RESUMEN
Patients with adenosine deaminase (ADA) deficiency exhibit spontaneous and partial clinical remission associated with somatic reversion of inherited mutations. We report a child with severe combined immunodeficiency (T-B- SCID) due to ADA deficiency diagnosed at the age of 1 month, whose lymphocyte counts including CD4+ and CD8+ T and NK cells began to improve after several months with normalization of ADA activity in Peripheral blood lymphocytes (PBL), as a result of somatic mosaicism caused by monoallelic reversion of the causative mutation in the ADA gene. He was not eligible for haematopoietic stem cell transplantation (HSCT) or gene therapy (GT); therefore he was placed on enzyme replacement therapy (ERT) with bovine PEG-ADA. The follow-up of metabolic and immunologic responses to ERT included gradual improvement in ADA activity in erythrocytes and transient expansion of most lymphocyte subsets, followed by gradual stabilization of CD4+ and CD8+ T (with naïve phenotype) and NK cells, and sustained expansion of TCRγδ+ T cells. This was accompanied by the disappearance of the revertant T cells as shown by DNA sequencing from PBL. Although the patient's clinical condition improved marginally, he later developed a germinal cell tumour and eventually died at the age of 67 months from sepsis. This case adds to our current knowledge of spontaneous reversion of mutations in ADA deficiency and shows that the effects of the ERT may vary among these patients, suggesting that it could depend on the cell and type in which the somatic mosaicism is established upon reversion.
Asunto(s)
Adenosina Desaminasa/metabolismo , Terapia de Reemplazo Enzimático , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Primarias Desconocidas/genética , Neoplasias Primarias Desconocidas/terapia , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/terapia , Adenosina Desaminasa/administración & dosificación , Adenosina Desaminasa/genética , Adenosina Desaminasa/inmunología , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Bovinos , Recuento de Células , Niño , Preescolar , Análisis Mutacional de ADN , Resultado Fatal , Humanos , Inmunofenotipificación , Lactante , Células Asesinas Naturales/patología , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/fisiopatología , Neoplasias Pulmonares/secundario , Masculino , Mosaicismo/efectos de los fármacos , Mutación/genética , Neoplasias Primarias Desconocidas/complicaciones , Neoplasias Primarias Desconocidas/patología , Neoplasias Primarias Desconocidas/fisiopatología , Receptores de Antígenos de Linfocitos T/metabolismo , Inmunodeficiencia Combinada Grave/complicaciones , Inmunodeficiencia Combinada Grave/patología , Inmunodeficiencia Combinada Grave/fisiopatología , Choque SépticoRESUMEN
Deficiency of the purine salvage pathway enzyme purine nucleoside phosphorylase causes a combined immunodeficiency and neurologic abnormalities and is usually fatal in childhood. We report the first successful transplantation of bone marrow from a sibling with identical class II human leukocyte antigens in this condition, demonstrating correction of both lymphocyte metabolic and functional abnormalities.
Asunto(s)
Trasplante de Médula Ósea , Síndromes de Inmunodeficiencia/etiología , Síndromes de Inmunodeficiencia/terapia , Purina-Nucleósido Fosforilasa/deficiencia , Niño , Estudios de Seguimiento , Prueba de Histocompatibilidad , Humanos , Errores Innatos del Metabolismo de la Purina-Pirimidina/complicaciones , Errores Innatos del Metabolismo de la Purina-Pirimidina/enzimología , Factores de Tiempo , Trasplante HomólogoRESUMEN
We report a 5-year-old girl with adenosine deaminase (ADA) deficiency who was asymptomatic during the first years of life. At 3 years of age, she developed chronic and recurrent sinopulmonary infections, and at 4 1/2 years of age she had one major infection with Streptococcus pneumoniae (bacteremia and septic arthritis of the hip). Immunologic evaluation at 5 years of age revealed persistent lymphopenia, decreased helper-suppressor T cell ratios, and low proliferative responses to mitogens. The IgG, IgM, and IgA levels were normal; the IgG2 level was low normal or below normal. The patient had specific antibodies against toxoids and viral antigens but failed to produce antibodies against Haemophilus influenzae type b and pneumococcal polysaccharides. Although no symptoms of allergy were present, she had persistent eosinophilia and elevated IgE levels. The patient had 0.6% of normal ADA activity in erythrocytes and approximately 1% of normal ADA activity in peripheral blood mononuclear cells. Beginning at 6 years of age, she was treated with weekly injections of polyethylene glycol-modified bovine ADA. This treatment was well tolerated and effectively reversed the biochemical consequence of ADA deficiency. Concomitantly, she improved clinically and her T lymphocyte numbers and blastogenic responses to mitogens in vitro became normal. The late onset of clinical symptoms and relatively benign clinical course in this patient emphasize the need to consider ADA deficiency in a broad spectrum of immunodeficient children.