Hereditary folate malabsorption is an autosomal recessive disorder caused by a pathogenic variant in SLC46A1, affecting proton-coupled folate transporter (PCFT) function. Infants with hereditary folate malabsorption often develop megaloblastic anemia and, without treatment, may experience serious neurodegenerative complications. Thalassemia is also an autosomal recessive genetic disorder. Major or compound heterozygous thalassemia is associated with severe complications and may require regular blood transfusions. A couple is seeking guidance on the recurrence risk of the condition that led to the loss of their two previous children. The second child's medical history and laboratory findings indicate a low vitamin B12 level 137.5 pg/mL, "reference range 211-911 pg/mL", elevated homocysteine 34.98 μmol/L, "reference range 3.7-13.9 μmol/L", and ferritin levels at 1129 ng/mL "reference range 18.2-341.2 ng/mL". Hematological results show a hemoglobin level of 6.4 g/dL, a total reticulocyte count of 3.39%, MCV of 82.7 fL, MCH of 26.9 pg, RDW of 19.0%, neutrophils at 27%, and lymphocytes at 42%. Hb-HPLC analysis revealed an HbA2 level of 4.6%. Whole-exome sequencing identified a homozygous pathogenic variant in the SLC46A1 gene (c.1127G>A), associated with hereditary folate malabsorption and a heterozygous pathogenic variant in the HBB gene (c.92+5G>C), linked to β-thalassemia. The first child's medical history also suggests low vitamin B12 levels and elevated homocysteine and ferritin levels. Hb-HPLC showed normal results, and genetic testing was not undertaken. The homozygous SLC46A1 (c.1127G>A) variant is lethal, whereas a heterozygous state with SLC46A1 (c.1127G>A) and HBB (c.92+5G>C) may not be associated with complications like transfusion-dependent thalassemia.

Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder caused by mutations in the SLC46A1 gene, leading to impaired intestinal and central nervous system folate transport. We present two male siblings with clinical features suggestive of HFM. The first infant exhibited pancytopenia, diarrhea, hypogammaglobulinemia, and neurological regression due to delayed diagnosis and treatment discontinuation, resulting in a fatal outcome. The second sibling was diagnosed early based on clinical suspicion and family history and showed favorable progress after timely parenteral folinic acid therapy. This report underscores the importance of early recognition, the limitations of genetic access in low-resource settings, and the critical role of parenteral folinic acid in preventing irreversible complications.

Hereditary folate malabsorption (HFM) is a rare, autosomal recessive disorder characterized by impaired intestinal absorption and impaired transport of folates across the choroid plexus into cerebral spinal fluid due to inactivating mutations in the human proton-coupled folate transporter (hPCFT) gene, which encodes the proton-coupled folate transporter (PCFT) SLC46A1. Understanding the structural impact of these mutations is crucial for elucidating the mechanistic basis for PCFT function and the pathophysiology of HFM. Recently, the cryo-electron microscopic structural characterization of the Gallus gallus PCFT was obtained, which shares significant sequence identity with hPCFT. We conducted molecular dynamics simulations of hPCFT based on this structure, to explore structural changes induced by functionally defective disease-causing and other mutant proteins and mutations that restore function. Simulations revealed that the mutually mechanistic basis for the loss of function is partial loss of structural integrity of hPCFT primarily manifested in an enlarged and distorted pore accompanied by loss of long-range contacts, less stable, fluctuating inner helices with reduced solvent accessibility, and a marked loss of ordered secondary structures. These changes are reversed by the introduction of compensatory mutations. These findings provide novel insights into the structural and functional consequences of PCFT mutations associated with HFM and provide correlations with kinetic and biochemical properties of the mutant proteins. 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. 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. 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. 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.