hydroxocobalamin and Vitamin-B-12-Deficiency

We describe 2 children with cobalamin G disease, a disorder of vitamin B

Topics: Anemia, Megaloblastic; Blood Chemical Analysis; Blood Transfusion; Child, Preschool; Disease Progression; Early Diagnosis; Failure to Thrive; Hematologic Tests; Humans; Hydroxocobalamin; Infant; Injections, Intramuscular; Male; Prognosis; Risk Assessment; Severity of Illness Index; Thrombotic Microangiopathies; Treatment Outcome; Vitamin B 12 Deficiency

The purpose of this narrative review is to highlight insights into the importance and frequency of metabolic vitamin B12 (B12) deficiency, reasons why it is commonly missed, and reasons for the widespread but mistaken belief that treatment of B12 deficiency does not prevent stroke or improve cognitive function. Metabolic B12 deficiency is common, being present in 10%-40% of the population; is frequently missed; is easily treated; and contributes importantly to cognitive decline and stroke in older people. Measuring serum B12 alone is not sufficient for diagnosis; it is necessary to measure holotranscobalamin or functional markers of B12 adequacy such as methylmalonic acid or plasma total homocysteine. B-vitamin therapy with cyanocobalamin reduces the risk of stroke in patients with normal renal function but is harmful (perhaps because of thiocyanate accumulation from cyanide in cyanocobalamin) in patients with renal impairment. Methylcobalamin may be preferable in renal impairment. B12 therapy slowed gray matter atrophy and cognitive decline in the Homocysteine and B Vitamins in Cognitive Impairment Trial. Undiagnosed metabolic B12 deficiency may be an important missed opportunity for prevention of dementia and stroke; in patients with metabolic B12 deficiency, it would be prudent to offer inexpensive and nontoxic supplements of oral B12, preferably methylcobalamin or hydroxycobalamin. Future research is needed to distinguish the effects of thiocyanate from cyanocobalamin on hydrogen sulfide, and effects of treatment with methylcobalamin on cognitive function and stroke, particularly in patients with renal failure.

Topics: Animals; Biomarkers; Delayed Diagnosis; Dementia; Dietary Supplements; Humans; Hydroxocobalamin; Prevalence; Risk; Stroke; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

Methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) are coenzymes for methionine synthase and methylmalonyl-CoA mutase, respectively. Hydroxylcobalamin (HOCbl) and cyanocobalamin (CNCbl) are frequently used for supplementation. MeCbl and AdoCbl have recently emerged as alternative forms in supplements. In the light of metabolic transformation of Cbl into its cofactor forms, this review discusses current evidence on efficacy and utility of different Cbl forms in preventing or treating Cbl deficiency. Cbl-transporting proteins bind and mediate the uptake of all aforementioned forms of Cbl. After internalization and lysosomal release, Cbl binds to the cytosolic chaperon MMACHC that is responsible for (i) flavin-dependent decyanation of [CN-Co(3+) Cbl to [Co(2+)]Cbl; (ii) glutathione-dependent dealkylation of MeCbl and AdoCbl to [Co(2+/1+)]Cbl; and (iii) glutathione-dependent decyanation of CNCbl or reduction of HOCbl under anaerobic conditions. MMACHC shows a broad specificity for Cbl forms and supplies the Cbl(2+) intermediate for synthesis of MeCbl and AdoCbl. Cobalamin chemistry, physiology, and biochemistry suggest that MeCbl and AdoCbl follow the same route of intracellular processing as CNCbl does. We conclude that supplementing MeCbl or AdoCbl is unlikely to be advantageous compared to CNCbl. On the other hand, there are obvious advantages of high parenteral doses (1-2 mg) of HOCbl in treating inborn errors of Cbl metabolism.

Topics: Biological Transport; Cobamides; Humans; Hydroxocobalamin; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Homocysteine; Humans; Hydroxocobalamin; Methylmalonic Acid; Transcobalamins; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

Topics: Algorithms; Diagnosis, Differential; Humans; Hydroxocobalamin; Injections, Intramuscular; Reference Values; Vitamin B 12; Vitamin B 12 Deficiency

Pernicious anaemia is an autoimmune atrophic gastritis inducing vitamin B12 deficiency by malabsorption. This disease may be diagnosed in the absence of any anaemia, on a neuropathy or when one or several autoimmune disorders co-exist. Typically, pernicious anaemia is revealed by macrocytic megaloblastic anaemia. Diagnosis is done on low serum vitamin B12, raised serum homocysteine, parietal cell and, intrinsic factor antibodies. Pernicious anaemia should be treated indefinitely by monthly intramuscular hydroxocobalamin. Because of an increased incidence of gastric carcinoma, endoscopy should be evenly performed.

Topics: Anemia, Pernicious; Autoantibodies; Diagnosis, Differential; Hematinics; Homocysteine; Humans; Hydroxocobalamin; Injections, Intramuscular; Prognosis; Risk Factors; Stomach Neoplasms; Vitamin B 12 Deficiency

Focal spinal cord lesions have been present in all previously reported cases of MRI appearances in myelopathy complicating vitamin B12 deficiency. We describe two further cases showing mild atrophy only and review the salient features of the previous 11 publications. MRI findings reflect quite closely the known pathological changes in this condition.

Topics: Adult; Aged; Atrophy; Female; Humans; Hydroxocobalamin; Magnetic Resonance Imaging; Male; Muscle Weakness; Neural Conduction; Paraparesis, Tropical Spastic; Sensation Disorders; Spinal Cord; Spinal Cord Diseases; Vitamin B 12 Deficiency

Topics: Adult; Aged; Alcoholism; Anemia, Macrocytic; Female; Folic Acid; Folic Acid Deficiency; Humans; Hydroxocobalamin; Hypothyroidism; Infant, Newborn; Liver Failure; Male; Pregnancy; Risk Factors; Time Factors; Vitamin B 12; Vitamin B 12 Deficiency

The 13 cases of methylcobalamin (MeCbl) deficiency presenting in early infancy have all been developmentally delayed, and the majority have had seizures, hypotonia, lethargy, and microcephaly. The CNS injury appears to occur during the first 6 months of postnatal life. The same symptoms are seen in acquired cobalamin (Cbl) deficiency in the same age group. MRI performed at age 18-19 months and after 13-14 months of large amounts of Cbl, in two cases showed delayed myelination, most pronounced in the cerebrum. Isolated MeCbl deficiency is the consequence of cblE and G mutations where the lesion is of a single Cbl-dependent enzyme, the methyltransferase. One effect of a deficiency of MeCbl, and of the associated failure of the methionine synthase reaction, is, therefore, an impairment of myelination of the brain of the newborn. The slow, but usually incomplete, improvement in psychomotor status after years of treatment with Cbl may be related to the eventual myelination. However, the hypotonia, lethargy, and impaired responsiveness react to treatment with Cbl within 24-48 hours, which suggests an expression of MeCbl deficiency on the CNS distinct from the delayed myelination. Although there is much to be learned, it is now clear that a normally functioning Cbl-dependent methyl transferase is required for development and function of the human brain.

Topics: Amino Acid Metabolism, Inborn Errors; Central Nervous System; Child; Child, Preschool; Developmental Disabilities; Humans; Hydroxocobalamin; Infant; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adolescent; Adult; Anemia; Anemia, Hemolytic; Anemia, Hypochromic; Female; Ferritins; Ferrous Compounds; Folic Acid; Folic Acid Deficiency; Humans; Hydroxocobalamin; Iron; Middle Aged; Pregnancy; Pregnancy Complications, Hematologic; Vitamin B 12 Deficiency

Topics: Amblyopia; Carbon Radioisotopes; Cyanides; Cystine; Diet; Erythrocytes; Folic Acid Deficiency; Glutathione; Humans; Hydroxocobalamin; Nicotiana; Optic Nerve; Peripheral Nervous System Diseases; Plants, Toxic; Smoking; Sulfur; Vitamin B 12 Deficiency

Vitamin B. Infant blood samples, collected at public healthcare clinics, are analysed for plasma cobalamin levels. Infants with plasma cobalamin <148 pmol/L are immediately treated with hydroxocobalamin and excluded from the RCT. Remaining infants (cobalamin ≥148 pmol/L) are randomly assigned (in a 1:1 ratio) to either a screening or a control group. In the screening group, baseline samples are immediately analysed for total homocysteine (tHcy), while in the control group, the baseline samples will be analysed after 12 months. Screening group infants with plasma tHcy >6.5 µmol/L, are given an intramuscular injection of hydroxocobalamin (400 µg). The primary outcomes are cognitive, language and motor development assessed using the Bayley Scales of Infant and Toddler Development at 12 months of age.. The study has been approved by the Regional Committee for Medical and Health Research Ethics (ref: 186505). Investigators who meet the Vancouver requirements will be eligible for authorship and be responsible for dissemination of study findings. Results will extend current knowledge on consequences of subclinical vitamin B. NCT05005897.

Topics: Dietary Supplements; Humans; Hydroxocobalamin; Infant; Randomized Controlled Trials as Topic; Vitamin B 12; Vitamin B 12 Deficiency; Vitamins

Vitamin B12 (VB12) deficiency can be treated with oral high-dose substitution or intramuscular (i.m.) injection of VB12. Whenever alternative routes of administration exist, patient preferences should be considered when choosing the treatment. We aimed to assess outpatient preferences towards oral or IM VB12 substitution and confirm noninferiority of early biomarker response with oral treatment, in a typical primary care population.. Prospective randomised nonblinded parallel-group trial. Patients were recruited by their general practitioner and randomly assigned to oral or IM treatment. Group O-oral was given 28 tablets of 1000 µg cyanocobalamin in a monthly punch card fitted with an electronic monitoring system. Group I-IM received four, weekly injections of 1000 µg hydroxocobalamin. Blood samples were drawn before the first administration and after 1, 2 and 4 weeks of treatment, and analysed for VB12, holotranscobalamin (HoloTc), homocysteine (Hcy) and methylmalonic acid (MMA). For group O-oral, treatment adher-ence and percentage of days with 2 dosing events were calcu-lated. Before and after 28 days of treatment, patients were asked to fill in a questionnaire about their preference for the therapy options and associated factors.. Between November 2013 and December 2015, 37 patients (age: 49.5 ± 18.5 years; women: 60.5%) were recruited for oral (19) or IM (18) treatment. Baseline values with 95% confidence intervals for serum VB12, HoloTc, Hcy and MMA were 158 pmol/l [145-172], 49.0 pmol/l [40.4-57.5], 14.8 µmol/l [12.0-17.7] and 304 nmol/l [219-390], respective-ly, in group O-oral and 164 pmol/l [154-174], 50.1 pmol/l [38.7-61.6], 13.0 µmol/l [11.0-15.1] and 321 nmol/l [215-427], respectively, in group I-IM (not significant). After 1 month of treatment, levels of VB12 and HoloTc showed a significant increase compared with baseline (group O-oral: VB12 354 pmol/l [298-410] and HoloTc 156 pmol/l [116-196]; group I-IM: VB12 2796 pmol/l [1277-4314] and HoloTc 1269 pmol/l [103-2435]). Hcy and MMA levels showed a significant decrease compared with baseline (group O-oral: Hcy 13.8 µmol/l [10.7-16.8] and MMA 168 nmol/l [134-202]; group I-IM: Hcy 8.5 µmol/l [7.1-9.8] and MMA 156 nmol/l [121-190]). HoloTc and MMA levels were normalised in all patients after 4 weeks of treatment, whereas normalisation of VB12 and Hcy was reached by all patients in group I-IM only. Response of VB12, HoloTc and Hcy was more pronounced in group I-IM (p <0.01) and the primary hypothesis that oral VB12 treatment would be noninfe-rior to IM treatment was rejected. Average adherence to thera-py was 99.6 ± 1.1% and days with 2 dosing events reached 5.6%. Before randomisation, preference was in favour of oral treatment (45.9%, n = 17) over IM administration (21.6%, n = 8). Twelve patients (32.4%) had no preference. Nine (24.3%) patients changed their preference after treatment. Patients who obtained their preferred route of administration main-tained their preference in the case of oral treatment and changed their preference after IM treatment.. Differences in VB12 levels between groups were higher than expected. Therefore, noninferiority of oral treat-ment had to be rejected. However, normalisation of HoloTc and MMA was reached by all patients after a 1-month treatment period. The clinical benefit of the exaggerated biomarker re-sponse after IM treatment within a typical primary care popula-tion is questionable. Midterm biomarker effects and patient preferences should be considered when a therapeutic scheme is chosen. Initial rating in favour of either IM or oral therapy can change over time and justifies repeated re-evaluation of patient preferences. (ClinicalTrials.gov ID NCT01832129).

Topics: Administration, Oral; Biomarkers; Female; Humans; Hydroxocobalamin; Injections, Intramuscular; Male; Middle Aged; Patient Preference; Primary Health Care; Prospective Studies; Surveys and Questionnaires; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

Long-term haemodialysis patients may be at risk of hydrosoluble vitamin deficiencies. This study aimed to test the hypothesis that in patients with serum B12 < 300 pmol/L, intramuscular hydroxocobalamin reduces erythropoietin requirements whilst maintaining haemoglobin concentrations (Hb).. Study design was prospective, non-randomized, open label, with single group assignment. In 61 patients hydroxocobalamin 1000 μg was given weekly for 3 weeks and erythropoietin dose adjusted to target a Hb of 11-12 g/L. The primary outcome was the change in erythropoietin requirements at 2 years. Secondary outcomes included assessment of change in biochemical or clinical parameters.. The erythropoietin dose reduced from 11 000 ± 7000 (10 000) IU to 5000 ± 6000 (3000) IU per week (P < 0.001) with no change in Hb 116 ± 16 (117) g/L before and after 114 ± 15 (113) g/L (P = 0.488) hydroxocobalamin supplementation. Serum albumin rose from 35 ± 4 (35) g/L to 36 ± 4 (36) g/L (P = 0.03). A significant rise in red cell folate (RCF) and serum vitamin B12 levels was observed. Serum ferritin rose despite a reduction in intravenous iron usage and no significant change in c-reactive protein or transferrin saturation.. In HD patients with B12 < 300 pmol/L, following treatment with hydroxocobalamin there was reduced erythropoietin requirements, maintained Hb and a small but significant rise in the serum albumin. RCF may be low in haemodialysis patients with metabolic cobalamin deficiency and rises significantly after supplementation. Hydroxocobalamin supplementation may have the potential to reduce the cost of anaemia management.

