Vitamin B12-responsive neonatal megaloblastic anemia and homocystinuria with associated reduced methionine synthase activity

Abstract

We present findings on an infant with neonatal megaloblastic anemia, homocystinuria, and neurologic dysfunction that included developmental delay and tonic seizures. There was no methylmalonic aciduria. Cyanocobalamin therapy was accompanied by complete hematologic and neurologic recovery, diminished homocystine excretion, and subsequently normal neurologic development. Cultured fibroblasts and lymphoblasts showed a reduced methionine synthase activity and a growth requirement for methionine. Cobalamin incorporation by the patient's lymphoblasts was normal, but the proportion of cellular methylcobalamin in the patient's lymphoblasts and fibroblasts were markedly reduced and that of adenosylcobalamin normal. The reduced methionine synthase activity was independent of assay reducing (thiol) conditions, but normal levels of activity accompanied culture of the patient's lymphoblasts in medium with markedly increased cobalamin concentration. The characteristics of the reduced methionine synthase of our patient differ significantly from that of the previously described infant with cobalamin E disease and suggest that genetic heterogeneity may characterize this mutation.

Genetic disorders of vitamin B12metabolism: eight complementation groups – eight genes

“…This suggested that the infant had a unique block in MS or the synthesis of MeCbl. Subsequently, two other patients were described with the same symptoms (Refs 99 , 100 ). Broken cell extracts from the original patient revealed that with added reducing agents, MS worked perfectly.…”

Delayed diagnosis of cobalamin E defect in an adolescent patient

“…Cobalamin treatment is usually given for anemia and biochemical abnormalities in patients, and cyanocobalamin is used for neurological and hematological improvement but hydroxycobalamin has been more effective than cyanocobalamin. [ 4 5 ] Hydroxycobalamin is beneficial for neurologic development. [ 4 ] However, the impact of treatment is less in biochemical parameters and generally hyperhomocysteinemia persists.…”

“…[ 3 ] Cobalamin treatment is usually given for anemia and biochemical abnormalities in patient, and cyanocobalamin is used for neurological and hematological improvement, but hydroxycobalamin has been more effective than cyanocobalamin. [ 4 5 ] Betaine is a potent methyl group donor, which has a role in remethylation of homocysteine to methionine using betaine–homocysteine methyltransferase that bypass methylcobalamin-dependent pathway. [ 6 ]…”

Hyperhomocysteinemia and Thrombosis

“…Because methyl-B 12 is a cosubstrate in the methionine synthase reaction, these mutations appear as functional methionine synthase deficiencies. 89,[114][115][116][117][118] No discrete mutations of methionine synthase associated with hyperhomocysteinemia have been described.…”