Primary immunodeficiencies related to folate and cobalamin transport and metabolism

Primary immunodeficiency diseases encompass a range of disorders that impact the immune system, resulting in a spectrum of phenotypes and cellular dysfunction. Manifestations may include recurrent infections, failure to thrive, immune dysregulation, as well as other symptoms. The underlying genetic abnormalities affect not only the immune system, but occasionally other organ systems as well. To date, there are over 500 genes known to cause primary immunodeficiency. Notably, inborn errors of metabolism can cause immunodeficiency by compromising critical transporters or enzymes. In particular, folate (vitamin B9) and cobalamin (vitamin B12) are essential for maintenance of hematopoietic function, neurological development, and fetal development. Variants in the genes MTHFD1, TCN2, and SLC46A1, are known to underlie folate and cobalamin-related immunodeficiency. More recently, pathogenic variants in SLC19A1 have been reported as a novel cause of folate deficiency. This review presents a timely overview of immunodeficiency diseases resulting from abnormalities in folate and cobalamin transport and metabolism.