Topics: Adult; Aged; Dietary Supplements; Erythrocyte Indices; Female; Folic Acid; Hematinics; Humans; Hydroxocobalamin; Male; Middle Aged; Nutritional Status; Prospective Studies; Renal Dialysis; Vitamin B 12 Deficiency

During infancy, minor developmental delays and gastrointestinal complaints are common, as is a biochemical profile indicative of impaired cobalamin status.. We investigated whether cobalamin supplementation can improve development or symptoms in infants with biochemical signs of impaired cobalamin function and developmental delay or feeding difficulties.. Infants <8 mo of age (n = 105) who were referred for feeding difficulties, subtle neurologic symptoms, or delayed psychomotor development were assessed for cobalamin status [by the measurement of serum cobalamin, plasma total homocysteine (tHcy), and plasma methylmalonic acid (MMA)]. Infants with biochemical signs of impaired cobalamin function, defined as a plasma tHcy concentration ≥6.5 μmol/L (n = 79), were enrolled in a double-blind, randomized controlled trial to receive 400 μg hydroxycobalamin intramuscularly (n = 42) or a sham injection (n = 37). Motor function [Alberta Infants Motor Scale (AIMS)] and clinical symptoms (parental questionnaire) were recorded at entry and after 1 mo.. During follow-up, cobalamin supplementation changed all markers of impaired cobalamin status (ie, plasma tHcy decreased by 54%, and MMA decreased by 84%), whereas no significant changes were seen in the placebo group (P < 0.001). The median (IQR) increase in the AIMS score was higher in the cobalamin group than in the placebo group [7.0 (5.0, 9.0) compared with 4.5 (3.3, 6.0); P = 0.003], and a higher proportion showed improvements in regurgitations (69% compared with 29%, respectively; P = 0.003).. In infants with biochemical signs of impaired cobalamin function, 1 intramuscular injection of cobalamin resulted in biochemical evidence of cobalamin repletion and improvement in motor function and regurgitations, which suggest that an adequate cobalamin status is important for a rapidly developing nervous system. This trial was registered at clinicaltrials.gov as NCT00710359 and NCT00710138.

Topics: Biomarkers; Child Development; Dietary Supplements; Double-Blind Method; Female; Folic Acid; Follow-Up Studies; Homocysteine; Humans; Hydroxocobalamin; Infant; Injections, Intramuscular; Linear Models; Male; Methylmalonic Acid; Surveys and Questionnaires; Vitamin B 12 Deficiency; Vomiting

Mild cobalamin (Cbl) deficiency is frequently found in older persons and is associated with cognitive and cerebral abnormalities. The effects of Cbl supplementation on these abnormalities are largely unknown.. In a single-blind, placebo-controlled intervention study, 16 healthy community-dwelling elderly subjects with low plasma Cbl concentration and no cognitive impairments were studied. Subjects underwent 1 month of treatment with placebo, followed by 5 months of treatment with intramuscular injections of hydroxycobalamin. Before and after measurements of plasma cobalamin, total homocysteine (tHcy), methylmalonic acid (MMA), quantitative electroencephalograph (qEEG), and psychometric tests were taken.. After Cbl supplementation, plasma Cbl concentrations increased, and plasma MMA and tHcy concentrations decreased. The performance on the Verbal Word Learning Test, Verbal Fluency and Similarities improved. qEEG showed more fast activity and less slow activity. Lower plasma tHcy concentrations were related to increased fast activity on qEEG on the one hand and improved performance on the Verbal Word Learning Test and Similarities on the other. Increased fast or decreased slow activity on qEEG was associated with improved performance on the Verbal Word Learning Test, Similarities and Verbal Fluency.. Electrographic signs of improved cerebral function and improved cognitive function were found after Cbl supplementation in older subjects with low plasma Cbl concentrations who were free of significant cognitive impairment. These improvements were related to a reduction of plasma tHcy concentration.

Topics: Aged; Aged, 80 and over; Aging; Brain; Cognition; Electroencephalography; Female; Humans; Hydroxocobalamin; Male; Methylmalonic Acid; Single-Blind Method; Vitamin B 12 Deficiency

Patients with previous stomach and terminal ileum resections are often treated with intramuscular vitamin B12 injections. Disadvantages are, on a worldwide scale, the frequent need for medical personnel to administer injections and the sometimes painful way of application. This study was designed to investigate the feasibility of intranasal hydroxocobalamin suppletion in cobalamin-deficient patients and to assess whether intranasal hydroxocobalamin application could be an alternative for intramuscular injection.. Six patients with plasma cobalamin concentrations of < 200 ng/L were recruited. A dose of 1500 micrograms hydroxocobalamin was applied intranasally at days 0, 14, and 21. Plasma cobalamin concentrations were determined 1 hour after hydroxocobalamin application and on days 0, 7, 21, 28, and 35.. All patients showed substantial increase of cobalamin concentrations 1 hour after intranasal application. In these 6 patients, there was an eightfold increase of mean baseline cobalamin concentrations. All patients showed a sustained increase of baseline cobalamin concentrations 1 week after prior intranasal application of hydroxocobalamin. No side effects were noted.. Intranasal application of hydroxocobalamin in cobalamin-deficient patients results in fast nasal absorption and leads to sustained increase of baseline cobalamin concentrations.

Topics: Administration, Intranasal; Dose-Response Relationship, Drug; Hematinics; Humans; Hydroxocobalamin; Radioimmunoassay; Time Factors; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Cobalt Isotopes; Coenzymes; Humans; Hydroxocobalamin; Kidney Diseases; Liver Diseases; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia, Pernicious; Clinical Trials as Topic; Humans; Hydroxocobalamin; Injections, Intramuscular; Vitamin B 12 Deficiency

Topics: Child, Preschool; Cognitive Dysfunction; Homocystinuria; Humans; Hydroxocobalamin; Infant; Macular Degeneration; Male; Mammals; Oxidoreductases; Vitamin B 12; Vitamin B 12 Deficiency

This case report describes a patient with early-onset cobalamin C deficiency who was started on treatment with high-dose parenteral hydroxocobalamin after diagnosis at 13 days of life. Prior to diagnosis, initial presenting symptoms included poor feeding, lethargy, apneic episodes, hypothermia, and hypotonia; these symptoms resolved after initiation of medication. Methylmalonic acid and homocysteine levels were trended and significantly improved with treatment. She was maintained on 2 mg/kg/day dosing of hydroxocobalamin. No adverse effects to treatment were observed. At the time of this report, the patient was 19 months of age; she had not manifested common findings of early-onset cobalamin C deficiency, including microcephaly, poor feeding, growth abnormalities, hypotonia, seizures, maculopathy, or neurodevelopmental delay. This report suggests that early initiation of high-dose hydroxocobalamin is safe and effective.

Topics: Amino Acid Metabolism, Inborn Errors; Female; Humans; Hydroxocobalamin; Infant, Newborn; Methylmalonic Acid; Muscle Hypotonia; Vitamin B 12 Deficiency

The early diagnosis of and intervention in vitamin B12 deficiency in exclusively breastfed infants by mothers with low vitamin B12 is crucial in preventing possible irreversible neurologic damage, megaloblastic anemia, and failure to thrive. We assess the usefulness of the early detection of asymptomatic B12 deficiency related to acquired conditions and highlight the importance of monitoring serum vitamin B12 levels during pregnancy. We describe demographic, clinical, dietary, and biochemical data, including the evolution of a vitamin B12 deficiency's functional biomarkers. We enrolled 12 newborns (5 males) with an age range of 1-2 months old that were exclusively breastfed and asymptomatic. These cases were referred to our metabolic unit due to alterations in expanded newborn screening: high levels of methylmalonic acid and/or total homocysteine (tHcy). All mothers were under a vegetarian diet except three who had abnormal B12 absorption, and all presented low or borderline serum B12 level and high plasma levels of tHcy. Supplementation with oral vitB12 re-established the metabolic homeostasis of the mothers. In infants, therapy with an intramuscular injection of 1.0 mg hydroxocobalamin led to the rapid normalization of the metabolic pattern, and a healthy outcome was observed. Acquired B12 deficiency should be ruled out before proceeding in a differential diagnosis of cobalamin metabolism deficits, methylmalonic acidemia, and homocystinuria.

Topics: Biomarkers; Early Diagnosis; Female; Homocysteine; Humans; Hydroxocobalamin; Infant; Infant Health; Infant, Newborn; Male; Methylmalonic Acid; Pregnancy; Vitamin B 12; Vitamin B 12 Deficiency

Transcobalamin deficiency is a rare autosomal recessive inborn error of cobalamin transport (prevalence: < 1/1000000) which clinically manifests in early infancy.. Our case report highlights that early detection of TC deficiency and early initiation of aggressive IM treatment is likely associated with disease control and an overall favorable outcome.

Topics: Adult; Female; Humans; Hydroxocobalamin; Mutation; Transcobalamins; Vitamin B 12 Deficiency

Topics: Anorexia; Fatigue; Female; Hand Dermatoses; Humans; Hydroxocobalamin; Hyperpigmentation; Hypesthesia; Injections, Intramuscular; Middle Aged; Paresthesia; Treatment Outcome; Vitamin B 12 Deficiency; Vitamin B Complex

Topics: Anemia, Pernicious; Attention; Erythrocyte Indices; Fatigue; Humans; Hydroxocobalamin; Injections, Intramuscular; Missed Diagnosis; Peripheral Nervous System Diseases; Vitamin B 12 Deficiency; Vitamin B Complex

In humans, absorption and tissue retention rates of intramuscularly administered hydroxocobalamin (OH-Cbl) are superior compared to cyanocobalamin (CN-Cbl). Supplementation with OH-Cbl has not been described in cats.. To evaluate effects of parenteral OH-Cbl supplementation on clinical signs, serum Cbl and methylmalonic acid (MMA) concentrations in hypocobalaminemic cats with gastrointestinal disease.. Twenty-three client-owned cats.. Prospective study. Serum Cbl and MMA concentrations were determined at enrollment (t0), immediately before the 4th OH-Cbl IM injection (300 μg, given q2 weeks) (t1), and 4 weeks after the 4th injection (t2). Severity of clinical signs (activity, appetite, vomiting, diarrhea, body weight) was graded at each time point and expressed as clinical disease activity score.. Median clinical disease activity score decreased significantly from t0 (6; range, 2-10) to t1 (1; range, 0-6) and t2 (1; range, 0-9). Median serum Cbl concentration increased significantly from 111 pmol/L (range, 111-218; reference range, 225-1451 pmol/L) at t0 to 1612 pmol/L (range, 526-14 756) (P < .001) at t1, and decreased again significantly to 712 pmol/L (range, 205-4265) (P < .01) at t2. Median baseline serum MMA concentration at t0 (802 nmol/L; range, 238-151 000; reference range, 120-420 nmol/L) decreased significantly (P < .001) to 199 nmol/L (range, 29-478) at t1, and was 205 nmol/L (range, 88-734) at t2. Serum MMA concentrations normalized in 22/23 cats at t1, and were not significantly higher at t2 compared to t1.. The herein described OH-Cbl injection scheme appears efficacious for normalization of cellular Cbl deficiency in cats with gastrointestinal disease.

Topics: Animals; Cat Diseases; Cats; Dietary Supplements; Gastrointestinal Diseases; Hydroxocobalamin; Methylmalonic Acid; Prospective Studies; Vitamin B 12; Vitamin B 12 Deficiency

Cobalamin metabolism disorders are rare, inherited diseases which cause megaloblastic anaemia and other clinical manifestations. Early diagnosis of these conditions is essential, in order to allow appropriate treatment as early as possible.. Here we report the case of a patient who was apparently healthy until the age of 20, when she presented with impaired renal function and normocytic anaemia. At the age of 34, when her first pregnancy resulted in an intrauterine death of a morphologically normal growth-restricted foetus, she was diagnosed with homocystinuria and methylmalonic aciduria due to cyanocobalamin C (cblC) defect, which was confirmed by molecular investigation. Consequently, hydroxocobalamin was administered to correct homocysteine plasma levels. This treatment was efficacious in lowering homocysteine plasma levels and restored anaemia and renal function. During a second pregnancy, the patient was also administered a prophylactic dose of low molecular -weight heparin. The pregnancy concluded with a full-term delivery of a healthy male.. This case emphasises the importance of awareness and appropriate management of rare metabolic diseases during pregnancy. We suggest that women with late-onset cblC defect can have a positive pregnancy outcome if this metabolic disease is treated adequately.

Topics: Abortion, Spontaneous; Adult; Anticoagulants; Enoxaparin; Female; Fetal Growth Retardation; Homocystinuria; Humans; Hydroxocobalamin; Leucovorin; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Vitamin B 12 Deficiency; Vitamin B Complex

We compare the effect of 8-week oral supplementation with cyano-B12 (currently used in vitamin pills) and hydroxo-B12 (predominant form in the diet) in a population with nutritional vitamin B12 deficiency.. Fifty-one healthy Indian adults with baseline serum cobalamin < 200 pmol/L were supplied for 8 weeks with daily oral supplements of 3-µg cyano-B12 (n = 15), 3-µg hydroxo-B12 (n = 16), or a placebo (n = 20). Blood at baseline, and each following week, was examined for total cobalamin, holotranscobalamin, methylmalonic acid, and homocysteine.. The study groups did not differ at baseline and were characterized by [median (range)] serum cobalamin [128 (68-191) pmol/L], holotranscobalamin [16 (6-41) pmol/L], methylmalonic acid [0.8 (0.3-1.7) µmol/L], homocysteine [17.9 (8.5-100.9) µmol/L], and a combined indicator of B12 status 4cB12 of - 1.65 (- 0.64 to - 4.07). The group supplemented with cyano-B12 showed a higher increase in total serum cobalamin than the group treated with hydroxo-B12, while other biomarkers changed comparably in the two groups. After 8 weeks of treatment, the biomarker values of the supplemented groups (pooled) differed significantly from the placebo group. Yet, the vitamin B12 status was still poor [cobalamin: 168 (87-302) pmol/L; holotranscobalamin: 19 (8-45) pmol/L; methylmalonic acid: 0.7 (0.2-1.7) µmol/L; homocysteine: 17.2 (2.6-96.8) µmol/L; 4cB12 = - 1.34 (- 0.33 to - 3.3)].. 8-week supplementation with 3-µg cyano-B12 elevated serum cobalamin more than 3 µg hydroxo-B12, but all other biomarkers changed similarly in both groups. Supplementation with 3 µg vitamin B12 did not reverse the low status in individuals with nutritional vitamin B12 deficiency.. REF/2017/02/013343.

Topics: Administration, Oral; Adult; Biomarkers; Cohort Studies; Dietary Supplements; Female; Humans; Hydroxocobalamin; India; Longitudinal Studies; Male; Middle Aged; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex; Young Adult

Topics: Female; Hallucinations; Humans; Hydroxocobalamin; Hyperhomocysteinemia; Nitrous Oxide; Psychotic Disorders; Receptors, N-Methyl-D-Aspartate; Vitamin B 12 Deficiency; Vitamin B Complex; Young Adult

An 18-year-old female patient presented to the emergency department with non-specific neurological and gastrointestinal symptoms and was found to be pancytopenic. Her vitamin B

Topics: Adolescent; Female; Humans; Hydroxocobalamin; Nitrous Oxide; Pancytopenia; Vitamin B 12 Deficiency

Prospective studies on maintenance treatment for Beagles with hereditary selective cobalamin (Cbl) malabsorption (Imerslund-Gräsbeck syndrome, IGS) are lacking. In our experience, measurement of methylmalonic acid (MMA), a Cbl-dependent metabolite, seems more helpful to monitor Cbl status as compared with serum Cbl concentrations.. To evaluate a standardized Cbl supplementation scheme in Beagles with IGS. We hypothesized that a single parenteral dose of 1 mg hydroxocobalamin (OH-Cbl) would maintain clinical and metabolic remission for up to 2 months.. Six client-owned juvenile Beagles with genetically confirmed IGS and 28 healthy control dogs.. Prospective study. Monthly IM OH-Cbl (1 mg) supplementation was done over a median of 9 months (range, 6-13) in 6 dogs, followed by bimonthly (every 2 months) injections in 5 dogs over a median of 6 months (range, 3-10). Health status was assessed by routine clinical examinations at injection time points and owner observations. Voided urine samples were collected immediately before OH-Cbl injections for measurement of MMA-to-creatinine concentrations using a gas-liquid chromatography-tandem mass spectrometry (GC-MS) method.. All dogs were clinically healthy while receiving monthly and bimonthly OH-Cbl supplementation. Urinary MMA results in healthy dogs ranged from 1.3 to 76.5 mmol/mol creatinine (median, 2.9). Median urinary MMA concentrations did not differ between dogs with IGS receiving monthly (n = 49; 5.3 mmol/mol creatinine; range, 2.3-50.4) and bimonthly (n = 31; 5.3 mmol/mol creatinine; range, 1.6-50) injections.. A maintenance parenteral dose of 1 mg OH-Cbl monthly or bimonthly appears adequate in Beagles with IGS monitored by metabolic testing.

