Indistinguishable hematologic abnormalities are seen in most patients with cobalamin (Cbl, vitamin B12) or folate deficiency. Approximately one third of Cbl-deficient patients develop a wide variety of non-focal neuropsychiatric abnormalities that are not seen in folate deficiency. Serum levels of homocysteine are elevated to a similar degree in Cbl-deficient patients with and without neuropsychiatric abnormalities, and in folate-deficient patients. Serum levels of eight other metabolites including methylmalonic acid also fail to elucidate the biochemical basis for the neuropsychiatric abnormalities. Levels of homocysteine and methylmalonic acid are often only slightly elevated in Cbl-deficient patients who have significant neuropsychiatric defects. Moderate elevations of homocysteine and methylmalonic acid occur in 20%-30% of various elderly populations (mean age 80) and may play a role in the similar neuropsychiatric abnormalities that occur increasingly with aging. Taken together, these studies suggest that an important unknown Cbl-dependent enzyme, metabolic abnormality, environmental factor, or genetic factor may play a major role in the pathophysiology of the neuropsychiatric abnormalities caused by Cbl deficiency.