vitamin-b-12 and Severe-Combined-Immunodeficiency

Over the last forty years, our laboratory has accumulated a collection of over 1000 cultured fibroblast lines derived from patients from around the world referred with signs of inborn errors of cobalamin or folate metabolism, including several hundred with complementation-confirmed diagnoses. By accurately classifying patient disorders into classes representing blocks affecting specific reactions, we have provide the basis for rational assessment of phenotypic heterogeneity, and development of methods for diagnosis, treatment and prognosis. These resources have been valuable in identification of causal genes for known inborn errors. Since 2000, we and our collaborators identified the genes for the cblA (MMAA), cblB (MMAB), cblC (MMACHC), cblD (MMADHC), and cblF (LMBRD1) disorders.. Whole exome sequencing of DNA from a patient with severe combined immunodeficiency (SCID), megaloblastic anemia and hemolytic uremic syndrome identified mutations in the MTHFD1 gene, which encodes a trifunctional enzyme involved in interconversion of folate coenzyme derivatives. This disorder demonstrates the importance de novo pyrimidine synthesis in the etiology of SCID. Mutations in the ABCD4 gene have been identified in four patients with accumulation of unbound cobalamin in lysosomes; this gene encodes a lysosomal membrane protein that plays a role in the transport of cobalamin across this membrane. Mutations in the HCFC1 gene on the X chromosome have been identified in several male patients that had received a diagnosis of cblC on the basis of complementation studies in cultured fibroblasts. HCFC1 encodes a transcription factor that regulates expression of a number of genes, including MMACHC, the gene that is mutated in patients with the cblC disorder. These studies demonstrate that with the advent of affordable whole exome sequencing, it has been possible to identify genes for novel inborn errors of cobalamin metabolism, often working from a small number of affected patients.

Topics: Anemia, Megaloblastic; ATP-Binding Cassette Transporters; Exome; Female; Folic Acid; Hemolytic-Uremic Syndrome; Host Cell Factor C1; Humans; Male; Methylenetetrahydrofolate Dehydrogenase (NADP); Minor Histocompatibility Antigens; Proto-Oncogene Proteins c-cbl; Severe Combined Immunodeficiency; Vitamin B 12

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.

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