Severe Combined Immunodeficiency Resulting From Mutations in MTHFD1 abstract Folate and vitamin B12 metabolism are essential for de novo purine

Folate and vitamin B12 metabolism are essential for de novo purine synthesis, and several defects in these pathways have been associated with immunodeficiency. Here we describe the occurrence of severe combined immunodeficiency (SCID) with megaloblastic anemia, leukopenia, atypical hemolytic uremic syndrome, and neurologic abnormalities in which hydroxocobalamin and folate therapy provided partial immune reconstitution. Whole exome sequencing identified compound heterozygous mutations in the MTHFD1 gene, which encodes a trifunctional protein essential for processing of singlecarbon folate derivatives. We now report the immunologic details of this novel genetic cause of SCID and the response to targeted metabolic supplementation therapies. This finding expands the known metabolic causes of SCID and presents an important diagnostic consideration given the positive impact of therapy. Pediatrics 2013;131: e629–e634 AUTHORS: Michael D. Keller, MD,a Jaya Ganesh, MD,b Meredith Heltzer, MD,a Michele Paessler, DO,c A.G. Christina Bergqvist, MD,d H. Jorge Baluarte, MD,e David Watkins, PhD,f David S. Rosenblatt, MD,f and Jordan S. Orange, MD, PhDg aDivision of Allergy and Immunology, bSection of Metabolic Disease, cDepartment of Pathology, dDivision of Neurology, and eDivision of Nephrology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; fDepartment of Human Genetics, McGill University, Montreal, Canada; and gDivision of Immunology, Allergy, and Rheumatology, Texas Children’s Hospital, Houston, Texas