Glutamate formiminotransferase deficiency is an autosomal recessive disorder and the second most common inborn error of folate metabolism. Features of a severe phenotype include elevated levels of formiminoglutamate (FIGLU) in the urine in response to histidine administration, megaloblastic anemia, and mental retardation. Features of a mild phenotype include high urinary excretion of FIGLU in the absence of histidine administration, mild developmental delay, and no hematologic abnormalities (summary by Hilton et al., 2003).

Folate-responsive megaloblastic anemia (MEGAF) is an autosomal recessive metabolic disorder characterized by megaloblastic anemia resulting from decreased folate transport into erythrocytes. Although serum levels of folate are normal, there is folate deficiency in tissues, including erythrocytes and possibly nerve cells. Serum homocysteine levels are increased and vitamin B12 levels may be decreased. Treatment with oral folate corrects the anemia and normalizes homocysteine (summary by Svaton et al., 2020)

Combined oxidative phosphorylation deficiency-18 (COXPD18) is an autosomal recessive disorder of mitochondrial function characterized by intrauterine growth retardation, hypotonia, visual impairment, speech delay, and lactic acidosis associated with decreased mitochondrial respiratory chain activity. Affected patients may also show hematologic abnormalities, mainly macrocytic anemia (summary by Hildick-Smith et al., 2013). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia is an inborn error of folate metabolism due to deficiency of methylenetetrahydrofolate dehydrogenase-1. Manifestations may include hemolytic uremic syndrome, macrocytosis, epilepsy, hearing loss, retinopathy, mild mental retardation, lymphopenia involving all subsets, and low T-cell receptor excision circles. Folinic acid supplementation is an effective treatment (summary by Ramakrishnan et al., 2016).