先天性葉酸吸収不全（症）

BACKGROUND: 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. CASE: 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. CONCLUSION: 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.