vitamin-b-12 and Hemolytic-Uremic-Syndrome

Haemolytic uremic syndrome and thrombotic thrombocytopenic purpura are overlapping clinical entities based on historical classification. Recent developments in the unfolding of the pathomechanisms of these diseases resulted in the creation of a molecular etiology-based classification. Understanding of some causative relationships yielded detailed diagnostic approaches, novel therapeutic options and thorough prognostic assortment of the patients. Although haemolytic uremic syndrome and thrombotic thrombocytopenic purpura are rare diseases with poor prognosis, the precise molecular etiology-based diagnosis might properly direct the therapy of the affected patients. The current review focuses on the theoretical background and detailed description of the available diagnostic possibilities, and some practical information necessary for the interpretation of their results.

Topics: ADAM Proteins; ADAMTS13 Protein; Analgesics, Non-Narcotic; Antimalarials; Complement System Proteins; Diagnosis, Differential; Hemolytic-Uremic Syndrome; Humans; Neuraminidase; Prognosis; Purpura, Thrombotic Thrombocytopenic; Quinine; Shiga Toxins; Streptococcus pneumoniae; Vitamin B 12; von Willebrand Factor

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

Topics: Fatal Outcome; Female; Hemolytic-Uremic Syndrome; Homocystinuria; Humans; Infant, Newborn; Methylmalonic Acid; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adult; Hemolytic-Uremic Syndrome; Humans; Male; Metabolic Diseases; Vitamin B 12

Over the last forty years, our laboratory has accumulated a collection of over 1000 cultured fibroblast lines derived from patients from around the world referred with signs of inborn errors of cobalamin or folate metabolism, including several hundred with complementation-confirmed diagnoses. By accurately classifying patient disorders into classes representing blocks affecting specific reactions, we have provide the basis for rational assessment of phenotypic heterogeneity, and development of methods for diagnosis, treatment and prognosis. These resources have been valuable in identification of causal genes for known inborn errors. Since 2000, we and our collaborators identified the genes for the cblA (MMAA), cblB (MMAB), cblC (MMACHC), cblD (MMADHC), and cblF (LMBRD1) disorders.. Whole exome sequencing of DNA from a patient with severe combined immunodeficiency (SCID), megaloblastic anemia and hemolytic uremic syndrome identified mutations in the MTHFD1 gene, which encodes a trifunctional enzyme involved in interconversion of folate coenzyme derivatives. This disorder demonstrates the importance de novo pyrimidine synthesis in the etiology of SCID. Mutations in the ABCD4 gene have been identified in four patients with accumulation of unbound cobalamin in lysosomes; this gene encodes a lysosomal membrane protein that plays a role in the transport of cobalamin across this membrane. Mutations in the HCFC1 gene on the X chromosome have been identified in several male patients that had received a diagnosis of cblC on the basis of complementation studies in cultured fibroblasts. HCFC1 encodes a transcription factor that regulates expression of a number of genes, including MMACHC, the gene that is mutated in patients with the cblC disorder. These studies demonstrate that with the advent of affordable whole exome sequencing, it has been possible to identify genes for novel inborn errors of cobalamin metabolism, often working from a small number of affected patients.

Topics: Anemia, Megaloblastic; ATP-Binding Cassette Transporters; Exome; Female; Folic Acid; Hemolytic-Uremic Syndrome; Host Cell Factor C1; Humans; Male; Methylenetetrahydrofolate Dehydrogenase (NADP); Minor Histocompatibility Antigens; Proto-Oncogene Proteins c-cbl; Severe Combined Immunodeficiency; Vitamin B 12

Atypical hemolytic uremic syndrome (aHUS) is mostly linked to defects in the regulation of alternative complement pathway, but a rare form is caused by an inherited defect of cobalamin 1 metabolism. Cobalamin C (cblC) deficiency is an autosomal recessive disorder of vitamin B12 metabolism that results from mutations in methylmalonic aciduria and homocysteinuria (MMACHC). The most severe form of cblC deficiency and the associated high mortality rate are mostly observed in neonates or in infants <6 months of age. Early diagnosis of cblC deficiency leads to early treatment and an improved prognosis. We describe the case of a 6-year-old girl with cblC disorder, who presented with severe multiorgan involvement at the age of 5 months and who was successfully treated with vitamin B12, betaine, coenzyme Q10 and l-carnitene, and who had a new homozygous mutation of MMACHC.

