Severe combined immunodeficiency resulting from mutations in MTHFD1

Pediatrics. 2013 Feb;131(2):e629-34. doi: 10.1542/peds.2012-0899. Epub 2013 Jan 6.

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.

Publication types

  • Case Reports

MeSH terms

  • 3-Hydroxyacyl CoA Dehydrogenases / deficiency
  • 3-Hydroxyacyl CoA Dehydrogenases / genetics
  • Anemia, Megaloblastic / diagnosis
  • Anemia, Megaloblastic / drug therapy
  • Anemia, Megaloblastic / genetics
  • Bone Marrow Examination
  • Cardiomyopathies / diagnosis
  • Cardiomyopathies / drug therapy
  • Cardiomyopathies / genetics
  • Combined Modality Therapy
  • DNA Mutational Analysis*
  • Drug Combinations
  • Drug Therapy, Combination
  • Exome / genetics
  • Female
  • Genetic Carrier Screening
  • Humans
  • Hydroxocobalamin / therapeutic use
  • Immunization, Passive
  • Infant
  • Infant, Newborn
  • Leukopenia / diagnosis
  • Leukopenia / drug therapy
  • Leukopenia / genetics
  • Lipid Metabolism, Inborn Errors / diagnosis
  • Lipid Metabolism, Inborn Errors / drug therapy
  • Lipid Metabolism, Inborn Errors / genetics
  • Methylenetetrahydrofolate Dehydrogenase (NADP) / genetics*
  • Minor Histocompatibility Antigens
  • Mitochondrial Myopathies
  • Mitochondrial Trifunctional Protein / deficiency
  • Nervous System Diseases
  • Opportunistic Infections / diagnosis
  • Opportunistic Infections / drug therapy
  • Opportunistic Infections / genetics
  • Peripheral Nervous System Diseases / diagnosis
  • Peripheral Nervous System Diseases / drug therapy
  • Peripheral Nervous System Diseases / genetics
  • Pneumonia, Pneumocystis / diagnosis
  • Pneumonia, Pneumocystis / drug therapy
  • Pneumonia, Pneumocystis / genetics
  • Retinitis Pigmentosa / diagnosis
  • Retinitis Pigmentosa / drug therapy
  • Retinitis Pigmentosa / genetics
  • Rhabdomyolysis
  • Sequence Analysis, DNA
  • Severe Combined Immunodeficiency / diagnosis
  • Severe Combined Immunodeficiency / drug therapy
  • Severe Combined Immunodeficiency / genetics*
  • Sulfadoxine / therapeutic use
  • Trimethoprim / therapeutic use
  • Vitamin B 12 / therapeutic use

Substances

  • Drug Combinations
  • Minor Histocompatibility Antigens
  • trimethoprim, sulfadoxine drug combination
  • Sulfadoxine
  • Trimethoprim
  • 3-Hydroxyacyl CoA Dehydrogenases
  • MTHFD1 protein, human
  • Methylenetetrahydrofolate Dehydrogenase (NADP)
  • Mitochondrial Trifunctional Protein
  • Vitamin B 12
  • Hydroxocobalamin

Supplementary concepts

  • Trifunctional Protein Deficiency With Myopathy And Neuropathy