Hereditary Folate Malabsorption
Hereditary folate malabsorption (HFM) is characterized by folate deficiency with 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 jerovicii pneumonia. Neurologic manifestations include developmental delays, cognitive and motor impairment, behavioral disorders and, frequently, seizures. The diagnosis of HFM is established in a proband: with anemia, impaired absorption of an oral folate load, and low cerebrospinal fluid (CSF) folate concentration (even after correction of the serum folate concentration); and/or by the identification of biallelic pathogenic variants in SLC46A1 on molecular genetic testing. Treatment of manifestations: Parenteral (intramuscular) or high-dose oral 5-formyltetrahydrofolate (5-formylTHF, folinic acid, Leucovorin(R)) or the active isomer of 5-formylTHF (Isovorin(R) or Fusilev(R)) can obviate the signs and symptoms 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). Prevention of primary manifestations: Early treatment readily corrects the systemic folate deficiency and can achieve sufficient CSF folate levels to prevent the neurologic consequences of HFM. Prevention of secondary complications: 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: periodic complete blood counts; measurements of serum and CSF folate concentrations; measurements of serum and CSF homocysteine concentrations; and monitoring of the affected individual's neurologic status. Serial measurement of immunoglobulins is not necessary once the levels return to the normal range and serum folate and hemoglobin levels 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 blood 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 folate intake above the maintenance dose prior to attempting to conceive; infants with HFM do not appear to be at an increased risk for neural malformations typically associated with maternal folate deficiency during pregnancy. HFM is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic and do not have clinical signs of folate deficiency. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If both pathogenic variants have been identified in the family, carrier testing for at-risk relatives, prenatal diagnosis for a pregnancy at increased risk, and preimplantation genetic diagnosis for HFM are possible.
Kronn D, Goldman ID. Hereditary folate malabsorption. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1673/