Cerebral folate deficiency (CFD) is a condition associated with low levels of a vital, transportable form of folate called 5-methyltetrahydrofolate (5-MTHF) in the cerebrospinal fluid (CSF) while folate levels are normal in other body (non-nervous) systems.

Symptoms of CFD usually reveal themselves at around four to six months of age, and while they may seem typical for infants, they are marked and intense in the presence of CFD.

  • Irritability,
  • unrest, and
  • sleep disturbances– Leading to
  • delayed development, 
  • deceleration of head growth,
  • decreased muscle tone and coordination.

In one-third of children, CFD also ushers in problems with voluntary movement, spasticity, speech difficulties, and epilepsy. This sounds like an onslaught of bad news; however, the situation is not bleak. Folate treatment, like administering a methyl folate supplement, can result in significant improvement of clinical symptoms and a return of 5-MTHF levels in the CSF to normal. Normal

levels lead to vast health improvements.

The conversion of folic acid into bodily useful folate is complex. First, the folic or folinic acid must be absorbed as folate, and the next key step in the conversion is transporting the folate through the blood. Two folate transporters come from the intestine. Defects in the genes of those transporters are associated with systemic methylfolate deficiency.

When folates are absorbed in the gut with the help of an essential chemical reducer called MTHFR (the “R” is for “reductase”), the folates are then converted to the main transportable form, 5-MTHF. Then, 5-MTHF crosses the blood-brain barrier. What it all comes down to, very simply, is that people with CFD aren’t able to reduce and transport vital folates in the nervous system, and that causes very real problems, even when the other systems of the body have plenty of 5-MTHF.

Low CSF (reminder: “cerebrospinal fluid”) folate levels were first reported in 1981, with CFD subsequently defined as “any neurological syndrome associated with a low CSF 5-MTHF, in the presence of normal folate metabolism outside the nervous system” (Pope, 2019). A variety of causes of CFD have been described, as indicated below, along with the clinical symptoms that typically accompany those causes.


Although prolonged CFD can clearly result in a range of clinical symptoms, the clinical outcomes are encouraging, showing that CFD is also a potentially treatable condition. The treatment, in these cases, is folate therapy, preferably with metabolically active forms of folate. Already converted from folic acid to a usable form of methylfolate, 5-MTHF is efficient, well absorbed in the intestine and could also prevent the potential negative effects of unconverted folic acid in the brain.

Oral folates have been used extensively to treat CFD, most successfully when started extremely early, and recent studies have suggested that administering folate either via intramuscular or intravenous routes may even improve CFD clinical outcomes even further. Since these treatments have resulted in such positive outcomes, a case could be made for screening the cerebrospinal fluid of patients with unexplained neurological disorders. If screening showed low

5-MTHF in the CSF, it is altogether possible that folate therapy could be a step toward relief and improved health in those patients, as well.

Pope S, Artuch R, Heales S, Rahman S. Cerebral folate deficiency: Analytical tests and differential diagnosis. J Inherit Metab Dis. 2019;1–18. 12092.



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