ABSTRACT
OBJECTIVE: To assess the feasibility of T-cell receptor excision circles (TRECs) quantification for neonatal mass screening of severe combined immunodeficiency (SCID). STUDY DESIGN: Real-time PCR based quantification of TRECs for 471 healthy control patients and 18 patients with SCID with various genetic abnormalities (IL2RG, JAK3, ADA, LIG4, RAG1) were performed, including patients with maternal T-cell engraftment (n = 4) and leaky T cells (n = 3). RESULTS: TRECs were detectable in all normal neonatal Guthrie cards (n = 326) at the levels of 10(4) to 10(5) copies/microg DNA. In contrast, TRECs were extremely low in all neonatal Guthrie cards (n = 15) and peripheral blood (n = 14) from patients with SCID, including those with maternal T-cell engraftment or leaky T cells with hypomorphic RAG1 mutations or LIG4 deficiency. There were no false-positive or negative results in this study. CONCLUSION: TRECs quantification can be used as a neonatal mass screening for patients with SCID.
Subject(s)
DNA Repair/genetics , Neonatal Screening/methods , Receptors, Antigen, T-Cell/genetics , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/genetics , Adolescent , Adult , Child , Child, Preschool , Feasibility Studies , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Predictive Value of Tests , Reverse Transcriptase Polymerase Chain Reaction , Ribonuclease P/blood , Severe Combined Immunodeficiency/blood , Young AdultABSTRACT
Autoimmune lymphoproliferative syndrome (ALPS) is characterized clinically by chronic non-malignant lymphoproliferation and autoimmunity and is caused by a genetic defect in programmed cell death (apoptosis). Most patients with ALPS have heterozygous mutations in the Fas gene. We describe an 11-year-old Brazilian boy with hepatosplenomegaly, lymphadenopathy, hemolytic anemia, and hypergammaglobulinemia since early infancy. T cell lines from the patient were defective in Fas-mediated apoptosis. He was diagnosed as having ALPS and found to have a novel Fas gene mutation (IVS4+1G>A). In addition, he presented with glomerulonephritis in infancy. An aunt and uncle who had the same Fas mutations also had histories of glomerulonephritis. Although glomerulonephritis is common in Fas-deficient mice, it is infrequent in human ALPS. Corticosteroid therapy ameliorated the glomerulonephritis in our patient, as well as his lymphoproliferation, anemia, and hypergammaglobulinemia. This study suggests that glomerulonephritis is one of the characteristic features of ALPS.
Subject(s)
Autoimmune Diseases/genetics , Autoimmune Diseases/pathology , Glomerulonephritis/genetics , Glomerulonephritis/pathology , Lymphoproliferative Disorders/genetics , Lymphoproliferative Disorders/pathology , Apoptosis , Autoimmune Diseases/complications , Brazil , Child , Glomerulonephritis/complications , Humans , Lymphoproliferative Disorders/complications , Male , Point Mutation , fas Receptor/geneticsABSTRACT
Mutations in the Bruton tyrosine kinase (BTK) gene are responsible for X-linked agammaglobulinemia (XLA), which is characterized by recurrent bacterial infections, profound hypogammaglobulinemia, and decreased numbers of mature B cells in the peripheral blood. We evaluated 17 male Brazilian patients from 13 unrelated families who showed markedly reduced numbers of blood B cells and hypogammaglobulinemia. BTK gene analysis detected mutations in 10 of the 13 presumed XLA families. Seven mutations (Q196X, G613D, R28L, 251-273del, Q234X, H364P, and R13X) had been reported previously, whereas the remaining three mutations (M501T, IVS15+1G>C, and IVS14+1G>A) were novel. Mutation IVS15+1G>C occurred in a splice donor site and caused exons 15 and 16 to be skipped, and IVS14+1G>A might cause exon 14 to be skipped. Flow cytometry revealed deficient expression of BTK protein in 10 of the 13 families. This is the first report of the diagnosis of XLA by analysis of mutations of the BTK gene in Brazilian patients.