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.