Topics: Anemia, Megaloblastic; Animals; Creatinine; Dog Diseases; Dogs; Drug Administration Schedule; Female; Hydroxocobalamin; Injections, Intramuscular; Malabsorption Syndromes; Male; Methylmalonic Acid; Prospective Studies; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Severe B

Topics: Adult; Aftercare; Diagnosis, Differential; Diet, Vegetarian; Feeding Behavior; Humans; Hydroxocobalamin; Injections, Intramuscular; Life Support Care; Male; Malnutrition; Pancytopenia; Retinal Hemorrhage; Treatment Outcome; Vision Disorders; Vitamin B 12; Vitamin B 12 Deficiency

The vitamin B

Topics: Abortion, Habitual; Adult; Anemia, Iron-Deficiency; Breast Feeding; Delayed Diagnosis; Developmental Disabilities; Dietary Supplements; Female; Ferrous Compounds; Hematinics; Humans; Hydroxocobalamin; Infant; Infant Nutritional Physiological Phenomena; Injections, Intramuscular; Maternal Nutritional Physiological Phenomena; Nutritional Status; Pancytopenia; Pregnancy; Severity of Illness Index; Treatment Outcome; Vitamin B 12 Deficiency

Cobalamin C disease is a multisystemic disease with variable manifestations and age of onset. Genotype-phenotype correlations are well-recognized in this disorder. Here, we present a large cohort of individuals with cobalamin C disease, several of whom are heterozygous for the c.482G>A pathogenic variant (p.Arg161Gln). We compared clinical characteristics of individuals with this pathogenic variant to those who do not have this variant. To our knowledge, this study represents the largest single cohort of individuals with the c.482G>A (p.Arg161Gln) pathogenic variant.. A retrospective chart review of 27 individuals from 21 families with cobalamin C disease who are followed at our facility was conducted.. 13 individuals (48%) are compound heterozygous with the c.482G>A (p.Arg161Gln) on one allele and a second pathogenic variant on the other allele. Individuals with the c.482G>A (p.Arg161Gln) pathogenic variant had later onset of symptoms and easier metabolic control. Moreover, they had milder biochemical abnormalities at presentation which likely contributed to the observation that 4 individuals (31%) in this group were missed by newborn screening.. The c.482G>A (p.Arg161Gln) pathogenic variant is associated with milder disease. These individuals may not receive a timely diagnosis as they may not be identified on newborn screening or because of unrecognized, late onset symptoms. Despite the milder presentation, significant complications can occur, especially if treatment is delayed.

Topics: Adolescent; Adult; Alleles; Carrier Proteins; Child; Child, Preschool; Disease Management; Female; Follow-Up Studies; Genetic Association Studies; Genetic Variation; Genotype; Heterozygote; Homocystinuria; Humans; Hydroxocobalamin; Infant; Infant, Newborn; Male; Mutation; Neonatal Screening; Phenotype; Retrospective Studies; Vitamin B 12 Deficiency; Young Adult

To explore the ocular manifestations of cobalamin C (cblC) deficiency, an inborn error of intracellular vitamin B12 metabolism.. Retrospective, observational case series.. Twenty-five cblC patients underwent clinical and ophthalmic examination at the National Institutes of Health between August 2004 and September 2012. Patient ages ranged from 2 to 27 years at last ophthalmic visit, and follow-up ranged from 0 to 83 months (median, 37 months; range, 13-83 months) over a total of 69 visits.. Best-corrected visual acuity, slit-lamp biomicroscopy, dilated fundus examination, wide-field photography, fundus autofluorescence imaging, sedated electroretinography, optical coherence tomography, genetics and metabolite assessment.. Visual acuity and presence and degree of retinal degeneration and optic nerve pallor.. Nystagmus (64%), strabismus (52%), macular degeneration (72%), optic nerve pallor (68%), and vascular changes (64%) were present. c.271dupA (p.R91KfsX14) homozygous patients (n = 14) showed early and extensive macular degeneration. Electroretinography showed that scotopic and photopic responses were reduced and delayed, but were preserved remarkably in some patients despite severe degeneration. Optical coherence tomography images through the central macular lesion of a patient with severe retinal degeneration showed extreme thinning, some preservation of retinal lamination, and nearly complete loss of the outer nuclear layer. Despite hyperhomocysteinemia, no patients exhibited lens dislocation.. This longitudinal study reports ocular outcomes in the largest group of patients with cblC deficiency systematically examined at a single center over an extended period. Differences in progression and severity of macular degeneration, optic nerve pallor, and vascular attenuation between homozygous c.271dupA (p.R91KfsX14) patients and compound heterozygotes were noted. The pace and chronicity of ophthalmic manifestations lacked strict correlation to metabolic status as measured during visits. Prenatal or early treatment, or both, may have mitigated ocular disease, leading to better functional acuity, but patients still progressed to severe macular degeneration. The effects of prenatal or early treatment, or both, in siblings; the manifestation of severe disease in infancy; the presence of comorbid developmental abnormalities; and the possible laminar structural defect noted in many patients are findings showing that cblC deficiency displays a developmental as well as a degenerative ocular phenotype.

Topics: Adolescent; Adult; Carrier Proteins; Child; Child, Preschool; Disease Progression; Electroretinography; Follow-Up Studies; Homocystinuria; Humans; Hydroxocobalamin; Injections, Intramuscular; Macular Degeneration; Nystagmus, Pathologic; Optic Nerve Diseases; Optical Imaging; Oxidoreductases; Phenotype; Retrospective Studies; Strabismus; Tomography, Optical Coherence; Visual Acuity; Vitamin B 12 Deficiency; Vitamin B Complex

Topics: Female; Humans; Hydroxocobalamin; Hyperpigmentation; Infant; Skin Pigmentation; Treatment Outcome; Vitamin B 12 Deficiency

Vitamin B12 (cyancobalamin, Cbl) has two active co-enzyme forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdCbl). There has been a paradigm shift in the treatment of vitamin B12 deficiency such that MeCbl is being extensively used and promoted. This is despite the fact that both MeCbl and AdCbl are essential and have distinct metabolic fates and functions. MeCbl is primarily involved along with folate in hematopiesis and development of the brain during childhood. Whereas deficiency of AdCbl disturbs the carbohydrate, fat and amino-acid metabolism, and hence interferes with the formation of myelin. Thereby, it is important to treat vitamin B12 deficiency with a combination of MeCbl and AdCbl or hydroxocobalamin or Cbl. Regarding the route, it has been proved that the oral route is comparable to the intramuscular route for rectifying vitamin B12 deficiency.

Topics: Administration, Oral; Cobamides; Drug Therapy, Combination; Humans; Hydroxocobalamin; India; Injections, Intramuscular; Vitamin B 12; Vitamin B 12 Deficiency

Cobalamin C (CblC) defects are inherited autosomal recessive disorders of vitamin B12 metabolism due to mutations in the MMACHC gene. Renal manifestations include thrombotic microangiopathy (TMA), acute or chronic renal failure, tubulointerstitial nephritis, and proximal renal tubular acidosis. However, reports about glomerular pathologies are scarce.. A 4-year-old boy presented with nephrotic syndrome, arterial hypertension, and chronic anemia but no signs of hemolysis. Renal biopsy showed TMA with ischemic glomerular collapse, foot process effacement, and tubulointerstitial fibrosis. Elevated serum levels of homocysteine suggested a cobalamin C disorder. This was confirmed by the identification of compound heterozygous mutations in the MMACHC gene. Initial therapy consisted of antihypertensive treatment including angiotensin converting enzyme inhibitor (ACEi) leading to blood pressure control and a significant reduction of proteinuria. After a definite diagnosis of CblC deficiency, hydroxocobalamin was introduced. Thereafter, homocysteine levels decreased, anemia resolved, and a further decline of proteinuria with normalization of serum protein levels was noted. Renal function remained stable.. Although uncommon, the clinical picture of CblC defects may be ruled by nephrotic syndrome mimicking glomerulonephritis, minimal change disease, or primary focal and segmental glomerulosclerosis. Key to a correct diagnosis is elevated serum levels of homocysteine, and a definite diagnosis can be confirmed by genetic testing.

Topics: Anemia; Angiotensin-Converting Enzyme Inhibitors; Biopsy; Carrier Proteins; Child, Preschool; Homocysteine; Humans; Hydroxocobalamin; Hypertension, Renal; Kidney; Male; Nephrotic Syndrome; Oxidoreductases; Thrombotic Microangiopathies; Vitamin B 12; Vitamin B 12 Deficiency

Cobalamin C (Cbl C) disease is an inborn error of intracellular cobalamin metabolism. Two distinct clinical types are defined according to the age of onset. We describe an 8 year old girl with late-onset Cbl C disease presenting with neuropsychiatric symptoms. Mutation analysis revealed homozygous c.394C>T (p.R132X) mutation in the MMACHC gene. Serial magnetic resonance imaging (MRI) before and after the treatment are provided. MRI of the brain before treatment showed bilateral patchy focal hyperintensities in the white matter and cortical atrophy. After treatment with intramuscular hydroxycobalamin, oral folinic acid, oral betaine, normalization of MRI findings can be achieved in addition to clinical improvement. We present this case to draw attention to the reversibility of clinical and MRI findings in the late onset Cbl C disease after treatment.

Topics: Age of Onset; Brain; Child; DNA Mutational Analysis; Female; Homocystinuria; Humans; Hydroxocobalamin; Magnetic Resonance Imaging; Mutation; Vitamin B 12; Vitamin B 12 Deficiency

A 20-year-old man was hospitalized for malignant hypertension, mechanical hemolysis, and kidney failure. Kidney biopsy confirmed glomerular and arteriolar thrombotic microangiopathy. Etiologic analyses, which included ADAMTS13 activity, stool culture, complement factor proteins (C3, C4, factor H, factor I, and MCP [membrane cofactor protein]), anti-factor H antibodies, HIV (human immunodeficiency virus) serology, and antinuclear and antiphospholipid antibodies, returned normal results. Malignant hypertension was diagnosed. Ten months later, we observed a relapse of acute kidney injury and mechanical hemolysis. Considering a diagnosis of complement dysregulation-related atypical hemolytic uremic syndrome (HUS), we began treatment with eculizumab. Despite the efficient complement blockade, the patient's kidney function continued to decline. We performed additional analyses and found that the patient's homocysteine levels were dramatically increased, with no vitamin B12 (cobalamin) or folate deficiencies. We observed very low plasma methionine levels associated with methylmalonic aciduria, which suggested cobalamin C disease. We stopped the eculizumab infusions and initiated specific treatment, which resulted in complete cessation of hemolysis. MMACHC (methylmalonic aciduria and homocystinuria type C protein) sequencing revealed compound heterozygosity for 2 causative mutations. To our knowledge, this is the first report of adult-onset cobalamin C-related HUS. Considering the wide availability and low cost of the homocysteine assay, we suggest that it be included in the diagnostic algorithm for adult patients who present with HUS.

Topics: Adult; Amino Acid Metabolism, Inborn Errors; Antibodies, Monoclonal, Humanized; Betaine; Biopsy; Carrier Proteins; Diagnosis, Differential; Drug Resistance; Homocysteine; Homocystinuria; Humans; Hydroxocobalamin; Hypertension, Malignant; Immunologic Factors; Kidney; Kidney Function Tests; Leucovorin; Lipotropic Agents; Male; Methionine; Methylmalonic Acid; Mutation; Oxidoreductases; Recurrence; Renal Dialysis; Treatment Outcome; Vitamin B 12 Deficiency; Vitamin B Complex

The clinical picture is the most important factor in assessing the significance of test results assessing cobalamin status because there is no 'gold standard' test to define deficiency. Serum cobalamin currently remains the first-line test, with additional second-line plasma methylmalonic acid to help clarify uncertainties of underlying biochemical/functional deficiencies. Serum holotranscobalamin has the potential as a first-line test, but an indeterminate 'grey area' may still exist. Plasma homocysteine may be helpful as a second-line test, but is less specific than methylmalonic acid. The availability of these second-line tests is currently limited. Definitive cut-off points to define clinical and subclinical deficiency states are not possible, given the variety of methodologies used and technical issues, and local reference ranges should be established. In the presence of discordance between the test result and strong clinical features of deficiency, treatment should not be delayed to avoid neurological impairment. Treatment of cobalamin deficiency is recommended in line with the British National Formulary. Oral therapy may be suitable and acceptable provided appropriate doses are taken and compliance is not an issue. Serum folate offers equivalent diagnostic capability to red cell folate and is the first-line test of choice to assess folate status.

