levoleucovorin and Homocystinuria

Topics: Aged; Betaine; Female; Homocysteine; Homocystinuria; Humans; Hyperhomocysteinemia; Leucovorin; Methylenetetrahydrofolate Reductase (NADPH2); Muscle Spasticity; Psychotic Disorders; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

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

Topics: Betaine; Biopsy; Child; Drug Therapy, Combination; Homocystinuria; Humans; Injections; Leucovorin; Male; Medication Adherence; Skin; Skin Diseases; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency; Vitamins; Wound Healing

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

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

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

Topics: 5,10-Methylenetetrahydrofolate Reductase (FADH2); Alcohol Oxidoreductases; Amino Acids; Drug Therapy, Combination; Female; Folic Acid; Homocystinuria; Humans; Infant; Leucovorin; Methionine; Methylenetetrahydrofolate Reductase (NADPH2); Pyridoxine; Skin; Tetrahydrofolates; Vitamin B 12