Genetic and Biochemical Consequences of Adenosine Deaminase Deficiency in Humans.

Adenosine deaminase deficiency accounts for ~15-20% of severe combined immunodeficiency in humans. The gene for adenosine deaminase is located on chromosome 20q12-q13.11 and codes for an aminohydrolase that catalyzes the deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. Absence of the enzyme causes a build-up of the substrates in addition to excess deoxyadenosine triphosphate, thereby compromising the regenerative capacity of the immune system. Due to underlying allelic heterogeneity, the disorder manifests as a spectrum, ranging from neonatal onset severe combined immunodeficiency to apparently normal partial adenosine deaminase deficiency. Tandem mass spectrometry coupled with high efficiency separation systems enables postnatal diagnosis of the disorder, while prenatal diagnosis relies on assaying enzyme activity in cultured amniotic fibroblasts or chorionic villi sampling. Screening of adenosine deaminase deficiency for relatives-at-risk may reduce costs of treatment and ensure timely medical intervention as applicable. This article reviews the genetic, biochemical and clinical aspects of adenosine deaminase deficiency.

Adenosin deaminasa en el síndrome de inmunodeficiencia combinada severa / Adenosine deaminase in severe combined immunodeficiency syndrome

La Adenosin deaminasa es una enzima del metabolismo de las purinas cuya función es transformar la adenosina en inosina y la desoxiadenosina en desoxiinosina. La unión de ecto-ADA1 a la superficie celular a través de CD26 contribuye a la regulación de citocinas y estimula la proliferación de células T mediante la activación de CD45. La deficiencia de esta enzima genera el síndrome de inmunodeficiencia combinada severa, caracterizado por la acumulación de metabolitos de adenina y desoxiadenosina, los cuales tienen efectos tóxicos sobre los linfocitos, afectando así la síntesis de ADN y en consecuencia la expansión clonal. Un diagnóstico temprano de esta inmunodeficiencia es esencial ya que reduce notablemente la morbilidad y mortalidad asociada con infecciones recurrentes. Los avances recientes en biología molecular y genética han conducido a la identificación de los defectos genéticos de muchas de las inmunodeficiencias primarias y al desarrollo de herramientas de diagnóstico y tratamiento prometedoras.

Adenosine deaminase is an enzyme of the purine metabolism whose function is to convert adenosine to inosine and deoxyadenosine to deoxyinosine. The ecto-ADA1 binding to the cell surface through CD26 contributes to the regulation of cytokines and stimulates the proliferation of T cells by activating CD45. The deficiency of this enzyme generates the severe combined immunodeficiency syndrome, characterized by the accumulation of deoxyadenosine and adenine metabolites, which have toxic effects on lymphocytes, affecting DNA synthesis and consequently, clonal expansion. Early diagnosis of this immunodeficiency is essential, as it significantly reduces morbidity and mortality associated with recurrent infections. Recent advances in molecular biology and genetics have led to the identification of genetic defects of many primary immunodeficiencies and the development of promising diagnostic tools and treatment.

Adenosin deaminasa como molécula coestimuladora y marcador de inmunidad celular / Adenosine deaminase as costimulatory molecule and marker of cellular immunity

La adenosin deaminasa (ADA), es una enzima del metabolismo de las purinas que ha sido objeto de mucho interés debido a que el defecto congénito de esta enzima causa el síndrome de inmunodeficiencia combinada severa. Una de las tres isoformas de la enzima (ecto-ADA) es capaz de unirse a la glicoproteína CD26 y a los receptores de adenosina A1 y A2B. La interacción ADA-CD26 produce una señal coestimuladora en los eventos de activación de las células T y en la secreción de IFN-g, TNF-a e IL-6. Durante dicha activación la actividad de la enzima está regulada de manera positiva por IL-2 e IL-12 y negativamente por IL-4, basado en un mecanismo de translocación. Diversos estudios señalan que los niveles séricos y plasmáticos de ADA se elevan en algunas enfermedades causadas por microorganismos que infectan principalmente a los macrófagos; así como en trastornos hipertensivos, lo cual podría representar un mecanismo compensatorio como consecuencia de la elevación de los niveles de adenosina y la liberación de mediadores hormonales e inflamatorios estimulados por la hipoxia.

