Table 3.

Hereditary Disorders in the Differential Diagnosis of FOLR1-Related Cerebral Folate Transport Deficiency

Gene(s)DisorderMOICSF FolateKey Feature(s)Comment
DHFR Dihydrofolate reductase deficiency (OMIM 613839)AR<10 nmol/LOnset w/in a few months after birth w/DD, usually macrocytic anemia, pancytopenia, & neurodegeneration of varying intensity 1
  • No response to folic acid
  • Corrects w/5-formylTHF
  • Can occur w/isolated macrocytosis w/o anemia 1, 2
MTHFR Methylenetetrahydrofolate reductase deficiency (OMIM 236250)AR<10 nmol/LNeurocognitive & motor impairment, DD w/seizures; clinical phenotype correlates w/extent of residual enzyme activity
  • Defect in remethylation of homocysteine to methionine
  • Plasma folate is low but not accompanied by anemia. 3
  • Treated w/betaine
MTHFS 5,10-methenyltetrahydrofolate synthetase deficiency (OMIM 618367)ARLow to normalNeurodevelopmental disorder w/microcephaly & seizures
  • Defect in 5-formylTHF metabolism 4
  • Treated w/5-methylTHF
SLC46A1 5 Hereditary folate malabsorption AR<10 nmol/LFolate deficiency resulting in anemia, pancytopenia, & immune deficiency w/DD leading to neurocognitive & motor impairment & seizuresModest doses of parenteral folate will correct anemia & other systemic manifestations, but if that is inadequate to correct CSF folate levels, neural manifestations will progress & become irreversible.

5-formylTHF = 5-formyltetrahydrofolate; 5-methylTHF = 5-methyltetrahydrofolate; AR = autosomal recessive; CSF = cerebral spinal fluid; DD = developmental delay; MOI = mode of inheritance

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SLC46A1 encodes the proton-coupled folate transporter (PCFT) protein.

From: FOLR1-Related Cerebral Folate Transport Deficiency

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