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'''''Synonyms and Keywords:''''' ADA Deficiency; SCID Due to ADA Deficiency; ADA-SCID


==Overview==
==Overview==


'''Adenosine deaminase deficiency''', or '''ADA deficiency''', is an inherited [[immunodeficiency]] [[syndrome]] accounting for about 25% of all cases of [[severe combined immunodeficiency]] (SCID).
Adenosine deaminase deficiency, or ADA deficiency, is an inherited [[immunodeficiency]] [[syndrome]] accounting for about 15% of all cases of [[severe combined immunodeficiency]] (SCID). This disease is due to a lack of the [[enzyme]] [[adenosine deaminase]] coded for by a [[gene]] on [[chromosome 20 (human)|chromosome 20]]. There is an accumulation of [[dATP]], which causes an increase in [[S-adenosylhomocysteine]]; both substances are toxic to immature [[lymphoid cell]]s, so fail to reach maturity. As a result, the [[immune system]] of the afflicted person is severely compromised or completely lacking. The enzyme adenosine deaminase is important for [[purine]] metabolism.
 
This disease is due to a lack of the [[enzyme]] [[adenosine deaminase]] coded for by a gene on [[chromosome 20 (human)|chromosome 20]]. There is an accumulation of [[dATP]], which causes an increase in [[S-adenosylhomocysteine]]; both substances are toxic to immature [[lymphoid cell]]s, so fail to reach maturity. As a result, the [[immune system]] of the afflicted person is severely compromised or completely lacking.
 
The enzyme adenosine deaminase is important for [[purine]] metabolism.


==Historical Perspective==
==Historical Perspective==
Adenosine deaminase (ADA) deficiency was first discovered by Dr. Eloise Giblett in 1972, when she received samples from a patient with [[severe combined immunodeficiency]] (SCID)  that was a candidate for bone marrow transplantation; examination of blood samples presented that the patients have no ADA activity. With discovering a second case with ADA deficiency and immunedeficiency, ADA deficiency was the first immunodeficiency in which the specific molecular defect was described.
* Adenosine deaminase (ADA) deficiency was first discovered by Dr. Eloise Giblett in 1972, when she received samples from a patient with [[severe combined immunodeficiency]] ([[Severe combined immunodeficiency|SCID]])  that was a candidate for [[Hematopoietic stem cell transplantation|bone marrow transplantation]]; examination of [[blood]] samples presented that the patients have no ADA activity.  
* With discovering the second case with ADA deficiency and immunodeficiency, ADA deficiency was the first [[immunodeficiency]] in which the specific molecular defect was described.<ref>Motulsky A, Gartler S. "Biographical Memoirs: Eloise R. Giblett". National Academy of Sciences</ref>


==Classification==
==Classification==
There is no established system for the classification of adenosine deaminase deficiency.
* There is no established system for the classification of adenosine deaminase deficiency.


==Pathophysiology==
==Pathophysiology==
Adenosine deaminase (ADA) is an ubiquitous enzyme found in all cells, It catalyzes the deamination of adenosine and deoxyadenosine to inosine and deoxyinosine. ADA deficiency is caused by mutations in the ADA1 gene at 20q13.11.  In the absence of functional ADA, there is an intracellular accumulation of adenosine and deoxyadenosine which leads a buildup of dATP and prevent de novo synthesis of nucleotides and deoxynucleotides in all cells, and inhibits ribonucleotide reductase and prevents DNA synthesis.
* Adenosine deaminase (ADA) is an ubiquitous [[enzyme]] found in all cells, It [[Catalysis|catalyzes]] the [[deamination]] of [[adenosine]] and [[deoxyadenosine]] to [[inosine]] and deoxyinosine.
* ADA deficiency is caused by [[Mutation|mutations]] in the ADA1 [[gene]] at 20q13.11.<ref>{{Cite journal
  | author = [[D. A. Wiginton]], [[G. S. Adrian]], [[R. L. Friedman]], [[D. P. Suttle]] & [[J. J. Hutton]]
| title = Cloning of cDNA sequences of human adenosine deaminase
| journal = [[Proceedings of the National Academy of Sciences of the United States of America]]
| volume = 80
| issue = 24
| pages = 7481–7485
| year = 1983
| month = December
| pmid = 6200875
}}</ref>
* In the absence of functional ADA, there is an [[intracellular]] accumulation of [[adenosine]] and [[deoxyadenosine]] which leads a buildup of [[Deoxyadenosine triphosphate|dATP]] and prevent [[de novo synthesis]] of [[Nucleotide|nucleotides]] and [[Deoxynucleotide 3'-phosphatase|deoxynucleotides]] in all cells, and inhibits [[ribonucleotide reductase]] which finally prevents [[DNA synthesis]].


