AB0574 A MONOGENIC DISEASE WITH WIDE RANGE OF SYMPTOMS: DEFICIENCY OF ADENOSINE DEAMINASE 2
Ezgi Deniz BatuEkim Z. TaşkıranHatice Asuman ÖzkaraŞule ÜnalNaz Güleray LafcıAbdülsamet ErdenÖmer KaradağFatma GümrükMualla ÇetinYelda BilginerHafize Emine SönmezDeniz Çağdaşİlhan TezcanSeza Özen
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Abstract:
Background
Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder caused by ADA2 mutations.Objectives
We aimed to investigate the characteristics of DADA2 patients along with the ADA2 enzyme levels.Methods
24 DADA2 patients who admitted to the Adult and Pediatric Rheumatology, Pediatric Haematology, and Pediatric Immunology Departments were included. All exons of the ADA2 gene were screened by Sanger sequencing in all DADA2 patients. Serum ADA2 enzyme activity was measured by modified spectrophotometric method.Results
24 DADA2 patients were included; Group 1, 14 DADA2 patients with polyarteritis nodosa (PAN)-like phenotype; Group 2, 9 patients with Diamond-Blackfan anemia (DBA)-like features and one with immune deficiency. 14 PAN-like DADA2 patients did not have the typical thrombocytosis seen in classical PAN. Inflammatory attacks were evident in only Group 1 patients. Serum ADA2 was low in all DADA2 patients except one who was tested after hematopoietic stem cell transplantation. There was no significant difference in ADA2 levels between PAN-like and DBA-like DADA2 patients (Figure 1). ADA2 activities of heterozygote family members were about half the level of the control subjects. However, in heterozygote DADA2 patients, serum ADA2 levels were as low as the ones of homozygote DADA2 patients. ADA2 mutations were affecting the dimerization domain in Group 1 patients and in the catalytic domain in Group 2 patients (Table 1).Conclusion
We suggest that enzyme activity of ADA2 should be assessed along with genetic analysis since there are heterozygote patients with absent enzyme activity. Our data confirms a possible genotype phenotype correlation where dimerization domain mutations are associated with a PAN-like phenotype whereas catalytic domain mutations are associated with hematological manifestations.References
[1] Navon Elkan P, et al. Mutant ADA2 in a PAN vasculopathy. N Engl J Med 2014;370(10):921-931 [2] Zhou Q, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 2014;370(10):911-920Acknowledgement
This study was supported by Scientific and Technological Research Council of Turkey (TÜBITAK) with grant numbers of 315S192. Prof. Nurten Akarsu performed the molecular studies of DBA patients and special thanks to her for great support.Disclosure of Interests
Ezgi Deniz Batu: None declared, Ekim Z. Taskiran: None declared, Hatice Asuman Özkara: None declared, Şule Ünal: None declared, Naz Guleray: None declared, Abdulsamet Erden: None declared, Omer Karadag: None declared, Fatma Gümrük: None declared, Mualla Çetin: None declared, Yelda Bilginer: None declared, Hafize Emine Sonmez: None declared, Deniz Cagdas Ayvaz: None declared, Ilhan Tezcan: None declared, Seza Özen Consultant for: Seza Ozen is receiving consultancy fees from Novartis, Speakers bureau: RocheKeywords:
Compound heterozygosity
Adenosine deaminase deficiency
Hypogammaglobulinemia
Heterozygote advantage
Severe Combined Immunodeficiency is the term applied to a group of rare genetic disorders characterised by defective or absent T and B cell functions. Patients usually present in first 6 months of life with respiratory/gastrointestinal tract infections and failure to thrive. Among the various types of severe combined immunodeficiency, enzyme deficiencies are relatively less common. We report the case of a 6 years old girl having severe combined immunodeficiency due to adenosine deaminase deficiency.
