Molecular Genetics of Hereditary Folate Malabsorption

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Abstract Hereditary folate malabsorption is a genetic disorder that results in the specific inability to absorb ingested folate in the intestine and to transport serum folate across the blood–brain barrier into the cerebrospinal fluid. Absorption of other vitamins and nutrients is unimpaired. Affected individuals come to medical attention during the first year of life with low serum and cerebrospinal folate levels, megaloblastic anaemia and immunologic and neurologic findings. The disorder is inherited as an autosomal recessive trait and is caused by mutations in the SLC46A1 gene, which encodes the proton‐coupled folate transporter (PCFT). Mutations at SLC46A1 have been identified in over 30 patients with hereditary folate malabsorption. Several of these result in failure to translocate PCFT at the cell membrane; one was shown to encode a protein that was targeted to the cell membrane but did not support folate uptake. Key Concepts Hereditary folate malabsorption is a rare autosomal recessive genetic disorder. The disorder results in decreased intestinal folate absorption and decreased serum folate levels. It also results in decreased cerebrospinal fluid folate levels owing to decreased folate transport across the blood–brain barrier. Patients have megaloblastic anaemia, immunological deficits and, in some cases, neurological problems. Hereditary folate malabsorption is caused by mutations in the SLC46A1 gene, which encodes the proton‐coupled folate transporter (PCFT). Treatment with parenteral folinic acid corrects both haematological and neurological problems in hereditary folate malabsorption. Study of patients with hereditary folate malabsorption demonstrated that PCFT was the physiological folate transporter in the small intestine. PCFT and folate receptor α are required for folate transport across the blood–brain barrier.