Hereditary Folate Malabsorption

Clinical characteristics: Hereditary folate malabsorption (HFM) is characterized by folate deficiency due to impaired intestinal folate absorption and impaired folate transport into the central nervous system. Findings include poor feeding, failure to thrive, and anemia. There can be leukopenia and thrombocytopenia, diarrhea and/or oral mucositis, hypoimmunoglobulinemia, and other immunologic dysfunction resulting in infections, most often Pneumocystis jirovecii pneumonia. Neurologic manifestations include developmental delays, cognitive and motor disorders, behavioral disorders, and seizures.

Diagnosis/testing: The diagnosis of HFM is established in a proband with: anemia, impaired absorption of an oral folate load, and very low cerebrospinal fluid (CSF) folate concentration (even after correction of the serum folate concentration); and/or biallelic pathogenic variants in SLC46A1 identified on molecular genetic testing.

Management: Targeted therapy: Early treatment with intramuscular or high-dose oral 5-formyltetrahydrofolate (5-formylTHF; also known as folinic acid or leucovorin) or, preferably, the active isomer of 5-formylTHF (Isovorin^® or Fusilev^®) readily corrects the systemic folate deficiency and, if the dose is sufficient, can achieve CSF folate levels that prevent or mitigate the neurologic consequences of HFM. Dosing is aimed at achieving CSF folate trough concentrations as close as possible to the normal range for the age of the affected individual (infants and children have higher CSF folate levels than adults).

Supportive care: Blood transfusion is rarely needed for severe anemia; in affected individuals with selective IgA deficiency, appropriate precautions for blood product transfusion should be taken.

Surveillance: To assess adequacy of treatment, surveillance should include: complete blood counts; measurement of serum and CSF folate concentrations; measurement of CSF homocysteine concentrations; and monitoring of neurologic and cognitive function. Serum immunoglobulins are monitored until they return to the normal range and serum folate level and hemogram remain normal and stable.

Agents/circumstances to avoid: If possible, folic acid should not be used for the treatment of HFM because it binds very tightly to the folate receptor. This may impair transport of physiologic folates across the choroid plexus.

Evaluation of relatives at risk: For at-risk sibs, molecular genetic testing when the family-specific pathogenic variants are known; otherwise, assessment of serum and CSF folate levels and, if warranted, intestinal absorption of folate, immediately after birth or as soon as the diagnosis is confirmed in the proband.

Pregnancy management: Affected women should increase their 5-formylTHF intake above the maintenance dose well in advance of attempting to conceive; infants with HFM do not appear to be at increased risk for neural malformations typically associated with maternal folate deficiency during pregnancy, but care must be taken to assure that maternal folate intake is increased and sufficient.

Genetic counseling: HFM is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC46A1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial SLC46A1 pathogenic variants. If both pathogenic variants have been identified in the family, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for HFM are possible.