constitutional megaloblastic anemia with severe neurologic disease

Dihydrofolate reductase deficiency

Dihydrofolate reductase deficiency (DHFR deficiency) is an ultra-rare condition with less than 20 reported cases within the literature, as of 2025. It is an inherited disorder of folate metabolism caused by biallelic pathogenic mutations in the DHFR gene. Functionally, loss or significant reduction of DHFR activity impairs biological processes such as the conversion of dihydrofolate (DHF) to tetrahydrofolate (THF), the conversion of folic acid to dihydrofolate, and the recycling of tetrahydrobiopterin from dihydrobiopterin. These disrupt processes important for normal DNA replication and cell division, as well as neurotransmitter synthesis. Presented symptoms vary greatly, but include megaloblastic anemia, cerebral folate deficiency, significantly reduced or absence of cerebrospinal-fluid folate (5-methyltetrahydrofolate) and neurological symptoms of varying type and severity such as seizures, developmental delay, and microcephaly. The disorder follows an autosomal recessive mode of inheritance pattern. Diagnosis is typically conducted through combinations of genetic testing, biochemical assessment of specific metabolites (tetrahydrobiopterin, folate) in the body, and measurement of DHFR enzyme presence and activity. Treatment with folinic acid has been shown to improve some patient symptoms. The first confirmed cases of the condition were reported in 2011.