Humans; Infant; Kidney; Lung; Male; Malonates; Metabolism, Inborn Errors; Methylmalonic Acid; Myocardium; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Humans; Malonates; Metabolism, Inborn Errors; Methylmalonic Acid; Pyridoxine; Vitamin B 12

Topics: Binding Sites; Biological Transport; Blood Proteins; Child, Preschool; Chromatography, Gel; HeLa Cells; Humans; Male; Metabolism, Inborn Errors; Protein Binding; Transcobalamins; Vitamin B 12

Topics: Acidosis; Humans; Male; Malonates; Metabolism, Inborn Errors; Methylmalonic Acid; Pediatric Nursing; Vitamin B 12

Topics: Anemia, Macrocytic; Anemia, Megaloblastic; Cobamides; Humans; Malonates; Metabolism, Inborn Errors; Methylmalonic Acid; Vitamin B 12; Vitamin B 12 Deficiency

The case is described of a child, age 6 1/2 years, with retarded mental development, mild neurological signs and abnormal metabolism of sulphur-containing amino acids and methylmalonate, due to an inborn error in the formation of vitamin B12 coenzymes. The patient was treated for almost three years with hydroxycobalamin, folic acid, pyridoxine and choline. Though physical growth was normal, she continued to demonstrate a moderate degree of mental retardation. A brother of the patient died at the age of 5 years, probably of a similar, but undiagnosed, disorder. As far as we are aware there are only four other reported cases similar to the case described here. Two of these patients died and in other other two the defect was so mild that no treatment was necessary and who, in fact, showed appreciable improvement during the follow-up period, which to date amounts to 3 years and 3 months. For reasons detailed in the discussion, it is suggested that the diagnosis of homocystinuria is not complete until studies of folate and vitamin B12 metabolism are undertaken at the same time, so as to identify the metabolic defect(s) responsible for the condition.

Topics: Child, Preschool; Female; Humans; Intellectual Disability; Metabolism, Inborn Errors; Vitamin B 12

A family is described in which two members (a father and a daughter), both with quiescent ulcerative colitis, had abnormally high serum concentrations of a vitamin B12 binding protein. This protein had the molecular weight of transcobalamin II on gel filtration, and behaved like transcobalamin II with respect to its elution from DE-23 cellulose, its inhibition at acid pH, its absorption by uncoated charcoal, its binding by anti-TC II antibodies, and its ability to transfer vitamin B12 to transformed lymphocytes. Its plasma clearance and tissue distribution when injected into rabbits was indistinguishable from that of transcobalamin II from normal subjects. It migrated on electrophoresis in the beta, gamma region. This is the first case report of related subjects in whom high serum concentrations of transcobalamin II have been observed.

Topics: Blood Proteins; Carrier Proteins; Humans; Lymphocytes; Male; Metabolism, Inborn Errors; Middle Aged; Transcobalamins; Vitamin B 12

Topics: Adolescent; Animals; Child, Preschool; Folic Acid; Humans; Infant; Male; Metabolism, Inborn Errors; Methyltransferases; Rats; Sheep; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia, Macrocytic; Anemia, Megaloblastic; Anemia, Pernicious; Gastrectomy; Humans; Ileum; Intrinsic Factor; Malabsorption Syndromes; Metabolism, Inborn Errors; Schilling Test; Time Factors; Vitamin B 12

Topics: Adult; Anemia, Macrocytic; Biological Transport; Carrier Proteins; Diarrhea; Electrophoresis, Polyacrylamide Gel; Female; Humans; Immunodiffusion; Immunoelectrophoresis; Immunologic Deficiency Syndromes; Infant, Newborn; Injections, Intramuscular; Malabsorption Syndromes; Metabolism, Inborn Errors; Pregnancy; Protein Binding; Radioisotopes; Vitamin B 12

Topics: Autoradiography; Carbon Radioisotopes; Carboxy-Lyases; Cells, Cultured; Fibroblasts; Glucose; Humans; Isomerases; Malonates; Metabolism, Inborn Errors; Methods; Propionates; Stimulation, Chemical; Time Factors; Vitamin B 12

Topics: Anemia, Macrocytic; Atrophy; Autopsy; Blood Vessels; Brain; Brain Chemistry; Cerebrosides; Child; Cholesterol; Chromatography, Thin Layer; Demyelinating Diseases; Esters; Fatty Acids; Fatty Acids, Unsaturated; Female; Galactose; Gliosis; Globus Pallidus; Homocystinuria; Humans; Malonates; Metabolism, Inborn Errors; Phosphatidylcholines; Phospholipids; Sphingomyelins; Sulfoglycosphingolipids; Vitamin B 12

