title: Severe combined immunodeficiency resulting from mutations in MTHFD1.
abstract: Folate and vitamin B(12) 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 single-carbon 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.
authors.affiliation: Children's Hospital of Philadelphia, 3550 Market St, 3rd Floor, Philadelphia, PA 19104, USA. kellermd@email.chop.edu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Keller
authors.forename: Jaya
authors.initials: J
authors.lastname: Ganesh
authors.forename: Meredith
authors.initials: M
authors.lastname: Heltzer
authors.forename: Michele
authors.initials: M
authors.lastname: Paessler
authors.forename: A G Christina
authors.initials: AG
authors.lastname: Bergqvist
authors.forename: H Jorge
authors.initials: HJ
authors.lastname: Baluarte
authors.forename: David
authors.initials: D
authors.lastname: Watkins
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000172:deficiency / Q000235:genetics; D000749:Anemia, Megaloblastic / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D001856:Bone Marrow Examination; D009202:Cardiomyopathies / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D003131:Combined Modality Therapy; D004252:DNA Mutational Analysis; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D059472:Exome / Q000235:genetics; D005260:Female; D006580:Genetic Carrier Screening; D006801:Humans; D006879:Hydroxocobalamin / Q000627:therapeutic use; D007116:Immunization, Passive; D007223:Infant; D007231:Infant, Newborn; D007970:Leukopenia / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D008052:Lipid Metabolism, Inborn Errors / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics*; D015778:Minor Histocompatibility Antigens; D017240:Mitochondrial Myopathies; D063991:Mitochondrial Trifunctional Protein / Q000172:deficiency; D009422:Nervous System Diseases; D009894:Opportunistic Infections / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D010523:Peripheral Nervous System Diseases / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D011020:Pneumonia, Pneumocystis / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D012206:Rhabdomyolysis; D017422:Sequence Analysis, DNA; D016511:Severe Combined Immunodeficiency / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D013413:Sulfadoxine / Q000627:therapeutic use; D014295:Trimethoprim / Q000627:therapeutic use; D014805:Vitamin B 12 / Q000627:therapeutic use
chemical_list: D004338:Drug Combinations; D015778:Minor Histocompatibility Antigens; C000301:trimethoprim, sulfadoxine drug combination; D013413:Sulfadoxine; D014295:Trimethoprim; D015094:3-Hydroxyacyl CoA Dehydrogenases; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D063991:Mitochondrial Trifunctional Protein; D014805:Vitamin B 12; D006879:Hydroxocobalamin