folate deficiency

Synopsis

 diarrhea
 loss of appetite
 weight loss
 weakness
 sore tongue
 headaches
 heart palpitations
 irritability
 behavioral disorders
 in pregnancy

• low birth weight
• premature infants
• neural tube defects (NTDs)

 macrocytic anemia (megaloblastic anemia)
 slow growth rate in infants

Pathology

Thus folate deficiency hinders DNA synthesis and cell division, affecting most notably bone marrow and cancer, both of which participate in rapid cell division.

RNA transcription, and subsequent protein synthesis, are less affected by folate deficiency as the mRNA can be recycled and used again (as opposed to DNA synthesis where a new genomic copy must be created).

Since folate deficiency limits cell division, erythropoiesis, production of red blood cells (RBCs) is hindered and leads to megaloblastic anemia which is characterized by large immature RBCs.

This pathology results from persistently thwarted attempts at normal DNA replication, DNA repair, and cell division and produces abnormally large cells (megaloblasts) with abundant cytoplasm capable of RNA and protein synthesis but with clumping and fragmentation of nuclear chromatin.

Some of these large cells, although immature, are released early from the marrow in an attempt to compensate for the anemia caused by lack of RBCs.

Both adults and children need folate to make normal RBCs and prevent anemia.

 susceptibility to neural tube defects (NTDs)

Deficiency of folate in pregnant women has been implicated in neural tube defects (NTDs) and so many cereals sold in developed countries are enriched with folate to avoid such complications.

The intracellular intake of folate through FR-α is critically important for embryogenesis as demonstrated in mouse where functional knockout of folate-binding protein 1 (Folp1, ortholog of FR-α) leads to exencephaly and is embryonically lethal.

Interestingly, a recent study showed that some mothers with an NTD pregnancy produce autoantibodies that bind to folate receptors on the placental membrane and therefore block the binding of folic acid.

Very few variations in FR-α and FR-β have been identified and none was found to be associated with an increased NTD risk.

On the other hand, a prevalent polymorphism (80A→G) in RFC-1 has been demonstrated as a genetic risk factor for NTDs especially when maternal folate status is low.

Cancer

Late studies suggested an involvement in tumorogenesis (especially in colon) through demethylation/hypomethylation of fast replicating tissues.

Drugs

A number of drugs interfere with the biosynthesis of folic acid and THF. Among them are the dihydrofolate reductase inhibitors such as trimethoprim, pyrimethamine and methotrexate; the sulfonamides (competitive inhibitors of para-aminobenzoic acid in the reactions of dihydropteroate synthetase).