Topics: Biomarkers; Diagnosis, Differential; Folic Acid; Folic Acid Deficiency; Humans; Hydroxocobalamin; Vitamin B 12 Deficiency

Topics: Female; Humans; Hydroxocobalamin; Leukoencephalopathies; Mental Disorders; Time Factors; Treatment Outcome; Vitamin B 12 Deficiency; Young Adult

Topics: Aged; Cervical Vertebrae; Diagnosis, Differential; Fingers; Follow-Up Studies; Humans; Hydroxocobalamin; Magnetic Resonance Imaging; Male; Paresthesia; Risk Assessment; Severity of Illness Index; Spinal Cord Diseases; Treatment Outcome; Vitamin B 12 Deficiency

The aim of this study is to examine retrospectively the clinical, biological and treatment features of anemia by vitamin B12 deficiency in the Hematology department of CHU Mohamed VI Marrakech. We report the results of a retrospective study conducted during six years (2005-2010). It included all patients with anemia (with or without thrombocytopenia or leukopenia) associated with vitamin B12 levels <200 pg / ml. One hundred twenty one cases were analyzed. The average age of patients was 62 years (38-89 years) with a female predominance (sex ratio F/M: 1.3). The clinical symptomatology is dominated by pallor (97.5%), cardiovascular signs (46%) and digestive symptoms (34.7%). Neurological signs were noted in 17.3% of cases. The blood count showed anemia (hemoglobin: mean= 6.9 g/dl), macrocythemia (MCV: mean= 109 fl). Leukopenia was noted in 35 patients (29%), thrombocytopenia in 34 patients (28%) and pancytopenia in 21 patients (17,3%). The average vitamin B12 was 72 pg/ml. The causes of B12 deficiency are pernicious anemia (43%), food-cobalamin malabsorption (43%), and in 14% of cases no etiology was found. Gastritis was found in 82.7% of our patients and Helicobacter pylori (HP) infection in 72.7% of cases. Reticulocyte crisis was observed after parenteral administration of hydroxocobalamine within an average of 8 days and normalization of blood counts, in all patients, within an average of 51 days. In patients with HP infection, eradication therapy of HP was performed. The cure rate of the HP is 90%.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Macrocytic; Anemia, Pernicious; Comorbidity; Diabetes Mellitus, Type 2; Female; Gastritis; Helicobacter Infections; Hematology; Hospital Departments; Humans; Hydroxocobalamin; Male; Middle Aged; Morocco; Postgastrectomy Syndromes; Retrospective Studies; Symptom Assessment; Vitamin B 12 Deficiency; Vitiligo

Cobalamin deficiency is associated with a wide spectrum of hematologic, neurologic, gastroenterologic and psychiatric disorders or symptoms. We report a case of a 50-year-old man with complex partial seizures with secondary generalization, mood oscillations and psychotic symptoms alternating with confusion and reversible dementia secondary to cobalamin deficiency in the absence of typical neurologic and/or hematologic symptoms and signs. Exclusion of epilepsy, acute, atrophic or expansive lesion of central nervous system and usual etiology associated with reversible dementia (infectious diseases, an endocrine etiology and deficiency of vitamins other than cobalamin); finding of cobalamin deficiency only and complete neuropsychiatric recovery after substitution, confirmed etiology. Typical and atypical psychiatric manifestations due to cobalamin deficiency that precede neurologic and/or hematologic signs and symptoms can recover completely after adequate replacement therapy.

Topics: Carbamazepine; Dementia; Diazepam; Electroencephalography; Haloperidol; Hematology; Humans; Hydroxocobalamin; Male; Middle Aged; Mood Disorders; Neurology; Psychotic Disorders; Seizures; Vitamin B 12 Deficiency

CblC deficiency produces a combination of methylmalonic aciduria (MMA) and homocystinuria (HCU), and is the most common error of cobalamin metabolism. Patients present a wide spectrum of symptoms, ranging from early severe multisystemic forms, to milder late-onset phenotypes. Cognitive and visual impairment are nearly constant. Hydroxocobalamin (OHCbl), betaine, folinic acid, levocarnitine and eventually dietary protein restriction are the main therapeutic approaches. Although early introduction of OHCbl is crucial, no standardized protocols regarding dose adaptation exist. No reports on long-term outcomes after high doses of this vitamin have been published.. In this study five patients with CblC deficiency (early severe forms) were treated with high doses of OHCbl for 18 to 30months. Clinical examinations, neurological assessment, and biochemical studies (plasma total homocysteine (tHcy), amino acids, hydroxocobalamin, and methylmalonic acid in urine) were periodically performed.. Variable clinical and biochemical outcomes were observed in patients treated with high doses of OHCbl. The best biochemical response was observed in those children with the worse metabolic control. By contrast, those patients with a concentration of tHcy around 50μmol/l or less showed only minor changes. Clinically, a considerable improvement was observed in those patients with severe problems in communication, expressive language and behavior.. According to our study, high OHCbl doses in CblC deficiency could have a greater benefit in those children with a prior history of suboptimal metabolic control, and also in those with severe neurological phenotypes. More specifically, we observed improvements in communication skills and behavior. These results should encourage further prospective trials to determine the optimal OHCbl regimen and to generate protocols and guidelines in this rare disorder.

Topics: Age of Onset; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Homocystinuria; Humans; Hydroxocobalamin; Male; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency

Combined methylmalonic acidemia with homocystinuria is a common form of methylmalonic acidemia in China. Patients with this disease can progress to death without timely and effective treatment. This study aimed to analyze the treatment outcomes of patients with combined methylmalonic acidemia and homocystinuria.. From September 2004 to April 2012, 58 patients with combined methylmalonic acidemia and homocystinuria (34 males and 24 females) were diagnosed and treated in our hospital. Fifty cases were from clinical patients including 42 early-onset cases and 8 late-onset cases. Their age when they were diagnosed ranged from 18 days to 30.8 years. The other 8 cases were from newborn screening. All the patients were treated with vitamin B12, betaine, folic acid, vitamin B6, and L-carnitine. The physical and neuropsychological development, general laboratory tests, the levels of amino acids, acylcarnitines, and homocysteine in blood, and organic acids in urine were followed up.. The follow-up period ranged from 1 month to 7.1 years. Three cases died (all were early-onset cases). In the other patients after treatment, the symptoms such as recurrent vomiting, seizures, lethargy, and poor feeding disappeared, muscle strength and muscle tension were improved, and general biochemical abnormalities such as anemia and metabolic acidosis were corrected. Among the surviving 55 cases, 49 had neurological impairments such as developmental delay and mental retardation. The median levels of blood propionylcarnitine and its ratio with acetylcarnitine, serum homocysteine, and urine methylmalonic acid were significantly decreased (P < 0.01), from 7.73 µmol/L (ranged from 1.5 to 18.61 µmol/L), 0.74 (ranged from 0.29 to 2.06), 97.3 µmol/L (ranged from 25.1 to 250 µmol/L) and 168.55 (ranged from 3.66 to 1032.82) before treatment to 2.74 µmol/L (ranged from 0.47 to 12.09 µmol/L), 0.16 (ranged from 0.03 to 0.62), 43.8 µmol/L (ranged from 17 to 97.8 µmol/L) and 6.81 (ranged from 0 to 95.43) after treatment, respectively.. Patients with combined methylmalonic acidemia and homocystinuria respond to a combined treatment consisting of supplementation of hydroxycobalamin, betaine, folic acid, vitamin B6 and L-carnitine with clinical and biochemical improvement. But the long-term outcomes are unsatisfactory, with neurological sequelae in most patients.

Topics: Adolescent; Adult; Amino Acid Metabolism, Inborn Errors; Betaine; Carnitine; Child; Child, Preschool; Female; Follow-Up Studies; Homocystine; Homocystinuria; Humans; Hydroxocobalamin; Infant; Infant, Newborn; Male; Methylmalonic Acid; Neonatal Screening; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency; Young Adult

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

Topics: Female; Humans; Hydroxocobalamin; Male; Vitamin B 12; Vitamin B 12 Deficiency

Neurological disorders related to vitamin B12 deficiency are common in prisons of tropical Africa. We collected 22 cases (20 men and 2 women). They all showed vitamin B12 deficiency associated with neurological signs that were represented by sclerosis combined with bone marrow (n = 9), peripheral neuropathy (n = 6), cerebellar syndrome (n = 2), a pyramidal syndrome of the lower limbs (n = 4) and optic neuropathy (n = 1). Laboratory tests showed a mean hemoglobin concentration of 7.2 ± 1.5 g/dl, mean 104 ± 28 fl, macrocytic anemia in 10 patients. Biermer's disease was identified in 9 patients, 3 patients showed the syndrome of non dissociation of vitamin B12, a gastrectomy in 2 patients and no etiology was identified in 8 patients.

Topics: Adult; Cohort Studies; Electromyography; Female; Guinea; Humans; Hydroxocobalamin; Magnetic Resonance Imaging; Male; Middle Aged; Nervous System Diseases; Prisons; Vitamin B 12 Deficiency

The cblG and cblC disorders of cobalamin (Cbl) metabolism are two inherited causes of megaloblastic anaemia. In cblG, mutations in methionine synthase (MTR) decrease conversion of hydroxocobalamin  (HOCbl) to methylcobalamin, while in cblC, mutations in MMACHC disrupt formation of cob(II)alamin (detected as HOCbl). Cases with undetectable methionine synthase (MS) activity are extremely rare and classified as 'cblG-variant'. In four 'cblG-variant' cases, we observed a decreased conversion of cyanocobalamin to HOCbl that is also seen in cblC cases. To explore this observation, we studied the gene defects, splicing products and expression of MS, as well as MS/MMACHC protein interactions in cblG-variant, cblG, cblC and control fibroblasts. We observed a full-size MS encoded by MTR-001 and a 124 kDa truncated MS encoded by MTR-201 in cblG, cblC, control fibroblasts and HEK cells, but only the MTR-201 transcript and inactive truncated MS in cblG-variant cells. Co-immunoprecipitation and proximity ligation assay showed interaction between truncated MS and MMACHC in cblG-variant cells. This interaction decreased 2.2, 1.5 and 5.0-fold in the proximity ligation assay of cblC cells with p.R161Q and p.R206W mutations, and HEK cells with knock down expression of MS by siRNA, respectively, when compared with control cells. In 3D modelling and docking analysis, both truncated and full-size MS provide a loop anchored to MMACHC, which makes contacts with R-161 and R-206 residues. Our data suggest that the interaction of MS with MMACHC may play a role in the regulation of the cellular processing of Cbls that is required for Cbl cofactor synthesis.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Anemia, Megaloblastic; Binding Sites; Carrier Proteins; Cells, Cultured; Gene Knockdown Techniques; HEK293 Cells; Humans; Hydroxocobalamin; Models, Molecular; Molecular Docking Simulation; Oxidoreductases; Protein Binding; Protein Isoforms; Protein Structure, Secondary; Vitamin B 12; Vitamin B 12 Deficiency

Pulmonary arterial hypertension (PAH) and renal thrombotic microangiopathy (rTMA) are rare diseases in childhood, frequently leading to death and end-stage renal disease, respectively. Their combined occurrence has been reported anecdotally. We investigated the clinical, biochemical, and genetic aspects of 5 children with the rare combination of PAH and rTMA. Onset of disease ranged from 1.5 to 14 years of age. The 2 youngest patients presented with concomitant pulmonary and renal disease; in the older patients, PAH was preceded by rTMA from age 2.5 to 7 years. Three patients presenting at ≤ 3 years of age died of right ventricular failure secondary to progressive PAH. In 2 patients, cobalamin C (cblC) deficiency was diagnosed postmortem. Three patients were treated with hydroxocobalamin; 1 died 2 weeks after diagnosis, 1 patient exhibited progressive pulmonary vasculopathy, and 1 patient is currently in stable condition. cblC deficiency was diagnosed biochemically 2 days to 18 years after initial presentation. Genetic analysis confirmed mutations in MMACHC in all patients; 4 patients were compound heterozygous, with all having base-pair substitutions (G>A or G>T) at nucleotide 276 in addition to frame-shift mutations. One patient had homozygous nonsense mutations of MMACHC. We established cblC deficiency as the denominator in the rare combination of PAH and rTMA in these children. Early recognition of cblC deficiency and vigorous treatment with hydroxocobalamin may beneficially affect the course of this devastating disease.

Topics: Adolescent; Carrier Proteins; Child, Preschool; Diagnosis, Differential; Disease Progression; DNA Mutational Analysis; Early Diagnosis; Fatal Outcome; Female; Follow-Up Studies; Hemolytic-Uremic Syndrome; Humans; Hydroxocobalamin; Hypertension, Pulmonary; Infant; Kidney; Male; Oxidoreductases; Proto-Oncogene Proteins c-cbl; Thrombotic Microangiopathies; Vitamin B 12 Deficiency

Topics: Anemia, Megaloblastic; Atrophy; Brain; Consanguinity; Electroencephalography; Female; Humans; Hydroxocobalamin; Infant; Injections, Intramuscular; Magnetic Resonance Imaging; Myoclonus; Neuroprotective Agents; Pancytopenia; Piracetam; Tremor; Vitamin B 12 Deficiency; Vitamin B Complex

Topics: Adult; Anaphylaxis; Humans; Hydroxocobalamin; Male; Multiple Sclerosis; Vitamin B 12; Vitamin B 12 Deficiency

A 35-year-old woman with a history of vitiligo, hypothyroidism and amenorrhoea presented with collapse and clinical features of cardiac failure. Laboratory investigations revealed pancytopaenia, the cause of which was found to be vitamin B12 deficiency due to pernicious anaemia. Treatment with intramuscular hydroxycobalamin was commenced and the patient improved steadily with concomitant improvement in her haematological indices. Clinical features of pernicious anaemia which can include marked pancytopaenia, diagnostic approach, associated conditions and approach to treatment are discussed. The importance of surveillance for gastrointestinal malignancy is emphasised.

Topics: Adult; Anemia, Pernicious; Autoimmune Diseases; Diagnosis, Differential; Female; Heart Failure; Humans; Hydroxocobalamin; Pancytopenia; Vitamin B 12 Deficiency

According to the ADA guidelines, metformin and lifestyle modifications are the first line therapies in the treatment of type 2 diabetes mellitus. Metformin does, however, cause vitamin B-12 malabsorption, which may increase the risk of developing vitamin B-12 deficiency--a clinically important and treatable condition. Here we report a case of 60 year old diabetic male presenting with clinical features of Vitamin B-12 deficiency on long term metformin therapy, which was confirmed on investigations. Patient showed symptomatic improvement with change in treatment.

Topics: Diabetes Mellitus, Type 2; Humans; Hydroxocobalamin; Hypoglycemic Agents; Malabsorption Syndromes; Male; Metformin; Middle Aged; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

A previously healthy 7-week-old boy developed bilateral central retinal artery occlusions in the presence of hyperhomocysteinemia and elevated serum methylmalonic acid and was found to have a transcobalamin receptor mutation. Retinal arterial occlusion is uncommon in young patients and typically prompts a systemic workup. In cases of atypical retinal arterial occlusion, hyperhomocysteinemia should be investigated.

Topics: Humans; Hydroxocobalamin; Hyperhomocysteinemia; Infant; Injections, Intramuscular; Male; Methylmalonic Acid; Mutation; Receptors, Cell Surface; Retinal Artery Occlusion; Tomography, Optical Coherence; Vision Disorders; Vitamin B 12 Deficiency; Vitamin B 6

Cobalamin (Cbl, B(12)) is an essential micronutrient required to fulfill the enzymatic reactions of cytosolic methylcobalamin-dependent methionine synthase and mitochondrial adenosylcobalamin-dependent methylmalonyl-CoA mutase. Mutations in the MMACHC gene (cblC complementation group) disrupt processing of the upper-axial ligand of newly internalized cobalamins, leading to functional deficiency of the vitamin. Patients with cblC disease present with both hyperhomocysteinemia and methylmalonic acidemia, cognitive dysfunction, and megaloblastic anemia. In the present study we show that cultured skin fibroblasts from cblC patients export increased levels of both homocysteine and methylmalonic acid compared to control skin fibroblasts, and that they also have decreased levels of total intracellular folates. This is consistent with the clinical phenotype of functional cobalamin deficiency in vivo. The protein changes that accompany human functional Cbl deficiency are unknown. The proteome of control and cblC fibroblasts was quantitatively examined by two dimensional difference in-gel electrophoresis (2D-DIGE) and liquid chromatography-electrospray ionization-mass spectrometry (LC/ESI/MS). Major changes were observed in the expression levels of proteins involved in cytoskeleton organization and assembly, the neurological system and cell signaling. Pathway analysis of the differentially expressed proteins demonstrated strong associations with neurological disorders, muscular and skeletal disorders, and cardiovascular diseases in the cblC mutant cell lines. Supplementation of the cell cultures with hydroxocobalamin did not restore the cblC proteome to the patterns of expression observed in control cells. These results concur with the observed phenotype of patients with the cblC disorder and their sometimes poor response to treatment with hydroxocobalamin. Our findings could be valuable for designing alternative therapies to alleviate the clinical manifestation of the cblC disorder, as some of the protein changes detected in our study are common hallmarks of known pathologies such as Alzheimer's and Parkinson's diseases as well as muscular dystrophies.

