Hereditary Folate Malabsorption

Excerpt

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 and growth, diarrhea and/or oral mucositis, anemia and frequently pancytopenia, hypoimmunoglobulinemia, and other immunologic dysfunction resulting in infections, 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, which encodes the proton-coupled folate transporter, identified on molecular genetic testing.

Management: Targeted therapy: Early treatment with high-dose intramuscular or, if that is not possible, oral 5-formyltetrahydrofolate (5-formylTHF; also known as folinic acid or leucovorin) or, preferably, the active isomer of 5-formylTHF (levoleucovorin) readily corrects the systemic folate deficiency and, if the dose is sufficient, can achieve CSF folate concentrations 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 concentrations than adults).

Supportive care: Blood transfusion is rarely needed for severe anemia; in affected individuals with selective immunoglobulin (Ig) A deficiency, appropriate precautions for blood product transfusion should be taken. Pneumocystis jirovecii pneumonia is treated with trimethoprim-sulfamethoxazole. Developmental and educational services as needed; anti-seizure medication (avoid phenytoin and valproic acid) per neurologist for those with seizures.

Surveillance: To assess adequacy of treatment, surveillance should include measurement of serum and CSF folate and homocysteine concentrations and complete blood counts. Serum immunoglobulins are monitored until they return to normal range and serum folate concentration and hemogram remain normal and stable. Assessment of neurologic and developmental milestones frequently during childhood; assessment of cognitive function to optimize folate dosing.

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. Phenytoin and valproic acid should be avoided due to their effects on folate intestinal absorption and metabolism, respectively.

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

Pregnancy management: Affected women should be certain to adhere to their required 5-formylTHF regimen well in advance of attempting to conceive; infants of mothers with HFM do not appear to be at increased risk for neural tube defects typically associated with maternal folate deficiency during pregnancy, but care must be taken to assure that maternal folate intake is 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 inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial SLC46A1 pathogenic variants. Once the SLC46A1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for HFM are possible.