Cerebral folate deficiency

[2][3] In addition, signs of psychomotor retardation, sleep disturbances, cerebellar ataxia, and delayed development of head growth can occur.

[11] In children with cerebral folate deficiency, the cerebrospinal fluid shows low levels of 5MTHF, and a loss of white matter in the brain (leukodystrophy) may occur.

[12]  There is inability for the 5MTHF to be transported across the blood-brain barrier, resulting in symptoms of seizures, delayed cognitive and motor processing, and autistic features.

[12] More commonly, CFD involves the malfunction and disruption of the folate receptor alpha (FRA).

If the individual has a mitochondrial disease, the FRA could be lacking adequate energy, resulting in the deficiency of folate in the brain.

For example, it can develop in AADC deficiency through the depletion of methyl donors, such as SAM and 5-MTHF, by O-methylation of the excessive amounts of L-dopa present in patients.

Over time, the treatment with folinic acid has shown to reduce a variety of symptoms of CFD.

The treatment of folinic acid can lead to improvements in walking, speech, interpersonal skills and reduction in seizures.

Cerebral CT-scan at 4 years old. Red arrows show brain calcifications (A) and diffuse white matter abnormalities (B). From Mafi et al., 2020 [ 10 ]
Folic acid metabolism and 5-MTHF transport across the choroid plexus epithelium in the brain. Red arrows and red crosses indicate the alternative pathway induced by FRα deficiency. Blue arrows indicate effects of folinic acid treatment. KEYS: 5-MTHF: 5-methylenetetrahydrofolate; B6: Vitamin B6; B12: Vitamin B12; CSF: cerebrospinal fluid; DHFR: dihydrofolate reductase; FRα: receptor of folate alpha; Gly: glycine; GSH: glutathione reduced states; GSSG: Glutathione oxidized states; MS: methionine synthase; MTHFD: methylenetetrahydrofolate dehydrogenase; MTHFR: methylenetetrahydrofolate reductase; MTHFS: methylenetetrahydrofolate synthetase; PC: phosphatidylcholine; PCFT: proton coupled folate transporter; PI: phosphatidylinositol; RFC: reduced folate carrier; SAH: S-adenosyl homocysteine; SAM: S-adenosyl-methionine; Ser: Serine; SHMT: serine-hydroxy methyl transferase; SM: sphingomyelin. Figure 1 from Mafi et al., 2020. [ 10 ]
Probable mechanism by which folic acid impedes the entry of 5-MTHF into the central nervous system in vulnerable individuals. From Tomoyuki Akiyama et al., 2022. [ 18 ] "Transport of folate compounds from the intestine to the brain and competitive inhibition of 5MTHF transport by FA. Conversion of FA to 5MTHF is limited in the intestine and is mainly handled by DHFR in the liver, although its enzymatic activity is low in humans. In contrast, folinic acid is efficiently metabolized to 5MTHF in the intestine and liver. When an excess amount of FA is taken, it cannot be fully reduced by DHFR in the liver and unmetabolized FA appears in the plasma. Because FA has higher affinity to FR1 expressed at the choroid plexus than 5MTHF, it can act as a competitive inhibitor against 5MTHF transport from the plasma to the CSF. In addition, FA cannot be metabolized to 5MTHF efficiently in the brain with extremely low DHFR activity. Thus, excess FA intake may lead to a less effective supply of 5MTHF to the brain compared with that of folinic acid supplementation. Dashed arrows indicate more than one-step enzymatic reactions.
5MTHF, 5-methyltetrahydrofolic acid ; CSF, cerebrospinal fluid ; DHFR, dihydrofolate reductase ; FA, folic acid; FR1, folate receptor 1; MTHFR, methylenetetrahydrofolate reductase ; THF, tetrahydrofolate "