hydroxocobalamin and Metabolism--Inborn-Errors

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

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

Functional methionine synthase reductase deficiency, also known as cobalamin E disorder, is a rare autosomal recessive inherited disease that results in an impaired remethylation of homocysteine to methionine. It presents with macrocytic anemia, hyperhomocysteinemia, and hypomethioninemia, and may also be accompanied with neurological impairment.. We describe two new cases of unrelated girls with megaloblastic anemia misclassified at first as congenital dyserythropoietic anemia with development of neurologic dysfunction in one of them.. The posterior finding of biochemical features (hyperhomocysteinemia and hypomethioninemia) focused the diagnosis on the inborn errors of intracellular vitamin B12. Subsequent molecular analysis of the methionine synthase reductase (MTRR) gene revealed compound heterozygosity for a transition c.1361C > T (p.Ser454Leu) and another, not yet described in literature, c.1677-1G > A (p.Glu560fs) in one patient, and a single homozygosis mutation, c.1361C > T (p.Ser545Leu) in the other one. These mutations confirmed the diagnosis of cobalamin E deficiency.. Treatment with hydroxocobalamin in combination with betaine appears to be useful for hematological improvement and prevention of brain disabilities in CblE-affected patients. Our study widens the clinical, molecular, metabolic, and cytological knowledge of deficiency MTRR enzyme.

Topics: Adult; Amino Acid Substitution; Anemia, Macrocytic; Betaine; Child; Female; Ferredoxin-NADP Reductase; Humans; Hydroxocobalamin; Hyperhomocysteinemia; Metabolism, Inborn Errors; Mutation, Missense

Topics: Adolescent; Biopsy; Complement System Proteins; Female; Hematuria; Humans; Hydroxocobalamin; Hypertension; Intellectual Disability; Kidney; Laser-Doppler Flowmetry; Metabolism, Inborn Errors; Proteinuria; Seizures; Ultrasonography

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

Cobalamin C (cblC) defect is the most common inborn error of vitamin B12 metabolism. Clinical features vary as does the severity of the disease. In most cases, the clinical symptoms of cblC defect tend to appear during infancy or early childhood as a multisystem disease with severe neurologic, ocular, hematologic, renal, and gastrointestinal signs. The neurologic findings are common and include hypotonia, developmental delay, microcephaly, seizures hydrocephalus, and brain MRI abnormalities. We report a case of a young boy with cblC defect, who did not undergo newborn screening, presenting at the age of 2 years with isolated pulmonary hypertension as the leading symptom. This novel way of presentation of cblC defect enlarges the spectrum of inherited diseases that must be considered in the differential diagnosis of pulmonary hypertension.

Topics: Betaine; Brain; Child, Preschool; Diagnosis, Differential; Drug Therapy, Combination; Folic Acid; Genetic Carrier Screening; Humans; Hydroxocobalamin; Hypertension, Pulmonary; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Infant; Infant, Newborn; Injections, Intramuscular; Lung; Magnetic Resonance Imaging; Male; Metabolism, Inborn Errors; Neonatal Screening; Proto-Oncogene Proteins c-cbl; Pulmonary Artery; Tomography, X-Ray Computed; Vitamin B 12 Deficiency

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

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

To evaluate prenatal treatment with hydroxycobalamin (OH-Cbl) in a pregnancy at risk for a severe form of the cobalamin C defect and postnatal treatment of the affected child.. Observational study with non-randomized intervention.. In contrast to reported pregnancies with affected fetuses in which maternal methylmalonic aciduria was found in the last trimester of pregnancy, there was no maternal methylmalonic aciduria in our case, given prenatal treatment with intramuscular OH-Cbl. We did not find that the concentration of odd long-chain fatty acids in cord blood erythrocytes reflects fetal methylmalonic academia. After birth, the infant was treated with intramuscular OH-Cbl and oral carnitine. Oral folate and betaine were added as adjunct therapy to decrease plasma total homocysteine. Because of inadequate metabolic control, a diet reduced in natural protein was introduced. The child had normal developmental milestones but had nystagmus, hyperpigmented retinopathy, and discrete truncal muscular hypotonia.. Despite prenatal and postnatal treatment, adequate metabolic control, absence of metabolic crises, and normal developmental milestones, this patient with the cobalamin C defect had characteristic symptoms of the disease.