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Markedly reduced or absent adenosine deaminase activity in man is associated with an autosomal recesive form of severe conbined immunodeficiency disease. To further define the genetic nature of this enzyme defect, we have quantitated immunologically active adenosine deaminase (CRM) in the hemolysate of homozygous deficient patients and their heterozygous parents. A highly specific radioimmunoassay was developed capable of detecting 0.05% of normal erythrocyte adenosine deaminase. Hemolysates from nine heterozygotes (five families) showed a wide range in CRM (32--100% of normal) and variable absolute specific activities with several being at least 1 SD BELOW THE NORMAL MEAN. Hemolysates from four unrelated patients showed less than 0.09% adenosine deaminase activity with CRM ranging from less than 0.06 to 5.6% of the normal mean. In conclusion, heterozygote and homozygote hemolysates from five of the eight families analyzed revealed variable levels of CRM suggesting heterogeneous genetic alteration or expression of the silent or defective allele(s) of adenosine deaminase.
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Because others had described a lack of the enzyme adenosine deaminase as associated with severe combined immunodeficiency, we surveyed kindreds with infants affected with such an immunodeficiency. Three infants in two families with severe combined immunodeficiency were found to have no detectable erythrocyte adenosine deaminase. Eleven family members heterozygous for adenosine deaminase deficiency were encountered among the first-degree relatives; adenosine deaminase deficiency and severe combined immunodeficiency were associated and inherited as autosomal recessive traits in both kindreds. Successful bone-marrow transplantation was carried out in two of these infants. Normal immunologic function was established in both children, but the deficiency of adenosine deaminase persisted in their erythrocytes. The enzyme deficiency did not impair the successful establishment of normal humoral and cellular immunity by transplants of bone-marrow cells from siblings who were either normal or heterozygous for adenosine deaminase deficiency.
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Adenosine deaminase deficiency
Heterozygote advantage
Autosomal recessive inheritance
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Deficiency of adenosine deaminase (ADA) activity causes an autosomally inherited form of severe combined immunodeficiency (ADA¯SC1D) disease (1, 2). It has been suggested that this form of SCID is caused by a defect in T- and B-cell differentiation due to the accumulation of adenine nucleosides in the absence of functional ADA (2). The cloning of sequences encoding human ADA (3, 4, 5) opened new ways to investigate the molecular basis of ADA¯SCID disease (6–10) and allowed studies aimed at the development of gene therapy protocols for ADA¯SCID patients (11–15).
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A study was performed on the family of a child with severe combined immunodeficiency and deficiency of the purine salvage pathway enzyme, adenosine deaminase (ADA). Sixteen relatives over three generations were studied. Erythrocyte ADA levels clearly indicated the heterozygous status of five members. A sixth member, whose erythrocyte ADA level of 48 nmol/hr/ml Hb was within two standard deviations (32) of the mean (76) was shown by ADA determination on platelets to be clearly heterozygous. Similarly, consideration of ADA data of either serum, platelets or lymphocytes only, would have failed to identify all heterozygotes. The survey shows that the identification of phenotype by the indirect means of enzyme level determination is enhanced by the simultaneous study of several tissues.
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This chapter contains sections titled: Introduction Consequences of Adenosine Deaminase Deficiency Physical-Chemical Properties of Adenosine Deaminase and Tissue Distribution The Role of Adenosine Deaminase in the Purine Salvage Pathway Cell Culture Models for Studying Adenosine Deaminase Deficiency Biochemical Mechanisms of the Immunodeficiency Caused by Adenosine Deaminase Deficiency Therapy Adenosine Deaminase Deficiency and Immunocompetency Significance to Biomedical Sciences
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The severe combined immunodeficiency caused by the absence of adenosine deaminase (SCID-ADA) was the first monogenic disorder for which gene therapy was developed. Over 30 patients have been treated worldwide using the current protocols, and most of them have experienced clinical benefit; importantly, in the absence of any vector-related complications. In this document, we review the progress made so far in the development and establishment of gene therapy as an alternative form of treatment for ADA-SCID patients. Keywords: Immunodeficiency, Adenosine, Deaminase Deficiency, Adenosine deaminase, severe combined immunodeficiency, gene therapy, hematopoietic stem cell, retrovirus, clinical trial
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