Topics: Amino Acid Metabolism, Inborn Errors; Carrier Proteins; Cell Line; Cells, Cultured; Fibroblasts; Folic Acid; Homocysteine; Humans; Hydroxocobalamin; Intracellular Space; Metabolic Networks and Pathways; Methylmalonic Acid; Mutation; Oxidoreductases; Phenotype; Proteome; Vimentin; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

A 28 month-old boy was hospitalized with pallor and weight stagnation. He had macrocytic anaemia and pancytopenia due to cobalamin deficiency and a rare homozygous mutation in the intrinsic factor gene. His sister showed similar symptoms at the age of 15 months. The heterozygous father had no symptoms, but did have a low cobalamin level. Gastroscopy with biopsies showed no pathology. All were given monthly cyanocobalamin injections which, however, caused leg cramps. Replacement with monthly hydroxocobalamin was successful.

Topics: Child, Preschool; Female; Growth; Homozygote; Humans; Hydroxocobalamin; Infant; Intrinsic Factor; Male; Mutation; Vitamin B 12 Deficiency; Vitamin B Complex

Topics: Amino Acid Metabolism, Inborn Errors; Dose-Response Relationship, Drug; Humans; Hydroxocobalamin; Vitamin B 12 Deficiency; Vitamin B Complex

Topics: Administration, Oral; Female; Folic Acid Deficiency; Humans; Hydroxocobalamin; Injections, Intramuscular; Pregnancy; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency

We report case of an infant who presented with failure to thrive and developmental delay at 4 months of age. He was diagnosed to have vitamin B12 deficiency and antibodies to intrinsic factor secondary to undiagnosed maternal pernicious anemia. The child was treated with hydroxocobalamin and now at 2 years of age, he is developing and growing within normal range. We review the literature on this rare cause of cobalamin deficiency in infants. We highlight the factors determining the outcome and situations where raised index of suspicion could help in recognizing this preventable cause of developmental delay and learning difficulties.

Topics: Adult; Anemia, Pernicious; Early Diagnosis; Failure to Thrive; Female; Humans; Hydroxocobalamin; Infant; Male; Treatment Outcome; Vitamin B 12 Deficiency; Vitamin B Complex

Topics: Aged, 80 and over; Humans; Hydroxocobalamin; Male; Referral and Consultation; Vitamin B 12 Deficiency; Vitamin B Complex

Pernicious anaemia can present with psychiatric symptoms before haematological or neurological manifestations appear. We describe a young woman who presented with insidious onset catatonia without evidence of psychosis or depression. Blood count and mean cell volume were normal and neurological findings were equivocal. Low B(12) levels and intrinsic factor antibodies were found only by chance when they were included in a battery of further investigations. B(12) replacement was followed by prompt improvement. This case provides an argument for wider screening for B(12) deficiency in certain individuals with psychiatric disorders.

Topics: Adult; Anemia, Pernicious; Antipsychotic Agents; Benzodiazepines; Brain; Catatonia; Delayed Diagnosis; Diagnosis, Differential; Female; Humans; Hydroxocobalamin; Injections, Intramuscular; Magnetic Resonance Imaging; Neuropsychological Tests; Olanzapine; Recurrence; Tomography, X-Ray Computed; Vitamin B 12 Deficiency

To report the successful pregnancy of a woman with methylmalonic acidemia and hyperhomocysteinemia, cblC type [cobalamin C (cblC) deficiency] (MIM 277400).. Retrospective chart review.. A 24-year-old woman presented at 14 weeks gestation with nausea, self-restricted protein diet, and weight loss. She had a past history of asymptomatic methylmalonic acidemia but had been lost to follow-up since the age of 15 years. Biochemical evaluation revealed combined methylmalonic acidemia and hyperhomocysteinemia. Complementation analysis confirmed cblC deficiency. One copy of the most common mutations in the MMACHC gene, c.271dupA, was identified. The women was treated from 15 weeks of gestation with a low protein diet (64 g/day) (1.1 g /kg of weight/day), L-carnitine (1 g per os 3 times daily to 3 g per os 3 times daily in the third trimester), aspirin (salicylic acid) 80 mg per day, folic acid 5 mg per day, and hydroxocobalamin 1 mg intramuscular every week to two times per week in the third trimester. The pregnancy was uneventful and the delivery at term. The newborn was healthy at delivery and at follow-up.. We report on the successful outcome of pregnancy in a treated woman with cblC disease. The pregnancy was uneventful for both fetus and mother with the delivery of a term healthy boy. There is a need for an international registry on the management and outcomes of pregnancy in women with inborn errors of metabolism.

Topics: Amino Acid Metabolism, Inborn Errors; Aspirin; Carnitine; Carrier Proteins; Cells, Cultured; Combined Modality Therapy; Diet, Protein-Restricted; DNA Mutational Analysis; Female; Folic Acid; Genetic Predisposition to Disease; Homocystinuria; Humans; Hydroxocobalamin; Live Birth; Male; Mutation; Oxidoreductases; Phenotype; Platelet Aggregation Inhibitors; Pregnancy; Pregnancy Complications; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex; Young Adult

Topics: Brain Ischemia; Celiac Disease; Diet, Gluten-Free; Duodenum; Humans; Hydroxocobalamin; Hyperhomocysteinemia; Male; Middle Aged; Platelet Aggregation Inhibitors; Stroke; Vitamin B 12 Deficiency; Vitamin B Complex

An 8-year-old girl presented with severe muscular weakness, peripheral neuropathy, ataxia, fever and macrocytic anaemia. Clinically, vitamin B(12) (cobalamin) deficiency was considered. Despite the lack of pre-treatment laboratory confirmation of the diagnosis, a therapeutic trial of hydroxocobalamin injections was begun. After several days, a partial clinical response was seen. Within 5 months all symptoms had resolved. After treatment was initiated, laboratory analysis of pre-treatment blood samples confirmed the presence of vitamin B(12) deficiency. Auto-antibodies to intrinsic factor and parietal cells, pathognomonic for pernicious anaemia, were confirmed. Vitamin B(12) deficiency owing to dietary deficiency is not uncommon in children in developing countries. Although nutritional deficiency might have played a role in our patient, this case illustrates that the neurological manifestations of pernicious anaemia can present at a young age in African populations.

Topics: Anemia, Pernicious; Ataxia; Child; Early Diagnosis; Female; Hematinics; Humans; Hydroxocobalamin; Muscle Weakness; Peripheral Nervous System Diseases; Vitamin B 12 Deficiency

Megaloblastic anemias are a subgroup of macrocytic anemias, in which distinctive morphologic abnormalities occur in red cell precursors in bone marrow, namely megaloblastic erythropoiesis. Of the many causes of megaloblastic anemia, the most common are disorders resulting from cobalamin or folate deficiency. The clinical symptoms are weakness, fatigue, shortness of breath and neurologic abnormalities. The presence of oral signs and symptoms, including glossitis, angular cheilitis, recurrent oral ulcer, oral candidiasis, diffuse erythematous mucositis and pale oral mucosa offer the dentist an opportunity to participate in the diagnosis of this condition. Early diagnosis is important to prevent neurologic signs, which could be irreversible. The aim of this paper is to describe the oral changes in a patient with megaloblastic anemia caused by a dietary deficiency of cobalamin.

Topics: Adult; Anemia, Megaloblastic; Female; Humans; Hydroxocobalamin; Mouth Diseases; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

Cobalamin C (cblC), a combined form of methylmalonic acidaemia and hyperhomocysteinaemia, is recognized as the most frequent inborn error of intracellular cobalamin metabolism. This condition can be detected by expanded newborn screening and can have an acute neonatal presentation that is life-threatening if not suspected and promptly treated. Intramuscular (IM) hydroxocobalamin (OHCbl) is the main treatment for patients with cblC, but formal dosing guidelines do not exist. A clinical improvement and a decrease of plasma methylmalonic acid (MMA) and total homocysteine (tHcy) levels, and an increase in methionine are typically observed after its initiation. It is well recognized that despite treatment, long-term complications such as developmental delay and progressive visual loss, may still develop. We describe the biochemical response of a 13-year-old boy with worsening metabolic parameters despite strict adherence to a conventional treatment regimen. We progressively increased the OHCbl dose from 1 to 20 mg IM per day and observed a dose-dependent response with an 80% reduction of plasma MMA (25 to 5.14 micromol/L; normal range <0.27 micromol/L), a 55% reduction of tHcy (112 to 50 micromol/L; normal range: 0-13 micromol/L) and a greater than twofold increase in methionine (17 to 36 micromol/L; normal range: 7-47 micromol/L). This suggests that higher OHCbl doses might be required to achieve an optimal biochemical response in cblC patients, but it is unknown whether it may slow or eliminate other complications. Future clinical trials to determine the benefits of higher-dose OHCbl therapy in patients with cblC and other disorders of intracellular cobalamin metabolism should be planned.

Topics: Adolescent; Amino Acid Metabolism, Inborn Errors; Dose-Response Relationship, Drug; Humans; Hydroxocobalamin; Hyperhomocysteinemia; Injections, Intramuscular; Male; Treatment Outcome; Vitamin B 12 Deficiency

Pernicious anaemia may manifest various neurological symptoms and signs ranging from the subtle to the dramatic. We describe a young man with cobalamin deficiency presenting with sensorimotor deficits, ataxia, dysarthria, mild cognitive deterioration and altered mood of insidious onset. The MRI brain findings were in keeping with a leucoencephalopathy without evidence of MRI changes in the spinal cord. This constellation of features has been reported rarely. His response to treatment as well as the marked improvement of the leucoencephalopathy on imaging suggests at least partial reversibility of the neurological deficits.

Topics: Adult; Anemia, Pernicious; Humans; Hydroxocobalamin; Leukoencephalopathies; Magnetic Resonance Imaging; Male; Vitamin B 12 Deficiency; Vitamin B Complex

We report a case of a 42-year-old woman with a background of autoimmune polyglandular syndrome, who developed a type I immediate hypersensitivity reaction to intramuscular cyanocobalamin. Intradermal testing showed a positive reaction to cyanocobalamin. The patient was subsequently treated with intramuscular hydroxycobalamin after negative intradermal testing to this alternative B(12) compound. A review of previously described cases of hypersensitivity to either compound provides a rationale for the management of this rare but serious side-effect.

Topics: Adult; Anemia, Pernicious; Drug Hypersensitivity; Female; Humans; Hydroxocobalamin; Hypersensitivity, Immediate; Injections, Intramuscular; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

We report the case of a 7 month-old girl that presented with acute anemia, generalized muscular hypotonia and failure to thrive. Laboratory evaluation revealed cobalamin deficiency, due to a vegan diet of the mother. The clinical triad of an acquired floppy baby syndrome with megaloblastic anemia and failure to thrive is pathognomic for infantile cobalamin deficiency. Neurological abnormalities are often irreversible and may be associated with delayed myelinization in the MRI. A normal cobalamin level in maternal serum and absence of anemia do not exclude subclinical deficiency. If cobalamin deficiency is suspected, e.g. in pregnant women on vegan diet, urinary methylmalonic acid excretion and plasma homocysteine levels should be determined and cobalamin substitution should be started at an early stage to avoid potentially irreversible damage of the fetus.

Topics: Anemia, Megaloblastic; Bone Marrow Examination; Diagnosis, Differential; Diet, Vegetarian; Failure to Thrive; Female; Follow-Up Studies; Humans; Hydroxocobalamin; Infant; Injections, Intravenous; Pregnancy; Pregnancy Complications; Time Factors; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency

Haematological sequellae of vitamin B12 deficiency are attributed to disturbed DNA synthesis, but vitamin B12 itself plays no role in DNA biosynthesis. A proposed explanation for this is the methylfolate trap hypothesis. This hypothesis states that B12 deficiency impairs overall folate metabolism because 5-methyltetrahydrofolate (5MTHF) becomes metabolically trapped. This trap results from the fact that 5MTHF can neither be metabolised via the methionine synthase pathway, nor can it be reconverted to its precursor, methylenetetrahydrofolate. Other manifestations of the methylfolate trap include cellular folate loss because of shorter 5MTHF polyglutamate chains and global hypomethylation. The methylfolate trap has never been demonstrated in humans. We describe a patient with B12 deficiency who was homozygous for the common methylenetetrahydrofolate reductase (MTHFR) C677T mutation. We analysed red blood cell (RBC) folate vitamers and global DNA methylation by liquid chromatography (LC) in combination with tandem mass spectrometry, and 5MTHF polyglutamate length by LC-electrochemical detection. Compared to post-B12 supplementation values, homocysteine was higher (52.9 micromol/l vs. 16.8 micromol/l), RBC folate was lower (268.92 nmol/l vs. 501.2 nmol/l), the 5MTHF fraction of RBC folate was much higher (94.5% vs. 67.4%), polyglutamate chain length was shorter (more tetra- and pentaglutamates), and global DNA methylation was 22% lower. This is the first time that virtually all features of the methylfolate trap hypothesis have been demonstrated in a human with vitamin B12 deficiency.

Topics: Chromatography, Liquid; DNA Methylation; Erythrocytes; Folic Acid; Homocysteine; Homozygote; Humans; Hydroxocobalamin; Male; Mass Spectrometry; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Tetrahydrofolates; Vitamin B 12; Vitamin B 12 Deficiency

Vitamin B12 and folate deficiencies are the main nutritional determinants of hyperhomocysteinemia, which is an independent risk factor for cardiovascular diseases. There is scarce information about nutritional status on vitamin B12 and serum levels of folate in Mexican older people. The objective was to evaluate the nutritional status of vitamin B12 and folic acid concentration in non-institutionalized, urban elderly men and women subjects. One hundred volunteers over 60 years were included in this cross-sectional study. Serum levels of vitamin B12 and folate were measured. In addition some biochemical and anthropometric indicators were also evaluated. Considering serum values of vitamin, 30% had vitamin B12 deficiency, 52% normal status and 18% with high levels. None subjects had folic acid deficiency, by the contrary, a high proportion (62%) showed elevated levels in serum. There was an effect of sex on vitamin B12 status. Elderly men showed significantly lower levels of vitamin B12, and it was according with significant higher prevalence of vitamin B12 deficiency in this group as compared with the women group. The high proportion of vitamin B12 deficiency found in this study underline a possible public health problem and guarantee further survey-studies about vitamin B12 status and to explore causes and consequences of the deficiency. Finally, due the sample size and the design of the study, the results must be seen with caution and not try to generalize.