Topics: Betaine; Carnitine; Female; Folic Acid; Hematinics; Humans; Hydroxocobalamin; Infant, Newborn; Lipotropic Agents; Male; Metabolism, Inborn Errors; Pregnancy; Prenatal Care; Prenatal Diagnosis; Vitamin B 12 Deficiency

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

Combined methylmalonicaciduria and homocystinuria is a disorder of intracellular cobalamin metabolism that remains a challenge to the physician unfamiliar with the diagnosis. We have followed six patients with combined methylmalonicaciduria and homocystinuria (four males, two females, age 4.2-24 years) for a median of 6.5 years (range 4-9 years). Age at diagnosis was between 18 days and 14 months in early-onset cases (n = 4) and 15 and 19 years in late-onset cases. Predominant clinical features include microcephaly, hydrocephalus, seizures, and white-matter changes on magnetic resonance imaging in early-onset cases. The white-matter changes may be secondary to impaired methylation owing to a lack of readily available methyl groups. Spastic quadriparesis and diplegia are long-term sequelae in late-onset cases. Management consists of hydroxycobalamin intramuscular injections, oral folate, betaine, and carnitine supplementation. Dietary protein restriction may be necessary when metabolic control remains difficult. The implementation of an emergency regimen should alleviate episodes of metabolic decompensation and reduce the rate of hospital admissions.

Topics: Adolescent; Adult; Betaine; Carnitine; Child; Child, Preschool; Female; Folic Acid; Gastrointestinal Agents; Hematinics; Homocystinuria; Humans; Hydrocephalus; Hydroxocobalamin; Injections, Intramuscular; Male; Metabolism, Inborn Errors; Methylmalonic Acid; Microcephaly; Seizures

An infant with combined methylmalonic aciduria and homocystinuria (cblC/D defect) presented with significant VSD. She underwent successful cardiac surgery at 53 days.

Topics: Female; Folic Acid; Heart Septal Defects, Ventricular; Homocysteine; Homocystinuria; Humans; Hydroxocobalamin; Infant, Newborn; Lactic Acid; Metabolism, Inborn Errors; Methionine; Methylmalonic Acid

We performed serial electroencephalograms (EEG) in a newborn with methylmalonic aciduria and homocystinuria to assess the effects of hydroxycobalamin (OHcbl) therapy on the CNS. Diagnosis was made at 22 days of age: she had torpor, failure to thrive and hypotonia of the limbs, and intermittent opisthotonus. The first EEG, performed on the first day of therapy, showed abnormal and immature transients, low voltage and very long flat periods in the discontinuous part of the tracing. These features quickly improved during therapy. After 13 days of OHcbl therapy, the EEG tracing became normal for conceptional age and showed normal sleep phases with only minor anomalies; only mild hypotonia still remained and biochemical parameters normalized. The decrease in blood homocysteine (index of blood detoxification) was statistically correlated to the reduction of the length of flat periods in EEG (p < 0.01). In conclusion, changes in neonatal EEG, particularly the length of interburst periods in the intermittent part of the tracing, appeared to be a reliable index for evaluating drug effectiveness in methylmalonic aciduria and homocystinuria.

Topics: Electroencephalography; Female; Homocysteine; Homocystinuria; Humans; Hydroxocobalamin; Infant, Newborn; Metabolism, Inborn Errors; Methylmalonic Acid

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

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

Topics: Age of Onset; Anemia, Hemolytic; Anemia, Megaloblastic; Blood Transfusion; Child; Child, Preschool; Dementia; Demyelinating Diseases; Diagnostic Errors; Family Health; Female; Gas Chromatography-Mass Spectrometry; Humans; Hydroxocobalamin; Metabolism, Inborn Errors; Methylation; Nuclear Family; Paralysis; 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

A case of methylmalonic aciduria is described. The clinical course was unusually mild, the child surviving to the age of 8 years. Studies on cultured fibroblasts confirmed a defect in propionate metabolism which was non-responsive to hydroxycobalamin in vitro. Polyethylene-glycol-induced cell fusion with a known methylmalonyl co-enzyme apomutase-deficient cell line showed genetic complementation indicating that in this patient the defect was in one of the enzymes required for 5-deoxyadenosyl cobalamin synthesis.

Topics: Apoenzymes; Cells, Cultured; Female; Fibroblasts; Humans; Hydroxocobalamin; In Vitro Techniques; Infant; Malonates; Metabolism, Inborn Errors; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Propionates

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

Granulocytes from a 6-year-old boy with congenital transcobalamin II (TC II) deficiency were found to have abnormally low antibacterial activity against Staphylococcus aureus and very low intracellular levels of the cobalamin coenzymes. Transfusion of hydroxocobalamin (OH-Cbl) bound to normal plasma temporarily restored granulocyte bactericidal activity and increased cellular levels of the cobalamin coenzymes. Granulocyte function was also temporarily restored by oral Leucovorin. The defect appeared to be causally related to the patient's TC II deficiency and indirectly to a deficiency of cobalamin and folate coenzymes.

Topics: Blood Proteins; Blood Transfusion; Child; Granulocytes; Humans; Hydroxocobalamin; Leucovorin; Male; Metabolism, Inborn Errors; Phagocyte Bactericidal Dysfunction; Transcobalamins

Topics: Animals; Chemical Phenomena; Chemistry; Cobamides; Humans; Hydroxocobalamin; Metabolism, Inborn Errors; 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