In addition, deoxyadenosine irreversibly binds to and inhibits S-adenosylhomocysteine hydrolase, a rise in S-adenosylhomocysteine since the enzyme adenosine deaminase is important in the purine salvage pathway; both substances are toxic to immature lymphocytes, which thus fail to mature. which also contributes to abnormal DNA synthesis.
* In addition, [[deoxyadenosine]] irreversibly binds to and inhibits S-adenosylhomocysteine hydrolase and causes rise in [[S-adenosylhomocysteine deaminase|S-adenosylhomocysteine]]. Since [[S-adenosylhomocysteine deaminase|S-adenosylhomocysteine]] is a toxic substance, thus immature [[Lymphocyte|lymphocytes]] fail to mature.<ref>{{Cite journal
| author = [[M. S. Hershfield]], [[N. M. Kredich]], [[D. R. Ownby]], [[H. Ownby]] & [[R. Buckley]]
| title = In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine in adenosine deaminase-deficient patients
| journal = [[The Journal of clinical investigation]]
| volume = 63
| issue = 4
| pages = 807–811
| year = 1979
| month = April
| doi = 10.1172/JCI109367
| pmid = 312296
}}</ref>


ADA-deficient individuals typically have severely reduced numbers of T, B, and natural killer (NK) cells.
* Patients with adenosine deaminase deficiency have severely reduced numbers of [[T cell|T]], [[B cell|B]], and [[Natural killer cell|natural killer]] (NK) cells. However, some patients may retain NK cells and even B cells. Patients with ADA-[[severe combined immunodeficiency]] ([[Severe combined immunodeficiency|SCID]]) often have [[myeloid]] [[dysplasia]] and [[bone marrow]] hypocellularity.<ref>{{Cite journal
| author = [[R. H. Buckley]], [[R. I. Schiff]], [[S. E. Schiff]], [[M. L. Markert]], [[L. W. Williams]], [[T. O. Harville]], [[J. L. Roberts]] & [[J. M. Puck]]
| title = Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants
| journal = [[The Journal of pediatrics]]
| volume = 130
| issue = 3
| pages = 378–387
| year = 1997
| month = March
| pmid = 9063412
}}</ref>


==Causes==
==Causes==
Adenosine deaminase deficiency is a disorder arising from mutation in the ADA1 gene at 20q13.11.
* Adenosine deaminase deficiency is a disorder arising from a mutation in the ADA1 gene at 20q13.11.


==Differentiating Adenosine deaminase deficiency from Other Diseases==
==Differentiating Adenosine deaminase deficiency from Other Diseases==
Adenosine deaminase deficiency must be differentiated from other diseases that cause clinical features of [[severe combined immunodeficiency]] , and complete DiGeorge syndrome. Although DiGeorge syndrome is associated with facial and cardiac anomalies which are not seen with ADA deficiency.
* Adenosine deaminase deficiency must be differentiated from other diseases that cause clinical features of [[severe combined immunodeficiency]] , and complete DiGeorge syndrome. Although DiGeorge syndrome is associated with facial and cardiac anomalies which are not seen with ADA deficiency.<ref>{{Cite journal
| author = [[Fausto Cossu]]
| title = Genetics of SCID
| journal = [[Italian journal of pediatrics]]
| volume = 36
| pages = 76
| year = 2010
| month = November
| doi = 10.1186/1824-7288-36-76
| pmid = 21078154
}}</ref>