Topics: Aged; Body Mass Index; Cardiovascular Diseases; Epidemiologic Methods; Female; Folic Acid Deficiency; Humans; Hydroxocobalamin; Hyperhomocysteinemia; Male; Mexico; Middle Aged; Nutritional Status; Sex Distribution; Sex Factors; Urban Population; Vitamin B 12 Deficiency

Pernicious anemia is a megaloblastic anemia caused by vitamin B12 deficiency, and is the end-stage of autoimmune gastritis that typically affects persons older than 60 years. It is the most common cause of vitamin B12 deficiency. Pernicious anemia can also be diagnosed concurrently with other autoimmune diseases. We report the occurrence of megaloblastic anemia in a 22-year-old woman with chronic autoimmune thyroiditis for 10.5 years. Recently, she presented with microcytic anemia, and iron deficiency anemia was diagnosed initially. After administration of ferrous sulfate, macrocytic anemia was revealed and vitamin B12 deficiency was detected. Pernicious anemia was highly suspected because of the endoscopic finding of atrophic gastritis, and high titer of antigastric parietal cell antibody, as well as elevated serum gastrin level. After intramuscular injections of hydroxycobalamine 100 microg daily for 10 days, and monthly later, her blood counts returned to normal.

Topics: Adult; Anemia, Iron-Deficiency; Anemia, Pernicious; Female; Ferrous Compounds; Gastritis, Atrophic; Hashimoto Disease; Hematinics; Humans; Hydroxocobalamin; Vitamin B 12 Deficiency

Topics: Amino Acid Metabolism, Inborn Errors; Betaine; Cobamides; Female; Homocysteine; Homocystinuria; Humans; Hydroxocobalamin; Infant; Macula Lutea; Methionine; Methylmalonic Acid; Retina; Retinal Degeneration; Vision, Ocular; Visual Acuity; Vitamin B 12 Deficiency

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

Vitamin B12 deficiency causes decreased Methionine Synthase and L-Methylmalonyl-CoA Mutase activity and results in accumulation of Homocysteine, Methylmalonic acid and Propionylcarnitine. Propionylcarnitine is included in tandem mass spectrometry-based newborn screening programs for detection of certain inborn errors of metabolism. We report two asymptomatic newborns with Vitamin B12 deficiency due to maternal deficiencies. One was detected incidentally at 3 weeks of age; the second on supplemental newborn screening based on elevated Propionylcarnitine at 2 days of age. This illustrates the potential for false negative results for Vitamin B12 deficiency screening by acylcarnitine profiling in newborn screening. Homocysteine and Methylmalonic acid may be better markers of Vitamin B12 deficiency. In conclusion, we suggest measuring Methylmalonic acid, Propionylcarnitine and Homocysteine levels in blood spots in expanded newborn screening in order to detect asymptomatic newborns with Vitamin B12 deficiency. Further studies are needed to establish the sensitivity of these three markers in screening for Vitamin B12 deficiency.

Topics: Acyl-CoA Dehydrogenase, Long-Chain; Anemia, Pernicious; Autoimmune Diseases; Biomarkers; Carnitine; Citrates; Cystathionine; False Negative Reactions; Female; Gastric Bypass; Heterozygote; Homocysteine; Humans; Hydroxocobalamin; Infant Food; Infant, Newborn; Malabsorption Syndromes; Male; Mass Spectrometry; Maternal-Fetal Exchange; Methylmalonic Acid; Neonatal Screening; Pregnancy; Pregnancy Complications; Vitamin B 12 Deficiency

Topics: Anemia, Megaloblastic; Evoked Potentials, Visual; Humans; Hydroxocobalamin; Magnetic Resonance Imaging; Male; Middle Aged; Paresthesia; Remission Induction; Spinal Cord Diseases; Vitamin B 12 Deficiency

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Evidence-Based Medicine; Female; Humans; Hydroxocobalamin; Male; Middle Aged; Vitamin B 12 Deficiency

Transcobalamin II is a serum transport protein for vitamin B12. Small variations in TC-II affinity were recently linked to a high homocysteine level and increased frequency of neural tube defects. Complete absence of TC-II or total functional abnormality causes tissue vitamin B12 deficiency resulting in a severe disease with megaloblastic anemia and immunologic and intestinal abnormalities in the first months of life. This condition was described in hereditary autosomal-recessive form. Low serum TC-II without any symptoms or clinical significance was noted in relatives of affected homozygotes.. To study 23 members of a four-generation family with hereditary vitamin B12 deficiency and neurologic disorders.. Thorough neurologic, hematologic and family studies were supplemented by transcobalamin studies in 20 family members.. Partial TC-II deficiency was found in 19 subjects. Apo TC-II (free TC-II unbound to vitamin B12) and total unsaturated B12 binding capacity were low in all tested individuals but one, and holo TC-II (TC-II bound by vitamin B12) was low in all family members. The presentation of the disease was chronic rather than acute. Early signs in children and young adults were dyslexia, decreased IQ, vertigo, plantar clonus and personality disorders. Interestingly, affected children and young adults had normal or slightly decreased serum vitamin B12 levels but were not anemic. Low serum B12 levels were measured in early adulthood. In mid-late adulthood megaloblastic anemia and subacute combined degeneration of the spinal cord were diagnosed. Treatment with B12 injections resulted in a significant improvement. The pedigree is compatible with an autosomal-dominant transmission. This family study suggests a genetic heterogeneity of TC-II deficiency.. We report the first family with a hereditary transmitted condition of low serum TC-II (partial TC-II deficiency) associated with neurologic and mental manifestations in childhood. Partial TC-II deficiency may decrease the amount of stored cobalamin, resulting in increased susceptibility to impaired intestinal delivery of cobalamin and predisposing to clinically expressed megaloblastic anemia at a later age. Partial TC-II deficiency should be suspected in families with megaloblastic anemia and in individuals with neurologic and mental disturbances--despite normal serum vitamin B12 levels. Low serum UBBC and apo TC-II should confirm the diagnosis. Early vitamin B12 therapy may prevent irreversible neurologic damage.

Topics: Adolescent; Adult; Aged; Anemia, Megaloblastic; Child; Female; Hematinics; Humans; Hydroxocobalamin; Infant; Male; Mental Disorders; Middle Aged; Transcobalamins; Vitamin B 12 Deficiency

Paraesthesia is a common presenting complaint in vitamin B12 deficiency. Since this condition is partially reversible with repletion, this is a diagnosis not to be missed. Two cases in which the diagnosis was initially overlooked are presented, emphasising that the paraesthesia associated with vitamin B12 deficiency may be central (myelopathic) or peripheral (neuropathic) in origin.

Topics: Electromyography; Hematinics; Humans; Hydroxocobalamin; Magnetic Resonance Imaging; Male; Middle Aged; Paresthesia; Vitamin B 12 Deficiency

Topics: Drug Hypersensitivity; Female; Hematinics; Humans; Hydroxocobalamin; Middle Aged; Pruritus; Skin Tests; Vitamin B 12; Vitamin B 12 Deficiency

Two siblings, a boy age 12 and his sister age 4 years, presented with proteinuria and hematuria, hypertension, and chronic hemolytic anemia. At age 13 years, the boy developed an episode of severe hypertensive encephalopathy and transient renal failure. Both children are attending normal school, have no neurologic symptoms, and only minimal pigmentary retinal abnormalities. Renal biopsy showed a chronic thrombotic microangiopathic nephropathy. Both patients had hyperhomocysteinemia and mild methylmalonic aciduria. Fibroblasts showed decreased cobalamin uptake, reduced methyl- and adenosyl-cobalamin formation, and deficient incorporation of formate and propionate, compatible with the Cbl-C complementation group, but milder than that found in cells from most patients. Both patients and their father carry a balanced reciprocal translocation. Parenteral hydroxycobalamin treatment reduced the homocysteine levels, and methylmalonic acid disappeared. Increasing the dosage of hydroxycobalamin from 1 to 2.5, then 5 mg daily together with betaine, further reduced homocysteine levels (boy from 118 to 23 microM and girl from 59 to 14 microM). With this treatment, hemolysis has stopped, hematuria has disappeared, proteinuria has almost normalized, and creatinine clearance has been stable. Investigations for chronic thrombotic microangiopathy should include testing for this unusual but treatable disorder, regardless of age of presentation.

Topics: Age of Onset; Child; Child, Preschool; Female; Hematinics; Hematuria; Hemolysis; Hemolytic-Uremic Syndrome; Homocysteine; Humans; Hydroxocobalamin; Kidney; Male; Methylmalonic Acid; Microcirculation; Proteinuria; Thrombosis; Vitamin B 12 Deficiency

Topics: Adult; Female; Humans; Hydroxocobalamin; Psychotic Disorders; Vitamin B 12 Deficiency

We investigated the relation between cobalamin deficiency, clinical changes and brain function in dementia patients. On admittance to the clinic, 24 patients had cobalamin deficiency, and dementia with additional symptoms of delirium. During cobalamin supplementation, the patients underwent repeated regional cerebral blood flow (rCBF) studies, psychiatric evaluations, and in some cases assessment with MMSE and the Organic Brain Syndrome scale. Fifteen patients who showed mild to moderate dementia improved clinically, and also showed a concomitant increase in their general CBF after treatment. In contrast, 9 patients who were severely demented showed no obvious clinical improvement, and no general blood flow change, although some regional flow increases were seen in sensory motor areas. We conclude that symptoms which probably indicated superimposed delirium such as clouding of consciousness, disorientation and clinical fluctuation, responded to the vitamin B12 supplementation, while the underlying dementia condition remained basically unchanged. The clinical improvement was also mirrored in general and focal rCBF changes.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cerebrovascular Circulation; Dementia, Vascular; Female; Homocysteine; Humans; Hydroxocobalamin; Injections, Intramuscular; Male; Methylmalonic Acid; Regional Blood Flow; Vitamin B 12 Deficiency

Topics: Administration, Oral; Anemia, Pernicious; Cyanides; Humans; Hydroxocobalamin; Infusions, Parenteral; Injections, Intramuscular; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Administration, Oral; Anemia, Pernicious; Humans; Hydroxocobalamin; Infusions, Parenteral; Injections, Intramuscular; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Administration, Oral; Aged; Anemia, Macrocytic; Cyanides; Drug Hypersensitivity; Female; Humans; Hydroxocobalamin; Infusions, Parenteral; Injections, Intramuscular; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Aged; Anemia, Pernicious; Cognition; Dementia; Hematinics; Humans; Hydroxocobalamin; Male; Psychometrics; Treatment Outcome; Vitamin B 12 Deficiency

Topics: Developing Countries; Humans; Hydroxocobalamin; India; Injections; Vitamin B 12 Deficiency

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

In chronic atrophic gastritis atrophy of the stomach glands leads to intrinsic factor deficit, with consequent failure to absorb vitamin B12 and gastric achylia, which predisposes to Giardia infection which in itself leads to depletion of vitamin B12. We describe the case of a patient with peripheral and central nervous system pathology due to lack of vitamin B12 secondary to the combined effect of these two disorders.. A 54 year old woman consulted us for paraesthesia and weakness of the legs which had been progressive for the previous two years. She presented with tactile hypoaesthesia, hypoparaesthesia, distal hyperreflexia and dysymmetry of the legs, ataxic-spastic gait and a positive Romberg sign. The investigations carried out showed the serum vitamin B12 level to be 3 pg/ml (N: 180-900), hemoglobin 13 g/dl and MCV 111 fl with MCHC 348/dl; neurophysiological studies: compatible with demyelinating motor polyneuropathy. Schilling test: deficit of absorption of vitamin B12 which was corrected on administration of intrinsic factor; gastroscopy; atrophic gastritis which confirmed the morbid anatomy findings. There was also flora containing Helicobacter and massive Giardia infection. Replacement and antibiotic therapy was followed by complete remission of the clinical picture.. We emphasize the excellent clinical response to treatment in spite of the time elapsed since onset of symptoms.

Topics: Amoxicillin; Anemia, Pernicious; Anti-Bacterial Agents; Antiprotozoal Agents; Bismuth; Duodenitis; Enzyme Inhibitors; Evoked Potentials, Somatosensory; Female; Gastritis, Atrophic; Giardiasis; Helicobacter Infections; Helicobacter pylori; Humans; Hydroxocobalamin; Malabsorption Syndromes; Metronidazole; Middle Aged; Neural Conduction; Omeprazole; Peripheral Nervous System Diseases; Remission Induction; Vitamin B 12 Deficiency

The occurrence of vitamin B12 (B12) deficiency in chronic haemodialysis patients and the need for its supplementation in these patients are still matters of debate. We measured serial predialysis serum B12 levels, at 3- to 6-month intervals, in 67 unselected patients on our high-flux haemodialysis programme. Over a 12-month period, there was a significant fall in serum B12 from 497 +/- 200 (SD) to 391 +/- 131 ng/l (p < 0.001). 22 patients developed subnormal serum B12 levels and were commenced on hydroxocobalamin supplements. We were unable to demonstrate B12 clearance during dialysis using blood side studies. Measurement of B12 in the dialysate showed that 0-4.5 microg B12 was cleared per dialysis. Using these B12 measurements, in vivo B12 clearance was estimated at 9.1 ml/min. Dietary studies on 24 unselected patients showed borderline or low B12 intake in 4 patients. Absorption studies by whole-body counting on 6 patients using 57Co and 58Co showed normal B12 absorption. The same radioisotope studies demonstrated no B12 adsorption to the dialyser membrane. This study demonstrates that low serum B12 levels occur in high-flux haemodialysis patients and that losses during dialysis and dietary deficiency may be contributing factors.

Topics: Adsorption; Adult; Aged; Diet; Female; Humans; Hydroxocobalamin; Intestinal Absorption; Male; Middle Aged; Renal Dialysis; Vitamin B 12; Vitamin B 12 Deficiency

The clinical significance of low serum vitamin B12 levels in elderly people is controversial. We aimed to document the prevalence of a low serum vitamin B12 (< 175 pmol/l) in patients referred to a geriatric medical unit, and to determine whether haemopoiesis is commonly affected in elderly patients with low serum vitamin B12. We studied prospectively 472 consecutive referrals to a geriatric medical unit; fifty-six (13%) had a low serum vitamin B12 level, of whom nineteen (34%) of the fifty-six also had evidence of Fe deficiency (serum ferritin < 45 ng/ml). Low vitamin B12 was associated with a raised mean erythrocyte volume (MCV; mean 96.0 (SD 6.7) fl), compared with a control group (91.7 (SD 6.0) fl; P = 0.001). However, only thirteen (23%) of the fifty-six patients with a low vitamin B12 had an MCV > or = 100 fl. Mean haemoglobin (Hb) levels were not significantly reduced in those with a low vitamin B12. In a subsequent study the haematological response to intramuscular hydroxocobalamin was examined in thirty-four patients with a low serum vitamin B12. Treatment resulted in a significant fall in MCV and rise in Hb; these effects could be detected both in those patients with an initially normal full blood count (change in MCV -1.2 (SD 1.2); Hb +0.5 (SD 0.6); P < 0.01) and in those with macrocytosis and/or anaemia (-9.1 (SD 11.8); +0.8 (SD 1.2); P < 0.05). A low serum vitamin B12 is common in geriatric medical patients. This is usually associated with an upset in erythropoiesis, although the abnormalities are often subtle and may not be apparent on inspection of the full blood count. Elderly patients with serum vitamin B12 < 175 pmol/l should be assumed to have vitamin deficiency even if their full blood count is normal.

