Jeffrey M. Sequeira, M.S., Thomas Opladen, M.D., Nenad Blau, Ph.D.,
Edward V. Quadros, Ph.D., and Jacob Selhub, Ph.D.
From the Division of Pediatric Neurology,
Department of Pediatrics, University Hospital
In infantile-onset cerebral folate deficiency, 5-methyltetrahydrofolate (5MTHF) levels in the cerebrospinal fluid are low, but folate levels in the serum and erythrocytes are normal. We examined serum specimens from 28 children with cerebral folate deficiency, 5 of their mothers, 28 age-matched control subjects, and 41 patients with an unrelated neurologic disorder. Serum from 25 of the 28 patients and 0 of 28 control subjects contained high-affinity blocking autoantibodies against membrane-bound folate receptors that are present on the choroid plexus. Oral folinic acid normalized 5MTHF levels in the cerebrospinal fluid and led to clinical improvement. Cerebral folate deficiency is a disorder in which autoantibodies can prevent the transfer of folate from the plasma to the cerebrospinal fluid.
Cerebral folate deficiency can be defined as any neuropsychiatric condition associated with low levels of 5-methyltetrahydrofolate (5MTHF), the active folate metabolite in the cerebrospinal fluid, in association with normal folate metabolism outside the central nervous system, as reflected by normal hematologic values, normal serum homocysteine levels, and normal levels of folate in serum and erythrocytes. Infantile-onset cerebral folate deficiency is a neurologic syndrome that develops four to six months after birth. Its major manifestations are marked irritability, slow head growth, psychomotor retardation, cerebellar ataxia, pyramidal tract signs in the legs, dyskinesias (e.g., choreoathetosis and ballismus), and in some cases, seizures.1,2
After the age of three years, central visual disturbances can become manifest and lead to optic atrophy and blindness.1,2 The only identifiable biochemical abnormality consistently found in these children is a low level of 5MTHF in the cerebrospinal fluid. Active folate transport across the blood–brain and blood–cerebrospinal fluid barriers is mediated primarily by membrane-associated folate receptors. 3
5MTHF, the predominant form of folate in plasma, binds to these receptors, which are anchored by a glycosylphosphatidylinositol (GPI) moiety to the endothelial surface in the brain and the basolateral surface of epithelial cells on the choroid plexus. 3-5 After folate binds to the receptors, it is internalized by the epithelial cells through receptor-mediated endocytosis, and from there passes into the brain interstitium and the cerebrospinal fluid.3-5
An important property of these receptors is their high affinity (affinity constant, 10 9 to 10
10 liters per mole) for several folate derivatives, including 5MTHF and folic acid. 4 The reduced folate carrier is a ubiquitously expressed, membrane-bound protein in tissue cells.
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