==Epidemiology and Demographics==
==Epidemiology and Demographics==
TThe incidence of ADA deficiency is approximately 1 per 200,000 livebirths worldwide. It accounts for nearly one-third of all cases of autosomal recessive severe combined immunodeficiency (SCID) and approximately 15 percent of all cases of SCID.
* The incidence of ADA deficiency is approximately 1 per 200,000 livebirths worldwide. It accounts for nearly one-third of all cases of [[autosomal recessive]] [[severe combined immunodeficiency]]([[Severe combined immunodeficiency|SCID]]) and approximately 15 percent of all cases of [[Severe combined immunodeficiency|SCID]].<ref>{{Cite journal
| author = [[R. H. Buckley]], [[R. I. Schiff]], [[S. E. Schiff]], [[M. L. Markert]], [[L. W. Williams]], [[T. O. Harville]], [[J. L. Roberts]] & [[J. M. Puck]]
| title = Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants
| journal = [[The Journal of pediatrics]]
| volume = 130
| issue = 3
| pages = 378–387
| year = 1997
| month = March
| pmid = 9063412
}}</ref>


==Risk Factors==
==Risk Factors==
There are no established risk factors for adenosine deaminase deficiency.
* There are no established risk factors for adenosine deaminase deficiency.


==Screening==
==Screening==
preferably, ADA deficiency  can be diagnosed in a newborn before the beginning of infections, with one well-documented example by screening of T-cell–receptor excision circles(TRECs). Since the goal of newborn screening is to detect treatable disorders that are threatening to life or long-term health before they become symptomatic and prompt treatment of SCID may notably reduce mortality and morbidity among patients. Infants with ADA deficiency without reconstitution of a functioning immune system generally die of overwhelming infection by one year of age.
* The goal of [[newborn screening]] is to detect treatable [[Disorder (medicine)|disorders]] that are threatening to life or long-term health, before they become symptomatic; and prompt treatment may notably reduce [[Morbidity & Mortality|mortality and morbidity]] among patients. Infants with ADA deficiency without reconstitution of a functioning [[immune system]] generally die of overwhelming [[infection]] by one year of age.<ref>{{Cite journal
| author = [[Kee Chan]] & [[Jennifer M. Puck]]
| title = Development of population-based newborn screening for severe combined immunodeficiency
| journal = [[The Journal of allergy and clinical immunology]]
| volume = 115
| issue = 2
| pages = 391–398
| year = 2005
| month = February
| doi = 10.1016/j.jaci.2004.10.012
| pmid = 15696101
}}</ref>


T cell receptor excision circles (TRECs) as a biomarker of naïve T cells, is a sensitive and specific, as well as cost effective, method for ADA deficiency newborn screening.
* ADA deficiency can be diagnosed in a newborn before the beginning of infections, with one well-documented example by screening of T-cell–receptor excision circles(TRECs).TRECs, formed during the differentiation of [[T cell|T cells]] in the [[thymus]].
* A quantitative [[real-time polymerase chain reaction]]([[Polymerase chain reaction|PCR]]) test can measure T cell receptor excision circles. TRECs serve as a [[biomarker]] of [[Naïve|naïve T cells]], which is a [[Sensitivity (tests)|sensitive]] and specific, as well as cost effective method for ADA deficiency newborn screening.<ref>{{Cite journal
| author = [[John M. Routes]], [[William J. Grossman]], [[James Verbsky]], [[Ronald H. Laessig]], [[Gary L. Hoffman]], [[Charles D. Brokopp]] & [[Mei W. Baker]]
| title = Statewide newborn screening for severe T-cell lymphopenia
| journal = [[JAMA]]
| volume = 302
| issue = 22
| pages = 2465–2470
| year = 2009
| month = December
| doi = 10.1001/jama.2009.1806
| pmid = 19996402
}}</ref>