Topics: Aged; Aged, 80 and over; Erythrocyte Volume; Erythropoiesis; Female; Ferritins; Humans; Hydroxocobalamin; Injections, Intramuscular; Male; Middle Aged; Prevalence; Prospective Studies; Vitamin B 12 Deficiency

Motor and somatosensory pathway functions were studied using motor evoked potentials (MEPs), somatosensory evoked potentials (SEPs) and F-wave responses in a woman with vitamin B12 deficiency. Initial evaluation before treatment revealed: 1) prolongation of central motor conduction to both the upper and lower limbs, and prolongation of peripheral conduction to the lower limbs; 2) prolongation of central conduction time to median nerve stimulation and absence of cortical SEPs to tibial nerve stimulation; and 3) prolongation of F-wave responses to tibial and peroneal nerve stimulation. After 11 months of treatment with hydroxocobalamin, follow-up studies disclosed: 1) normalization of central motor conduction to the upper limbs, peripheral motor conduction to the lower limbs and improvement of central motor conduction to the lower limbs; 2) normalization of central conduction time to median nerve stimulation but persistent absence of cortical SEPs to tibial nerve stimulation; and 3) normalization of F-wave responses. These data suggest that both central and peripheral conductions of motor and somatosensory pathways may respond to hydroxocobalamin therapy, and that MEPs are useful in the early detection of central and peripheral motor pathway function recovery following treatment with vitamin B12 deficiency.

Topics: Adult; Evoked Potentials, Motor; Evoked Potentials, Somatosensory; Female; Humans; Hydroxocobalamin; Vitamin B 12 Deficiency

Ketone bodies were assayed in the urine of ten-week-old vitamin B12-deficient rats by a high-performance liquid chromatography. The urinary excretion of ketone bodies (352.5 +/- 68.3 mumol/day) as well as of methylmalonic acid was increased significantly by dietary vitamin B12 deficiency.

Topics: Animals; Chromatography, High Pressure Liquid; Hydroxocobalamin; Ketone Bodies; Male; Methylmalonic Acid; Rats; Rats, Wistar; Vitamin B 12 Deficiency; Weight Gain

Topics: Humans; Hydroxocobalamin; Vitamin B 12; Vitamin B 12 Deficiency

Ten cases of pernicious anaemia seen over a 15-year period (1973-1988) in a Lagos hospital are presented. Their ages ranged from 34 to 67 with a mean of 53.6 years. Females outnumbered males 6 to 4. Complications seen include gastric carcinoma, myelopathy, peripheral neuropathy, skin hyperpigmentation, hair depigmentation and diarrhoea. Reluctance to consider the diagnosis owing to firmly held notions of its rarity and a penchant for empirically treating chronic anaemias with all available haematinics and blood transfusion are probably contributory to its underdiagnosis. The fact that seven of the patients presented were seen in the last three years and three of them in the last one year raises the possibility of an increasing incidence of pernicious anaemia in Africans. The disease may be much less rare in Africans than once believed, and medical education should emphasize its existence and advocate greater care in the management of chronic anaemias.

Topics: Achlorhydria; Adult; Aged; Anemia, Pernicious; Autoantibodies; Autoimmune Diseases; Bone Marrow; Diagnosis, Differential; Fatigue; Female; Humans; Hydroxocobalamin; Incidence; Intrinsic Factor; Male; Middle Aged; Nigeria; Peripheral Nervous System Diseases; Pigmentation Disorders; Psychophysiologic Disorders; Retrospective Studies; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Amblyopia; Contraindications; Cyanides; Humans; Hydroxocobalamin; Injections, Intramuscular; Smoking; Vitamin B 12; Vitamin B 12 Deficiency

Platelet monoamine oxidase (MAO) activity has previously been shown to be increased in patients with senile dementia of Alzheimer type (SDAT) and in patients with megaloblastic anaemia. Moreover, low serum B12 levels were found to be 4-5 times more frequent in SDAT compared with an unselected population of similar age. In the present investigation, platelet MAO activity was estimated in 14 SDAT patients with relatively low serum B12 levels and in 4 patients with pernicious anaemia. Before B12 therapy, platelet MAO activity was significantly increased in both patient groups compared with a control group. After B12 therapy, platelet MAO activity was significantly reduced in both patient groups to apparently normal levels. The present results show that B12 status is a controlling factor of platelet MAO activity and confirm that a significant connection exists between vitamin B12 deficiency and primary degenerative dementia disorders, such as SDAT.

Topics: Aged; Alzheimer Disease; Anemia, Pernicious; Blood Platelets; Female; Humans; Hydroxocobalamin; Injections, Intramuscular; Male; Monoamine Oxidase; Vitamin B 12; Vitamin B 12 Deficiency

Treatment of rats with the vitamin B12 analogue hydroxy-cobalamin[c-lactam] (HCCL) impairs methylmalonyl-CoA mutase function and leads to methylmalonic aciduria due to intracellular accumulation of propionyl and methylmalonyl-CoA. Since accumulation of these acyl-CoAs disrupts normal cellular regulation, the present investigation characterized metabolism in hepatocytes and liver mitochondria from rats treated subcutaneously with HCCL or saline (control) by osmotic minipump. Consistent with decreased methylmalonyl-CoA mutase activity, 14CO2 production from 1-14C-propionate (1 mM) was decreased by 76% and 82% after 2-3 wk and 5-6 wk of HCCL treatment, respectively. In contrast, after 5-6 wk of HCCL treatment, 14CO2 production from 1-14C-pyruvate (10 mM) and 1-14C-palmitate (0.8 mM) were increased by 45% and 49%, respectively. In isolated liver mitochondria, state 3 oxidation rates were unchanged or decreased, and activities of the mitochondrial enzymes, citrate synthetase, succinate dehydrogenase, carnitine palmitoyltransferase, and glutamate dehydrogenase (expressed per milligram mitochondrial protein) were unaffected by HCCL treatment. In contrast, activities of the same enzymes were significantly increased in both liver homogenate (expressed per gram liver) and isolated hepatocytes (expressed per 10(6) cells) from HCCL-treated rats. The mitochondrial protein per gram liver, calculated on the basis of the recovery of the mitochondrial enzymes, increased by 39% in 5-6 wk HCCL-treated rats. Activities of lactate dehydrogenase, catalase, cyanide-insensitive palmitoyl-CoA oxidation, and arylsulfatase A in liver were not affected by HCCL treatment. Hepatic levels of mitochondrial mRNAs were elevated up to 10-fold in HCCL-treated animals as assessed by Northern blot analysis. Thus, HCCL treatment is associated with enhanced mitochondrial oxidative capacity and an increased mitochondrial protein content per gram liver. Increased mitochondrial oxidative capacity may be a compensatory mechanism in response to the metabolic insult induced by HCCL administration.

Topics: Animals; Blotting, Northern; Carnitine O-Palmitoyltransferase; Citrate (si)-Synthase; DNA, Mitochondrial; Glutamate Dehydrogenase; Hydroxocobalamin; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Mitochondria, Liver; Oxygen Consumption; Proteins; Rats; Rats, Inbred F344; RNA; Succinate Dehydrogenase; Vitamin B 12 Deficiency

Vitamin B-12 (cobalamin) deficiency results in decreased L-methylmalonyl-coenzyme A (CoA) mutase activity. The consequence of this defect on the cellular CoA pool was studied in rats with functional vitamin B-12 deficiency induced by administration of the cobalamin analogue hydroxy-cobalamin [c-lactam] or by dietary vitamin B-12 deficiency. Both types of vitamin B-12 deficiency were associated with methylmalonic acidemia (100-300-fold increases in plasma methylmalonic acid concentration compared with controls), but overall fuel homeostasis was intact. Liver from rats treated with hydroxy-cobalamin [c-lactam] contained a threefold greater concentration of total CoA (free CoA plus all acyl-CoA) compared with saline-treated rats. Fractionation of the CoA pool revealed higher levels of CoA, propionyl-CoA, methyl-malonyl-CoA, acid-insoluble CoA, as well as total CoA in the rats treated with hydroxy-cobalamin [c-lactam] compared with controls. Similar increases in liver CoA content were seen in dietary vitamin B-12 deficiency in both the fed and fasted states. To examine the hypothesis that sequestration of hepatic CoA as propionyl-CoA and methylmalonyl-CoA could increase CoA biosynthesis, the effect of propionate on CoA biosynthesis was studied in hepatocytes isolated from control rats. Propionate (1 mM) increased the formation of 14C-CoA from [14C]pantothenate (10 microM) by 27% in the hepatocyte system. When butyrate (1 mM) was provided as substrate, propionate (10 mM) increased [14C]CoA formation by 63%.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Glucose; Chromatography, High Pressure Liquid; Coenzyme A; Diet; Hydroxocobalamin; Hydroxybutyrates; Liver; Male; Methylmalonic Acid; Muscles; Rats; Rats, Inbred F344; Vitamin B 12 Deficiency

The administration in vivo of the cobalamin analogue hydroxycobalamin[c-lactam] inhibits hepatic L-methylmalonyl-CoA mutase activity. The current studies characterize in vivo and in vitro the hydroxycobalamin[c-lactam]-treated rat as a model of disordered propionate and methylmalonic acid metabolism. Treatment of rats with hydroxycobalamin[c-lactam] (2 micrograms/h by osmotic minipump) increased urinary methylmalonic acid excretion from 0.55 mumol/day to 390 mumol/day after 2 weeks. Hydroxycobalamin[c-lactam] treatment was associated with increased urinary propionylcarnitine excretion and increased short-chain acylcarnitine concentrations in plasma and liver. Hepatocytes isolated from cobalamin-analogue-treated rats metabolized propionate (1.0 mM) to CO2 and glucose at rates which were only 18% and 1% respectively of those observed in hepatocytes from control (saline-treated) rats. In contrast, rates of pyruvate and palmitate oxidation were higher than control in hepatocytes from the hydroxycobalamin[c-lactam]-treated rats. In hepatocytes from hydroxycobalamin[c-lactam]-treated rats, propionylcarnitine was the dominant product generated from propionate when carnitine (10 mM) was present. The addition of carnitine thus resulted in a 4-fold increase in total propionate utilization under these conditions. Hepatocytes from hydroxycobalamin[c-lactam]-treated rats were more sensitive than control hepatocytes to inhibition of palmitate oxidation by propionate. This inhibition of palmitate oxidation was partially reversed by addition of carnitine. Thus hydroxycobalamin[c-lactam] treatment in vivo rapidly causes a severe defect in propionate metabolism. The consequences of this metabolic defect in vivo and in vitro are those predicted on the basis of propionyl-CoA and methylmalonyl-CoA accumulation. The cobalamin-analogue-treated rat provides a useful model for studying metabolism under conditions of a metabolic defect causing acyl-CoA accretion.

Topics: Acyl Coenzyme A; Animals; Carnitine; Hydroxocobalamin; Lactams; Liver; Male; Malonates; Malonyl Coenzyme A; Propionates; Rats; Vitamin B 12 Deficiency

L1210 cell line cells were made deficient in Cbl by propagation in a medium devoid of CNCbl in which fetal calf serum had been replaced by bovine serum albumin. These Cbl-deficient cells gradually ceased to multiply when the medium contained 5-CH3THF, although cell growth was resumed following the addition of CNCbl, OHCbl or folic acid. The results of this study provide experimental proof for the 'methyl trap' hypothesis. In contrast to the above effect of CNCbl, cobinamide and Cbl analogues which were produced by a reaction of OHCbl with ascorbic acid did not have any growth-inducing effect on the cells which had been cultured in a 5-CH3THF-supplemented medium and had ceased to multiply. Nor did these analogues have an inhibitory effect on CNCbl-dependent growth.

Topics: Animals; Ascorbic Acid; Cell Division; Cobalt Radioisotopes; Cobamides; Culture Media; Folic Acid; Growth Inhibitors; Hydroxocobalamin; Leukemia L1210; Mice; Serum Albumin, Bovine; Vitamin B 12; Vitamin B 12 Deficiency

The use of hydroxocobalamin (OH-B12), betaine, carnitine, and folinic acid were studied in two children with the cobalamin C form of methylmalonic acidemia and homocystinuria. When daily injections of 1 mg OH-B12 were discontinued for 3 weeks, there was no significant change in total plasma homocysteine or methionine levels and only a modest increase in methylmalonate. Orally administered OH-B12 1 mg/d in one patient was associated with an increase in plasma homocystine and a decrease in methionine within 1 month. Withdrawal of betaine 250 mg/kg/d was also associated with a rise in plasma homocystine and a fall in methionine levels. Carnitine 100 mg/kg/d lead to an increase in urinary excretion of propionylcarnitine, but did not affect plasma methylmalonate levels. No beneficial biochemical effect of folinic acid could be documented at a dose of 25 mg/d. Our results suggest that daily injections of OH-B12 are not necessary to maintain metabolic control and that orally administered OH-B12 is unlikely to be effective. Betaine appears to act synergistically with OH-B12 and should be part of the treatment regimen. Although there are theoretical reasons for using L-carnitine and folinic acid, we could not document their effectiveness in these two patients.

Topics: Administration, Oral; Amino Acid Metabolism, Inborn Errors; Betaine; Carnitine; Child, Preschool; Female; Fibroblasts; Homocystinuria; Humans; Hydroxocobalamin; Infant; Injections, Intramuscular; Leucovorin; Male; Malonates; Methylmalonic Acid; Vitamin B 12; Vitamin B 12 Deficiency

Seventeen patients were treated for vitamin B12 deficiency with i.m. injection of 1 mg hydroxocobalamin every three months as maintenance therapy for eight to 20 years after an initial depot treatment of one or two series of five i.m. injections on alternate days. In three of four patients given two depot series less than or equal to 3 months apart, and with no antibody to transcobalamin II (TC II) detected previously, abnormally high values of serum cobalamins were measured at the end of injection intervals after seven to 12 years. No increase in unsaturated B12 binding capacity (UB12BC) was found in contrast to findings in patients given identical therapy, in whom an early increase above the normal level occurred associated with antibody to TC II. One depot series followed by i.m. injection of 1 mg hydroxocobalamin every third month secured values within the normal range for serum cobalamin, UB12BC and total B12 binding capacity (TB12BC).

Topics: Delayed-Action Preparations; Humans; Hydroxocobalamin; Injections, Intramuscular; Time Factors; Vitamin B 12; Vitamin B 12 Deficiency

Hydroxocobalamin and cyanocobalamin have been compared as the 'flushing dose' in the Schilling test. In healthy, haematologically normal subjects excretion of the test dose was greater following a hydroxocobalamin flushing dose than following a cyanocobalamin flushing dose, and to a lesser extent this was also true in patients requiring investigation. There were occasional discrepant results, but in general it appears that, although reference values differ, hydroxocobalamin is a suitable replacement for cyanocobalamin in the Schilling test.

