Abstract
Disorders of cobalamin and folate intracellular metabolism that result in defective
remethylation of homocysteine to methionine are associated with leukodystrophy, whereas
disorders of cobalamin transport generally are not. Cobalamin derivatives are needed
for only two reactions in man; remethylation of homocysteine to methionine, with methylcobalamin
as a cofactor for methionine synthase, and the conversion of methylmalonyl-coenzyme
A to succinyl coenzyme A by methylmalonyl-CoA mutase, with adenosylcobalamin as a
cofactor. Mutations at various metabolic steps affect the synthesis of adenosylcobalamin
(CblA, CblB, and CblD2), methylcobalamin (CblE, CblG, and CblD1), or both of these
(CblF, CblD, and CblC). The most common disorder of folate metabolism, 5,10-methylenetetrahydrofolate
deficiency, also affects remethylation and presents with leukodystrophy. Pathways
of cobalamin and folate metabolism intersect at one site, methionine synthase. Patients
with the remethylating disorders present acutely or chronically with significant neurologic,
hematologic, vascular, and other symptoms. Circulating levels of cobalamin and folate
are usually normal in these disorders, and initial diagnosis is aided by measurement
of homocysteine and methylmalonic acid in blood or urine, together with hematologic
tests. Current diagnosis is often by newborn screening. These disorders all show autosomal
recessive inheritance, and all are treatable, although with variable outcome.
Keywords
cobalamin - folic acid - leukoencephalopathy - CblC - homocysteine
