Folate Deficiency in Children

Folate exists in a number of different chemical forms. Folic acid (pteroylglutamic acid) is the synthetic form used in fortified foods and supplements. Naturally occurring folates in foods (pteroylpolyglutamate) are not used as well as folic acid. Folate coenzymes are involved in a variety of reactions, including synthesis of deoxyribonucleic acid and purine, amino acid interconversion, and conversion of homocysteine to methionine. Because of its role in protein synthesis, the risk of deficiency is increased during periods of rapid growth or increased cellular metabolism.

Impaired folate status may be associated with long-term drug treatment of various non-neoplastic diseases, including the use of high-dose nonsteroidal anti-inflammatory drugs; the anticonvulsants diphenylhydantoin and phenobarbital; and methotrexate used in the treatment of rheumatoid arthritis, psoriasis, asthma, and inflammatory bowel disease.

Folate deficiency may result from poor nutrient intake or poorly prepared foods ; malabsorption (hereditary folate malabsorption, celiac disease, inflammatory bowel disease, alcoholism); diseases with a high cell turnover rate (sickle cell anemia, psoriasis); inborn errors of folate metabolism (methylene tetrahydrofolate reductase, methionine synthase reductase, glutamate formiminotransferase deficiencies) ; or autoantibodies against the cerebral folate receptor in the choroid plexus.

Anemia
Anemia due to decreased folate intake usually becomes manifest under clinical conditions that have increased vitamin requirements (e.g., pregnancy, growth in infancy, chronic hemolysis). The normal infant daily requirement is 25–35microg/day. The anemia is macrocytic (mean corpuscular volume >100 fL). Variations in RBC shape and size are common . The reticulocyte count is low, and nucleated RBCs demonstrating megaloblastic morphology often are seen in the blood. Neutropenia and thrombocytopenia rarely may be present, particularly in patients with long-standing and severe deficiencies. The neutrophils are large, some with hypersegmented nuclei. The bone marrow is hypercellular because of erythroid hyperplasia, and megaloblastic changes are prominent. Large, abnormal neutrophilic forms (giant metamyelocytes) with cytoplasmic vacuolation also are seen.

Hereditary folate malabsorption presents within 1–3 mo of age with recurrent or chronic diarrhea, failure to thrive, oral ulcerations, neurologic deterioration, and megaloblastic anemia. Neurologic outcome is poor once central nervous system manifestations are present. It is not possible to achieve the normal cerebrospinal fluid (CSF)-serum folate ratio of 3:1 despite normalization of serum levels. Children with this disorder also have depressed immunity and are susceptible to opportunistic infections.

Treatment of hereditary folate malabsorption may be possible with intramuscular folinic acid; some patients may respond to high-dose oral folinic acid therapy.

Cerebral folate deficiency presents within 4–6 mo of age with irritability, microcephaly, developmental delay, cerebellar ataxia, pyramidal tract signs, choreoathetosis, ballismus, and seizures. Subsequently, blindness due to optic atrophy develops. Serum and red blood cell 5-methyltetrahydrofolate levels are normal, but markedly low in the CSF. A high-affinity blocking autoantibody against the membrane-bound folate receptor in the choroid plexus may be the cause of the infantile cerebral folate deficiency.

Treatment with oral folinic acid corrects the low CSF folate levels and improves the clinical manifestations