Adenosine deaminase (ADA) is an enzyme of purine metabolism which has been the subject of much interest because the congenital defect of this enzyme causes severe combined immunodeficiency syndrome. One of the three isoforms of the enzyme (ecto-ADA) is capable of binding to the glycoprotein CD26 and adenosine receptors A1 and A2B. ADA-CD26 interaction produces a costimulatory signal in the events of T cell activation and secretion of IFN-g, TNF-a and IL-6. During this activation, the enzyme activity is regulated positively by IL-2 and IL-12 and negatively by IL-4, based on the mechanism of translocation. Diverse studies suggest that seric and plasmatic levels of ADA rise in some diseases caused by microorganisms infecting mainly the macrophages and in hypertensive disorders, which may represent a compensatory mechanism resulting from increased adenosine levels and the release of hormones and inflammatory mediators estimulated by hipoxia.

Deficiencia proteica: impacto sobre el timo de ratas en crecimiento / Protein deficiency: effect of thymus of growing rats

Se analiza las consecuencias provocadas por desequilibrios nutricionales sobre el contenido de DNA y la actividad de las enzimas ADA y PNP en timo de ratas en crecimientos. Ratas Wistar al destete fueron alimentadas con: 1- dieta libre de proteínas hasta asemejar cuadros de malnutrición proteica leve, moderada y severa; 2- dieta conteniendo harina de maíz en baja concentración (6,5 por ciento). La subnutrición durante la lactancia se obtuvo duplicando la camada (12-14 crías por madre). Como controles se utilizaron ratas bien nutridas de igual edad, que desde el destete recibieron dieta stock. Al finalizar la experiencia, se les extrajo el timo (Pt)(mg). Se determinó DNA (mg/órgano), el número de núcleos, el tamaño celular- Pt(mg)/No. de Núcleos- y la actividad de las enzimas ADA y PNP (umol de ácido úrico x 10 - 1/P)(P=Pt(mg) /P corporal 0.75). Los resultados muestran que tanto la subnutrición durante la lactancia, como la malnutrición proteica al destete y la administración de dieta de baja calidad, afectan la proliferación celular en el timo, Sólo la carencia de proteína o su baja calidad, aumenta la actividad de ADA y PNP

Terapia génica: ficcion o realidad / Gene therapy: fact or fantasy

The great advances in molecular biology have encouraged the treatment of diseases through gene intervention. According to present knowledge, all diseases somehow have their origin or are related to genes. Different stages must be overcome to intervene in genes: a) Identification of the genes to intervene. Methodologies have been developed and a number of genes identified b) Codification of its structure. The technology for this purpose is already know and the process had been automated c) Locate the adequate vector that, without damaging the cell, is capable to introduce in nucleus the genetic material. There are many studied alternatives. However the ideal vector, that would select the target cells, be risk-free and guarantee prolonged results, has not been found yet d) To achiev the gene expression, codifying the respective protein or its inhibition, according to the case. Some success has been obtained in this field, but technology has to be improved to obtain a uniform and satisfactory response. Advances achieved in the last years have been impressive and technologies will presumably continue to improve

Erythrocyte adenosine deaminase deficiency in Brazil

A atividade da adenosina deaminase eritrocitária (E.C.3.5.4.4) foi feita em 300 doadores de sangue através de determinaçäo quantitativa em espectrofotômetro. Valores normais de 1,7 + ou - 0,7 u.i./g Hb/min/37-C foram estabelecidos, e foi encontrado um indivíduo heterozigoto que exibiu atividade de 0,5 u.i./g Hb/min/37-C, o que permitiu a determinaçäo da freqüência do gene em 0,0033 e a probabilidade da ocorrência de um homozigoto deficiente em 100.000 nascimentos