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Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease).

Abstract：

:This first detailed report of a female patient with functional methionine synthase deficiency due to the cblE defect describes treatment with several vitamins and cofactors and clinical progress for 17 years. Before treatment, major findings were microcephaly, psychomotor retardation, episodic reduced consciousness, megaloblastic anaemia, increased plasma free homocystine (> 20 mumol/L), low plasma methionine (< 10 mumol/L) and increased excretion of formiminoglutamate. On high-dose folic acid, biochemical abnormalities such as formiminoglutamate excretion and homocystinuria nearly normalized, but clinical and haematological abnormalities remained. On replacement of folate with methylcobalamin, alertness, motor function, speech and the electroencephalogram improved, biochemical features were similar, but the mean corpuscular volume increased. The best control was observed on a combination of folate and methylcobalamin. At 17 years of age she remains severely mentally retarded. In cultured fibroblasts methionine synthesis was reduced (0.03 nmol/mg/per 16 h, controls 2.4-6.9); methionine synthase activity was normal under high reducing conditions but decreased on limiting the reducing agent, dithiothreitol, to 5 mmol/L (18% of total, controls 51-81%); formation of methylcobalamin was low (4.5% of total cobalamins, control 57.5%) and complementation studies indicated the cblE defect. Methionine formation showed only minor increases in cells grown in folate- or cobalamin-supplemented medium. Serine synthesis, which was low in normal medium, increased with cobalamin supplementation. These studies suggest further heterogeneity within cblE mutants, show the difficulty of establishing the enzyme defect in vitro, and indicate a role for folate in addition to cobalamin in treatment.

journal_name

J Inherit Metab Dis

journal_title

Journal of inherited metabolic disease

authors

Fowler B,Schutgens RB,Rosenblatt DS,Smit GP,Lindemans J

doi

10.1023/a:1005372730310

subject

Has Abstract

pub_date

1997-11-01 00:00:00

pages

731-41

issue

eissn

0141-8955

issn

1573-2665

journal_volume

pub_type

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Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease).