Table 2.

Hereditary Disorders in the Differential Diagnosis of Hereditary Folate Malabsorption

Gene(s)DisorderMOIKey Feature(s)Comment
FOLR1 Cerebral folate transport deficiency 1, 2ARVery 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. 1The 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) 3ARA 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 anemia 4 (See Disorders of Intracellular Cobalamin Metabolism.)ARMegaloblastic anemia, DD, & cognitive & other neurologic deficitsMTR & 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)AREarly onset, megaloblastic anemia, hemolytic uremic syndrome, microangiopathy w/retinopathy & SCID-like syndromeMTHFD1 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.)XL 5
AR		Presents in infancy w/recurrent, persistent infections & profound lymphopenia w/diminished or absent immunoglobulinsAffected 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.

AR = autosomal recessive; CMV = cytomegalovirus; CSF = cerebrospinal fluid; DD = developmental delay; HFM = hereditary folate malabsorption; MOI = mode of inheritance; SCID = severe combined immunodeficiency; XL = X-linked

1.
2.
3.
4.
5.

IL2RG-related severe combined immunodeficiency (SCID) is inherited in an X-linked manner. The other listed genes associated with SCID are inherited in an autosomal recessive manner.

From: Hereditary Folate Malabsorption

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