hydroxocobalamin and Thrombotic-Microangiopathies

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

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

Inborn errors of cobalamin (Cbl) metabolism form a large group of rare diseases. One of these, Cbl deficiency type C (CblC), is a well-known cause of thrombotic microangiopathy (TMA), especially in infants. However, there has only been a single published case of TMA associated to Cbl deficiency type G (CblG), also known as methionine synthase deficiency (MSD).. A 21-month-old boy presented with pallor and oral ulcers during episodes of upper respiratory infection (URI). Further examination revealed signs of TMA, and the patient progressed to acute renal failure (ARF). Renal biopsy showed TMA. Evaluation for infection and autoantibodies were negative. The C3 and C4 complement fractions were normal. Analysis of the bone marrow aspirate suggested megaloblastic anemia and signs of hematopoiesis activation (secondary to peripheral hemolysis). Although the serum vitamin B12 level was normal, the patient was treated with cyanocobalamin, with no improvement. The ARF and hematologic parameters improved with conservative treatment. A severe relapse occurred during the follow-up, with normal ADAMTS13 activity. The presumed diagnosis was atypical hemolytic uremic syndrome, and the patient was started on eculizumab, but his response was poor, even when the dosage was increased. At this point it was also recognized that his developmental speech was delayed. Based on these findings, whole exome sequencing was performed, leading to the detection of two novel deleterious variants in the gene coding for methionine synthase, confirming the diagnosis of MSD. Subsequent treatment consisted of elevating the patient's serum homocysteine level and starting him on hydroxicobalamin, with normalization of all hematologic parameters although the microalbuminuria remained.. Methionine synthase deficiency is very rare and characterized by megaloblastic anemia and neurological symptoms. We report the second case of MSD associated to TMA previously diagnosed as aHUS in which the patient had a poor response to eculizumab.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Acute Kidney Injury; ADAMTS13 Protein; Anemia, Megaloblastic; Antibodies, Monoclonal, Humanized; Atypical Hemolytic Uremic Syndrome; Biopsy; Bone Marrow; Exome Sequencing; Humans; Hydroxocobalamin; Hyperhomocysteinemia; Infant; Kidney; Language Development Disorders; Male; Metabolism, Inborn Errors; Recurrence; Thrombotic Microangiopathies; Vitamin B 12; Vitamin B Complex

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

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