Severe combined immunodeficiency resulting from mutations in MTHFD1

Michael D Keller; Jaya Ganesh; Meredith Heltzer; Michele Paessler; A G Christina Bergqvist; H Jorge Baluarte; David Watkins; David S Rosenblatt; Jordan S Orange

doi:10.1542/peds.2012-0899

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.

Authors

Michael D Keller¹, Jaya Ganesh, Meredith Heltzer, Michele Paessler, A G Christina Bergqvist, H Jorge Baluarte, David Watkins, David S Rosenblatt, Jordan S Orange

Affiliation

¹ Children's Hospital of Philadelphia, 3550 Market St, 3rd Floor, Philadelphia, PA 19104, USA. kellermd@email.chop.edu

PMID: 23296427
DOI: 10.1542/peds.2012-0899

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