Topics: Amino Acids; Ammonia; Carbon Dioxide; Carbon Radioisotopes; Cells, Cultured; Child, Preschool; Cobamides; Diet Therapy; Dietary Proteins; Female; Fibroblasts; Genetic Counseling; Humans; In Vitro Techniques; Infant; Isomerases; Liver; Male; Malonates; Metabolism, Inborn Errors; Pregnancy; Prenatal Diagnosis; Propionates; Succinates; Vitamin B 12; Vomiting

Topics: Amino Acid Isomerases; Amino Acids; Anemia, Macrocytic; Autopsy; Brain; Brain Chemistry; Cells, Cultured; Child; Culture Media; Fibroblasts; Homocysteine; Humans; Intellectual Disability; Liver; Lung; Lyases; Malonates; Metabolism, Inborn Errors; Methionine; Spleen; Vitamin B 12

Topics: Administration, Oral; Anemia, Macrocytic; Child; Consanguinity; Female; Folic Acid; Folic Acid Deficiency; Humans; Injections, Intramuscular; Intestinal Absorption; Leucovorin; Metabolism, Inborn Errors; Recurrence; Stomatitis; Vitamin B 12; Yeast, Dried

Topics: Acidosis; Agranulocytosis; Blood Glucose; Cephalometry; Child Development; Diet Therapy; Electroencephalography; Female; Growth Disorders; Humans; Infant; Intelligence; Isoleucine; Lymphocytosis; Malonates; Metabolism, Inborn Errors; Methionine; Otitis Media; Threonine; Valine; Vitamin B 12

Topics: Acidosis; Awards and Prizes; Child; Coenzymes; Female; Fetal Diseases; Humans; Infant, Newborn; Infant, Newborn, Diseases; Isomerases; Lactates; Malonates; Metabolism, Inborn Errors; Methane; Pregnancy; Propionates; Pyruvates; Succinates; Valerates; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Amino Acid Metabolism, Inborn Errors; Biotin; Coenzymes; Humans; Infant; Maple Syrup Urine Disease; Metabolism, Inborn Errors; Phenotype; Pyridoxine; Thiamine; Vitamin B 12; Vitamin D

Topics: Body Weight; Diet Therapy; Female; Humans; Infant, Newborn; Malonates; Metabolism, Inborn Errors; Proteins; Vitamin B 12

Topics: Adult; Amblyopia; Child; Child, Preschool; Cyanides; Female; Humans; Male; Metabolism, Inborn Errors; Neuritis; Optic Atrophy; Scotoma; Smoking; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Amino Acid Metabolism, Inborn Errors; Coenzymes; Diet Therapy; Dietary Proteins; Glucose-6-Phosphatase; Glucosidases; Glucosyltransferases; Glycogen Storage Disease; Humans; Hydrocortisone; Metabolism, Inborn Errors; Pyridoxine; Thyroxine; Tyrosine; Vitamin B 12

Topics: Coenzymes; Female; Homocysteine; Humans; Infant; Isomerases; Male; Metabolism, Inborn Errors; Methionine; Methyltransferases; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adolescent; Adult; Cells, Cultured; Child; Child, Preschool; Cobalt Isotopes; Deoxyadenosines; Enzyme Activation; Fibroblasts; Folic Acid; Homocysteine; Humans; Hydroxocobalamin; Infant; Infant, Newborn; Male; Malonates; Metabolism, Inborn Errors; Methylation; Methyltransferases; Vitamin B 12

Topics: Adult; Amblyopia; Animals; Biological Transport; Cystinuria; Dipeptides; Female; Glycine; Hartnup Disease; Humans; Intestinal Absorption; Metabolic Diseases; Metabolism, Inborn Errors; Methionine; Nitrogen; Peptides; Proteins; Smoking; Tyrosine; Vitamin B 12

Topics: Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Choline; Female; Lipotropic Agents; Maternal-Fetal Exchange; Metabolism, Inborn Errors; Methionine; Nutritional Requirements; Pregnancy; Pregnancy, Animal; Prenatal Care; Protein Deficiency; Rats; Vitamin B 12

