FOLR1

Cerebral folate transport deficiency1,2

AR

Very low CSF folate concentrations but, unlike HFM, normal serum folate hemogram. Neurologic signs occur much later, usually in 2nd 3rd yrs of life, although there are earlier exceptions.1

The defect is due to loss of function of FOLR1, which, along w/PCFT, is required for folate transport into the CSF.

FTCD

Glutamate formiminotransferase deficiency (OMIM 229100)3

AR

A severe form of the disorder is assoc w/megaloblastic anemia, DD, cognitive deficits.

FTCD encodes a bifunctional enzyme that channels 1-carbon units from formiminoglutamate (a metabolite of the histidine degradation pathway) to the folate pool.

MTR (cblG)MTRR (cblE)

Homocystinuria-megaloblastic anemia4 (See Disorders of Intracellular Cobalamin Metabolism.)

AR

Megaloblastic anemia, DD, cognitive other neurologic deficits

MTR MTRR encode 2 enzymes required for methionine synthesis from homocysteine. Age of appearance of disorder ranges from infancy to adulthood depending on specific pathogenic variant. Serum folate is normal. Affected persons respond to cobalamin.

MTHFD1

Methylenetetrahydrofolate dehydrogenase 1 deficiency (combined immunodeficiency megaloblastic anemia ± hyperhomocysteinemia) (OMIM 617780)

AR

Early onset, megaloblastic anemia, hemolytic uremic syndrome, microangiopathy w/retinopathy SCID-like syndrome

MTHFD1 is a component of a trifunctional enzyme required for provision of one-carbons in biosynthetic processes. ADA AK2 CD247 CD3D CD3E CORO1A DCLRE1C IL2RG IL7R JAK3 PRKDC PTPRC RAG1

RAG2

Typical SCID (genetically clinically heterogeneous group of disorders w/defective cellular humoral immune function) (See X-Linked SCID.)

XL5AR

Presents in infancy w/recurrent, persistent infections profound lymphopenia w/diminished or absent immunoglobulins

Affected persons have frequent infections w/opportunistic organisms (e.g., Pneumocystis jirovecii, CMV). There may be secondary anemia vitamin deficiencies that may confuse this disorder w/HFM.