Topics: Carrier Proteins; DNA; DNA Mutational Analysis; Female; Hemolytic-Uremic Syndrome; Homozygote; Humans; Infant; Mutation; Oxidoreductases; Vitamin B 12

The present study was undertaken to investigate the clinical characteristics of hemolytic uremic syndrome (HUS) secondary to cobalamin C disorder (cbl-C disorder).. We reviewed retrospectively the medical records of 3 children with HUS secondary to cbl-C disorder who had been treated between April 1, 2009 and October 31, 2013.. The 3 patients with HUS secondary to cbl-C disorder presented with progressive hemolytic anemia, acute renal failure, thrombocytopenia, poor feeding, and failure to thrive. Two of the 3 patients once had high blood pressure. The mutations of c.609G>A (p.W203X), c.217C>T (p.R73X) and c.365A>T (p.H122L) in the methylmalonic aciduria (cobalamin deficiency) cbl-C type, with homocystinuria gene were detected in the 3 patients. In these patients the levels of lactate dehydrogenase and homocysteine in serum were elevated and the level of methylmalonic acid (MMA) in urine was also elevated. After treatment with hydroxocobalamin, 2 patients were discharged with no obvious abnormal growth and neurological development and 1 patient died of multiple organ failure.. The results of this study demonstrated that cbl-C disorder should be investigated in any child presenting with HUS. The high concentrations of homocysteine and MMA could be used for timely recognization of the disease. Once the high levels of plasma homocystein and/or plasma or urine MMA are detected, the treatment with parenteral hydroxocobalamin should be prescribed immediately. The early diagnosis and treatment would contribute to the good prognosis of the disease.

Topics: Carrier Proteins; Child, Preschool; China; Female; Follow-Up Studies; Genetic Predisposition to Disease; Hemolytic-Uremic Syndrome; Homocysteine; Humans; Infant; Male; Mutation; Oxidoreductases; Rare Diseases; Retrospective Studies; Risk Assessment; Sampling Studies; Severity of Illness Index; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency

Pernicious anaemia is an autoimmune disease caused by intrinsic factor antibody; it leads to vitamin B12 deficiency and is marked by ineffective erythropoiesis. Haematological features reveal macrocytosis, hyperchromasia and hypersegmented neutrophils. Schistocytes are typically seen in microangiopathy, such as in thrombotic thrombocytopaenic purpura (TTP)/haemolytic uraemic syndrome or disseminated intravascular haemolysis (DIC). We report a case of a patient with severe anaemia who presented to the emergency room. Peripheral smear revealed macrocytosis, hypersegmented neutrophils and marked schistocytosis. The patient also had high reticulocyte count with high serum lactate dehydrogenase, elevated D-dimer, low fibrinogen and low haptoglobin. Vitamin B12 level came back low and the presence of intrinsic factor antibody confirmed pernicious anaemia. ADAMTS13 level was noted to be mildly reduced, which raised the suspicion of the association of acquired TTP with pernicious anaemia. Acquired TTP is another autoimmune disorder and its association with pernicious anaemia needs further evaluation.

Topics: ADAM Proteins; ADAMTS13 Protein; Aged; Anemia, Macrocytic; Anemia, Pernicious; Autoantibodies; Autoimmune Diseases; Erythrocyte Count; Erythrocytes, Abnormal; Erythropoiesis; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Haptoglobins; Hemolytic-Uremic Syndrome; Humans; Intrinsic Factor; L-Lactate Dehydrogenase; Neutrophils; Purpura, Thrombotic Thrombocytopenic; Vitamin B 12

Topics: Diacylglycerol Kinase; Hemolytic-Uremic Syndrome; Humans; Pneumococcal Infections; Signal Transduction; Vitamin B 12