Topics: Acidosis; Amino Acids; Aminobutyrates; Brain; Chromatography, Paper; Fibroblasts; Homocystine; Humans; Hydro-Lyases; Infant, Newborn; Infant, Newborn, Diseases; Isomerases; Kidney; Liver; Male; Malonates; Metabolism, Inborn Errors; Methionine; Transferases; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adenine; Allopurinol; Athetosis; Bone Marrow; Carbon Isotopes; Child; Child, Preschool; Chorea; Compulsive Behavior; Diet Therapy; Erythrocytes; Folic Acid; Glycine; Humans; Intellectual Disability; Male; Metabolism, Inborn Errors; Movement Disorders; Purines; Self Mutilation; Transferases; Uric Acid; Vitamin B 12

Topics: Amniotic Fluid; Female; Fetal Diseases; Gestational Age; Humans; Infant, Newborn; Malonates; Metabolism, Inborn Errors; Pregnancy; Vitamin B 12

Topics: Acidosis; Anemia; Blood Cells; Child, Preschool; Chromatography, Paper; Dietary Proteins; Humans; Infant; Infant, Newborn; Malonates; Metabolism, Inborn Errors; Vitamin B 12

Topics: Coenzymes; Folic Acid; Humans; Malonates; Metabolism, Inborn Errors; Methionine; Vitamin B 12

Topics: Amino Acid Metabolism, Inborn Errors; Carbohydrate Metabolism, Inborn Errors; Disaccharides; Electrolytes; Humans; Intestinal Absorption; Lipid Metabolism, Inborn Errors; Malabsorption Syndromes; Metabolism, Inborn Errors; Monosaccharides; Vitamin B 12

Topics: Amino Acid Metabolism, Inborn Errors; Aminobutyrates; Brain; Homocysteine; Homocystine; Homocystinuria; Humans; Infant; Kidney; Liver; Male; Malonates; Metabolism, Inborn Errors; Methionine; Sulfides; Transferases; Vitamin B 12

Methylmalonic aciduria is an inborn error of metabolism characterized by neonatal or infantile ketoacidosis. Leukocytes isolated from the peripheral blood of a 1-year-old child with this disorder converted negligible quantities of propionate-3-C(14) to carbon dioxide, but oxidized succinate-1,4-C(14) normally, an indication of a block in the conversion of propionate to succinate. Parenteral administration of vitamin B(18) resulted in a reduction in methylmalonic acid excretion and an increase in propionate oxidation by leukocytes in vitro. The results suggest a mutation of methylmalonyl-CoA isomerase, a vitamin B(12), dependent enzyme which converts methylmalonyl-CoA to succinyl-CoA, and provide the first demonstration of vitamin B(12) "dependency" in man.

Topics: Acidosis; Amino Acid Metabolism, Inborn Errors; Carbon Dioxide; Carbon Isotopes; Coenzyme A; Humans; Hydro-Lyases; Infant; Isomerases; Leukocytes; Malonates; Metabolism, Inborn Errors; Molecular Biology; Mutation; Propionates; Pyridoxal Phosphate; Succinates; Vitamin B 12; Xanthurenates

Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Metabolism, Inborn Errors; Proteinuria; Vitamin B 12

Topics: Adult; Aged; Anemia, Macrocytic; Biological Assay; Blood Proteins; Bone Marrow Examination; Cerebral Ventriculography; Child; Child, Preschool; Dietary Fats; Electroencephalography; Erythrocytes; Female; FIGLU Test; Folic Acid; Humans; Hydrolases; Infant; Intellectual Disability; Intestinal Absorption; Liver; Liver Function Tests; Male; Metabolism, Inborn Errors; Middle Aged; Oxidoreductases; Transferases; Vitamin B 12; Xylose

Topics: Anemia, Macrocytic; Child; Child, Preschool; Female; Humans; Infant; Male; Metabolism, Inborn Errors; Vitamin B 12

Topics: Adenosine Triphosphate; Anemia, Hemolytic; Anemia, Hemolytic, Congenital Nonspherocytic; Biological Transport; Child; Erythrocytes; Folic Acid; Glucose; Hemolysis; Humans; Metabolism, Inborn Errors; Potassium; Pyruvate Kinase; Pyruvate Metabolism, Inborn Errors; Reticulocytes; Vitamin B 12

Topics: Anemia; Anemia, Macrocytic; Anemia, Megaloblastic; Bone Marrow Examination; Child; Fluids and Secretions; Folic Acid; Humans; Infant; Metabolism, Inborn Errors; Nucleosides; Orotic Acid; Prognosis; Purine-Pyrimidine Metabolism, Inborn Errors; Pyridoxine; Thyroxine; Uridine; Urine; Vitamin B 12