hydroxocobalamin and Hemolytic-Uremic-Syndrome

Topics: Age of Onset; Child; Hematinics; Hemolytic-Uremic Syndrome; Humans; Hydroxocobalamin; Kidney Function Tests; Kidney Transplantation; Thrombotic Microangiopathies

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

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

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