Topics: Adult; Aged; Aged, 80 and over; Drug Evaluation; Fasting; Female; Humans; Hydroxocobalamin; Male; Middle Aged; Schilling Test; Vitamin B 12; Vitamin B 12 Deficiency

A 64-year-old woman developed an acute organic psychosis secondary to thyrotoxicosis and B12 deficiency, without the overt clinical features of pernicious anemia. The psychosis resolved with B12 and thyroid hormone replacement. The patient relapsed after an erroneous iatrogenic tripling of the levothyroxine dosage, but her condition normalized after dosage correction.

Topics: Acute Disease; Female; Folic Acid; Humans; Hydroxocobalamin; Hyperthyroidism; Middle Aged; Neurocognitive Disorders; Thyroxine; Vitamin B 12 Deficiency

Gross neuropathy consequent upon selective malabsorption of vitamin B12 was diagnosed in a 6 year old Bangladeshi girl brought to Great Britain for further investigation of an unexplained illness of three years' duration. The initial peripheral blood count was normal. Treatment with vitamin B12 has led to substantial recovery.

Topics: Child; Female; Humans; Hydroxocobalamin; Malabsorption Syndromes; Nervous System Diseases; Vitamin B 12 Deficiency

The activities of 5-methyltetrahydrofolate (5-CH3THF) related enzymes and DNA polymerase alpha were determined in bone marrow cells obtained from patients with vitamin B12 deficient megaloblastic anemia and compared with those from healthy volunteers and patients with hemolytic anemia. 5-CH3THF homocysteine methyltransferase activity was significantly lower than that in the control subjects. 5,10-methylenetetrahydrofolate reductase activity was only slightly elevated to that in the control subjects. DNA polymerase alpha activity was significantly higher than that in the control. High deoxyuridine suppression test values in vitamin B12 deficient bone marrow cells were improved by tetrahydrofolate, but not by 5-CH3THF. These data indicate that, even though the reverse reaction catalyzed by 5,10-methylenetetrahydrofolate reductase may be operative in vitamin B12 deficiency, it is not sufficient to correct the disturbance in folate metabolism in vitamin B12 deficiency. Increased DNA polymerase alpha activity may be due to compensation for disarranged DNA synthesis.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; 5,10-Methylenetetrahydrofolate Reductase (FADH2); Adult; Aged; Alcohol Oxidoreductases; Anemia, Macrocytic; Anemia, Megaloblastic; Bone Marrow; Bone Marrow Cells; Deoxyuridine; DNA Polymerase II; DNA-Directed DNA Polymerase; Female; Folic Acid; Humans; Hydroxocobalamin; Leucovorin; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Tetrahydrofolates; Thymidine; Vitamin B 12; Vitamin B 12 Deficiency

A case of hereditary transcobalamin II deficiency with neurological involvement is described. The patient presented in early infancy with megaloblastic anaemia and was treated with folinic acid from 6 weeks of age. The diagnosis of transcobalamin II deficiency was not made until he was 2 years old when he showed severely retarded intellectual development, ataxia and pyramidal deficit in the limbs. Following treatment with hydroxocobalamin, his condition has slowly improved but he has remained with a severe neurological deficit. The consequences of vitamin B12 deficiency on neurological development in infancy are discussed.

Topics: Age Factors; Anemia, Macrocytic; Anemia, Megaloblastic; Blood Proteins; Child; Genes, Recessive; Humans; Hydroxocobalamin; Intellectual Disability; Male; Nervous System Diseases; Transcobalamins; Vitamin B 12 Deficiency

Thin-layer chromatography and bioautography were used to study the cobalamin pattern of plasma, erythrocytes, and hepatic tissue from patients with cobalamin deficiency on maintenance therapy with hydroxocobalamin (Vibeden), a cyanocobalamin depot preparation (Betolvex), or cyanocobalamin tablets (Behepan). The cobalamin pattern in plasma is dominated by the form in which it is administered. The results of assaying the erythrocytes and liver biopsies show that the cobalamins administered are converted to the coenzyme forms in vivo, irrespective of the type of cobalamin preparation.

Topics: Administration, Oral; Cobamides; Erythrocytes; Humans; Hydroxocobalamin; Injections; Liver; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Aged; Aminosalicylic Acid; Anemia, Macrocytic; Anemia, Megaloblastic; Anticonvulsants; Antineoplastic Agents; Colchicine; Humans; Hydroxocobalamin; Intestinal Absorption; Neomycin; Stomach Neoplasms; Vitamin B 12; Vitamin B 12 Deficiency

In response to specific treatment of vitamin B12 deficient, anaemic patients there is an influx of folate into the young, circulating red cells. To separate new and old cells, capillary tubes filled with whole blood were centrifuged and the packed red cell column divided into top (T), middle (M) and bottom (B) layer. The newest cells are found in the T layer. The increase in red cell folate (RCF) concentration starts before, during or after the reticulocyte response, and is therefore not directly related to folate metabolism in the red precursor cells in the marrow. The low RCF concentration at the peak of the reticulocyte response in some of the cases demonstrates that the folate material, which may have been accumulated in the red precursor cells in the marrow, may be lost by the time the red cells enter the peripheral blood. The influx of folate into the young, circulating red cells is rapidly followed by an efflux of folate, suggesting that much of the folate material is still in the monoglutamate form. A new influx of folate is noted after a time lapse of from 5 to 10 d. Iron deficiency seems to prevent the uptake of folate by the circulating red cells.

Topics: Aged; Anemia, Pernicious; Erythrocytes; Female; Folic Acid; Humans; Hydroxocobalamin; L-Lactate Dehydrogenase; Male; Middle Aged; Primary Myelofibrosis; Pteroylpolyglutamic Acids; Vitamin B 12; Vitamin B 12 Deficiency

In 28 patients suffering from subacute combined degeneration of the spinal cord, vitamin B12 metabolism was investigated. Two postulates, proving vitamin B12 deficiency and excluding another cause for the clinical symptoms, have to be fulfilled. Two patients had no disturbance in their vitamin B12 metabolism. Seven patients had a distinct vitamin B12 deficiency. In the remaining 19 patients we found a mild vitamin B12 deficiency. Of these patients, 5 had had a subtotal gastrectomy, one had had a low absorption of vitamin B12, and 13 patients we could not find a distinct cause for the vitamin B12 deficiency. It is not impossible that nutritional habits can be hold responsible for this deficiency. The question whether these 13 patients should be treated with vitamin B12 for the rest of their lives is difficult to answer. It is a conditio sine qua non that in the patients with S.C.D. the vitamin B12 metabolism is examined circumstantially. By so doing, it may be possible to detect, in cases with minor clinical signs and symptoms of S.C.D., the cause of their illness.

Topics: Adult; Aged; Diagnosis, Differential; Female; Folic Acid; Folic Acid Deficiency; Follow-Up Studies; Humans; Hydroxocobalamin; Intestinal Absorption; Male; Middle Aged; Nerve Degeneration; Recurrence; Spinal Cord; Spinal Cord Diseases; Vitamin B 12; Vitamin B 12 Deficiency

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

The concentrations of vitamin B12 in the sera from 77 patients diagnosed as suffering from the toxic optic neuropathy associated with tobacco smoking were compared with control levels and with serum folic acid concentrations from the same patients. Of these, 17 patients had associated pernicious anaemia. Serum vitamin B12 levels were significantly lower, whereas the folic acid concentrations showed great variation. Folic acid levels in the serum tended to be high when the vitamin B12 level was low (r = 0.29). The results suggest that the role of folic acid in the genesis of the optic neuropathy is not marked. However persistently low levels of folic acid occurred in one subject and significant clinical improvement resulted only from specific therapy.

Topics: Adult; Aged; Anemia, Pernicious; Female; Folic Acid; Folic Acid Deficiency; Humans; Hydroxocobalamin; Male; Middle Aged; Optic Nerve Diseases; Smoking; Visual Acuity; Vitamin B 12; Vitamin B 12 Deficiency

A 17-year-old boy with vitamin B12 deficiency that occurred after a small bowel resection developed bilateral centrocecal scotomas during folic acid therapy and improved on therapy including vitamin B complex.

Topics: Adolescent; Folic Acid; Gangrene; Humans; Hydroxocobalamin; Infectious Mononucleosis; Intestine, Small; Malabsorption Syndromes; Male; Optic Nerve Diseases; Postoperative Complications; Scotoma; Vitamin B 12; Vitamin B 12 Deficiency

Five patients presenting clinically with a form B12-deficiency neuromyelopathy, with cord involvement in all and proximal muscle weakness in two of them, were investigated for their neurologic, hematologic and vitamin status. Megaloblastosis and achlorhydria were present in all, and impaired absorption of 57Co vitamin B12 and of D-xylose was detected in four. Total cyanide extracted vitamin B12 (A) was lowered in all cases and noncyanide extractable (B) in four of the five, being zero in three. All five responded to injections of hydroxocobalamin. In two patients sequential estimations showed that both A and B, especially the latter, rose steeply initially, normalizing at 50% of A after some weeks. Moiety B is suggested to be physiologically the more active and dissociable form of vitamin B12. Markedly elevated initial serum folate levels, and their subsequent fall under treatment with B12, indicated the operation of the "methyltetrahydrofolate trap". Blood levels of thiamin, nicotinic acid and pantothenic acid were within normal limits. However, serum riboflavin (B2) total vitamin B6 and pyridoxal were reduced in all where tested. Vitamin B6 deficiency could have resulted from its own malabsorption and have contributed to be B12 deficiency. Vitamin B2 and B6 levels also corrected themselves on B12 therapy. The B-vitamin deficiencies in our patients probably resulted from intestinal malabsorption, with a possible factor of malnutrition consequent to their strictly vegetarian diet.

Topics: Achlorhydria; Adolescent; Adult; Animals; Demyelinating Diseases; Diet, Vegetarian; Erythrocyte Count; Humans; Hydroxocobalamin; Malabsorption Syndromes; Male; Megaloblasts; Milk; Spinal Cord Diseases; Vitamin B 12 Deficiency; Vitamin B 6 Deficiency; Vitamin B Complex

Topics: Adolescent; Adult; Anemia, Macrocytic; Anemia, Pernicious; Carbonic Anhydrases; Electrophoresis; Erythrocytes; Female; Folic Acid Deficiency; Humans; Hydroxocobalamin; Isoenzymes; Male; Middle Aged; Spectrophotometry; Time Factors; Vitamin B 12 Deficiency

Topics: Anemia, Macrocytic; Anemia, Pernicious; Blood Cell Count; Diet, Vegetarian; Drug-Related Side Effects and Adverse Reactions; Folic Acid; Folic Acid Deficiency; Humans; Hydroxocobalamin; Intestinal Diseases; Potassium; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Administration, Oral; Anemia, Pernicious; Delayed-Action Preparations; Erythrocytes; Hemoglobins; Humans; Hydroxocobalamin; Injections, Intramuscular; Injections, Intravenous; Intrinsic Factor; Postgastrectomy Syndromes; Schilling Test; Time Factors; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Animals; Hydroxocobalamin; Malonates; Sheep; Sheep Diseases; Vitamin B 12 Deficiency

Topics: Aged; Anemia; Anemia, Aplastic; Anemia, Hemolytic; Anemia, Hypochromic; Blood Transfusion; Diet; Female; Folic Acid; Folic Acid Deficiency; Humans; Hydroxocobalamin; Iron; Male; Middle Aged; Vitamin B 12 Deficiency

Topics: Alcohol Oxidoreductases; Animals; Chromatography, Ion Exchange; Deoxyadenosines; Hepatectomy; Hydroxocobalamin; Liver; Liver Regeneration; Rats; Ribonucleotides; Spectrophotometry; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adolescent; Adult; Aged; Anemia, Pernicious; Autoradiography; Chromatography, Thin Layer; Diet, Vegetarian; Female; Folic Acid Deficiency; Humans; Hydroxocobalamin; Intestinal Diseases; Leukemia; Liver; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Postgastrectomy Syndromes; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Amblyopia; Cyanides; Humans; Hydroxocobalamin; Nicotiana; Plants, Toxic; Smoking; Vitamin B 12; Vitamin B 12 Deficiency

1. Kidney-cortex slices and the perfused livers of vitamin B(12)-deficient rats removed propionate from the incubation and perfusion media at 33 and 17% respectively of the rates found with tissues from rats receiving either a normal or a vitamin B(12)-supplemented diet. There was a corresponding fall in the rates of glucose synthesis from propionate in both tissues. 2. The addition of hydroxocobalamin or dimethylbenzimidazolylcobamide coenzyme to kidney-cortex slices from vitamin B(12)-deficient rats in vitro failed to restore the normal capacity for propionate metabolism. 3. Although the vitamin B(12)-deficient rat excretes measurable amounts of methylmalonate, no methylmalonate production could be detected (probably because of the low sensitivity of the method) when kidney-cortex slices or livers from deficient rats were incubated or perfused with propionate. 4. The addition of methylmalonate (5mm) to kidney-cortex slices from rats fed on a normal diet inhibited gluconeogenesis from propionate by 25%. 5. Methylmalonate formation is normally only a small fraction of the flux through methylmalonyl-CoA. This fraction increases in vitamin B(12)-deficient tissues (as shown by the urinary excretion of methylmalonate) presumably because the concentration of methylmalonyl-CoA rises as a result of low activity of methylmalonyl-CoA mutase (EC 5.4.99.2). Slow removal of methylmalonyl-CoA might depress propionate uptake owing to the reversibility of the steps leading to methylmalonyl-CoA formation.

Topics: Animals; Coenzyme A; Coenzymes; Depression, Chemical; Gluconeogenesis; Hydroxocobalamin; Isomerases; Kidney; Liver; Malonates; Perfusion; Propionates; Rats; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia, Pernicious; Diagnosis, Differential; Female; Gastrointestinal Diseases; Glossitis; Humans; Hydroxocobalamin; Middle Aged; Time Factors; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Antibodies; Humans; Hydroxocobalamin; Protein Binding; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adult; Aged; Diabetes Complications; Diabetic Neuropathies; Electromyography; Female; Glucose Tolerance Test; Humans; Hydroxocobalamin; Male; Middle Aged; Neural Conduction; Neurologic Examination; Optic Atrophy; Vision Disorders; Vitamin B 12 Deficiency

Topics: Anemia, Pernicious; History, 20th Century; Humans; Hydroxocobalamin; Spinal Cord Diseases; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia, Pernicious; Erythrocyte Count; Humans; Hydroxocobalamin; Intrinsic Factor; Liver Extracts; Reticulocytes; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Humans; Hydroxocobalamin; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adult; Blood; Humans; Hydroxocobalamin; Injections, Intramuscular; Injections, Intravenous; Male; Middle Aged; Urine; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia; Anemia, Macrocytic; Cobalt Isotopes; Drug Therapy; Fluids and Secretions; Humans; Hydroxocobalamin; Metabolism; Urine; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Aged; Female; Humans; Hydroxocobalamin; Male; Middle Aged; Vitamin B 12 Deficiency

Topics: Anemia; Anemia, Pernicious; Blood Chemical Analysis; Creatine; Creatinine; Humans; Hydroxocobalamin; Injections; Injections, Intramuscular; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

Topics: Female; Humans; Hydroxocobalamin; Male; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia; Anemia, Pernicious; Diagnosis; Gastroenterology; Humans; Hydroxocobalamin; Kidney Diseases; Schilling Test; Vitamin B 12 Deficiency