Diarrhea-positive hemolytic uremic syndrome (HUS) is a common cause of acute renal failure in children. Diarrhea-negative (D-), or atypical HUS, is etiologically distinct. A Medline search identified seven previously reported D- cases of HUS secondary to cobalamin C (cblC) disease presenting in infancy. An infantile presentation is reported to be associated with a high mortality rate (6/7 cases). We describe the results of a 5-year longitudinal follow-up in a child diagnosed with D- HUS secondary to cblC disease in infancy. Mutation analysis in this patient identified homozygosity for the 271 dupA mutation (c.271 dupA) in the cblC MMACHC gene. We briefly review the published experience in cblC-associated HUS to highlight the clinical characteristics of this uncommon, but potentially treatable, condition.

Topics: Acute Kidney Injury; Betaine; Brain Diseases, Metabolic, Inborn; Carnitine; Carrier Proteins; Combined Modality Therapy; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Hemolytic-Uremic Syndrome; Homocystinuria; Homozygote; Humans; Hydroxocobalamin; Infant, Newborn; Longitudinal Studies; Methylmalonic Acid; Mutation; Oxidoreductases; Proto-Oncogene Proteins c-cbl; Treatment Outcome; Vitamin B 12

cblC disease is a cause of hemolytic uremic syndrome (HUS), which has been primarily described in neonates and infants with severe renal and neurological lesions.. Two sisters aged 6 and 8.5 years presented with a latent hemolytic process characterized by undetectable or low plasma haptoglobin, respectively, associated with renal failure and gross proteinuria. Renal biopsies performed in both patients found typical findings of thrombotic microangiopathy suggesting the diagnosis of HUS. Both patients were free of neurologic signs.. Biochemical investigations found a cobalamin processing deficiency of the cblC type. Search for additional factors susceptible to worsen endothelial damage revealed homozygosity 677C--> T mutation in the methylenetetrahydrofolate reductase gene as well as heterozygosity for a 3254T--> C mutation in factor H in the patient with the most severe clinical presentation. Long-term subcutaneous administration of hydroxocobalamin in combination with oral betaine and folic acid resulted in clinical and biological improvement in both patients.. cblC disease may be a cause of chronic HUS with delayed onset in childhood. Superimposed mutation of factor H gene might influence clinical severity.

Topics: Anemia; Betaine; Child; Combined Modality Therapy; Complement Factor H; Drug Therapy, Combination; Endothelium, Vascular; Female; Folic Acid; Genetic Predisposition to Disease; Genotype; Haptoglobins; Hemolytic-Uremic Syndrome; Humans; Hydroxocobalamin; Hypertension; Kidney; Methylenetetrahydrofolate Reductase (NADPH2); Mutation, Missense; Nephrotic Syndrome; Plasma Exchange; Point Mutation; Proteinuria; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-cbl; Renal Dialysis; Vitamin B 12

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

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

Anew case of cobalamin C disease associated with hemolytic-uremic syndrome (HUS) in the neonatal period is described. A 28-day-old boy presented with failure to thrive, hypotonia, pancytopenia, and features of HUS (microangiopathic hemolytic anemia, thrombocytopenia, and renal failure). The possibility of the diagnosis of an underlying vitamin B12 disorder was prompted by evidence of megaloblastic changes on the peripheral smear and by finding in the literature a suggested association of neonatal HUS with this cobalamin-related metabolic disorder. Amino acid analysis showed elevated homocysteine levels in the plasma and increased levels of both homocysteine and methyl malonic acid in the urine. Diagnosis of cobalamin C disease was confirmed by complementation studies using skin fibroblasts. Therapy included parenteral hydroxocobalamin, carnitine, and leucovorin calcium (folinic acid). Cobalamin C disease should be considered in the diagnosis of patients presenting with HUS in infancy who have unexplained megaloblastosis, pancytopenia, neurologic impairment, and failure to thrive. Early diagnosis and institution of therapy may be effective in improving survival and quality of life.

Topics: Diagnosis, Differential; Hemolytic-Uremic Syndrome; Humans; Infant, Newborn; Kidney; Male; Vitamin B 12; Vitamin B 12 Deficiency

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

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

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

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