==Natural History, Complications, and Prognosis==
==Natural History, Complications, and Prognosis==
===Natural History===
===Natural History===
Patients with ADA deficiency may present with multiple recurrent severe [[Infection|infections]], [[chronic diarrhea]], and [[failure to thrive]] ([[FTT]]) in the first few months of life . Variability in genetic mutations cause various phenotypes of ADA deficiency, and there are also a few patients with a later onset and relatively milder disease.  
* Infants with adenosine deaminase deficiency are typically healthy at birth, protected by acquired maternal [[immunoglobulin G]] ([[Immunoglobulin G|IgG]]) [[antibodies]] in the first few months of life.<ref>{{Cite journal
| author = [[Jennifer M. Puck]]
| title = Neonatal screening for severe combined immunodeficiency
| journal = [[Current opinion in pediatrics]]
| volume = 23
| issue = 6
| pages = 667–673
| year = 2011
| month = December
| doi = 10.1097/MOP.0b013e32834cb9b0
| pmid = 22001765
}}</ref>
* As this protection diminishes, patients with ADA deficiency may present with multiple recurrent severe [[Infection|infections]], [[chronic diarrhea]], and [[failure to thrive]]([[FTT]]) in the first few months of life.  
* Infants with adenosine deaminase(ADA) deficiency with [[severe combined immunodeficiency]] [[phenotype]] without reconstitution of a functioning immune system usually die of overwhelming infection by one year of age.<ref>{{Cite journal
| author = [[Kathryn V. Whitmore]] & [[Hubert B. Gaspar]]
| title = Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency
| journal = [[Frontiers in immunology]]
| volume = 7
| pages = 314
| year = 2016
| month =
| doi = 10.3389/fimmu.2016.00314
| pmid = 27579027
}}</ref>
* Variability in [[Genetics|genetic]] [[Mutation|mutations]] cause various [[Phenotype|phenotypes]] of ADA deficiency, and there are also a few patients with a later onset and relatively milder disease.<ref>{{Cite journal
| author = [[A. Fischer]]
| title = Severe combined immunodeficiencies (SCID)
| journal = [[Clinical and experimental immunology]]
| volume = 122
| issue = 2
| pages = 143–149
| year = 2000
| month = November
| pmid = 11091267
}}</ref>


===Complications===
===Complications===
Patients are at risk for infections from opportunistic infections usually follow more common infections. [[Pneumocystis jirovecii pneumonia|P. jiroveci]] and [[Fungal pneumonia|fungal pneumonias]] cause death in classic cases. [[Cytomegalovirus infection|CMV]], [[Varicella zoster virus|VZV]], and [[Herpes simplex virus|HSV]] infections typically occur in infants who have already had treatable infections. Neurologic compromise from polio and other [[Enterovirus|enteroviruses]] impedes stem cell reconstitution.
* Patients are at risk for [[Opportunistic infection|opportunistic infections]] usually follow more common infections. [[Pneumocystis jirovecii pneumonia|P. jiroveci]] and [[Fungal pneumonia|fungal pneumonias]] cause death in classic cases.
* [[Cytomegalovirus infection|CMV]], [[Varicella zoster virus|VZV]], and [[Herpes simplex virus|HSV]] infections typically occur in infants who have already had treatable infections. Neurologic compromise from polio and other [[Enterovirus|enteroviruses]] impede stem cell reconstitution.<ref>{{Cite journal
| author = [[G. Morgan]], [[R. J. Levinsky]], [[K. Hugh-Jones]], [[L. D. Fairbanks]], [[G. S. Morris]] & [[H. A. Simmonds]]
| title = Heterogeneity of biochemical, clinical and immunological parameters in severe combined immunodeficiency due to adenosine deaminase deficiency
| journal = [[Clinical and experimental immunology]]
| volume = 70
| issue = 3
| pages = 491–499
| year = 1987
| month = December
| pmid = 3436096
}}</ref>
* Lymphoma is an invariably fatal complication that occurs among patients with a later onset and in patients treated successfully with [[enzyme]] replacement therapy.<ref>{{Cite journal
| author = [[Maitham Husain]], [[Eyal Grunebaum]], [[Ahmed Naqvi]], [[Adelle Atkinson]], [[Bo-Yee Ngan]], [[Alessandro Aiuti]] & [[Chaim M. Roifman]]
| title = Burkitt's lymphoma in a patient with adenosine deaminase deficiency-severe combined immunodeficiency treated with polyethylene glycol-adenosine deaminase
| journal = [[The Journal of pediatrics]]
| volume = 151
| issue = 1
| pages = 93–95
| year = 2007
| month = July
| doi = 10.1016/j.jpeds.2007.03.059
| pmid = 17586199
}}</ref>


===Prognosis===
===Prognosis===
ADA deficiency is fatal, generally within the first year of life, unless the underlying defect is corrected.Early diagnosis through population-wide newborn screening and early transplantation in the absence of infectious complications may improve [[hematopoietic cell]] [[Organ transplant|transplantation]] (HCT) outcomes. Among patients transplanted under 3.5 months of age without infection, survival post-transplant is about 95 percent, and overall survival is 90 percent.  
* ADA deficiency is fatal, generally within the first year of life, unless the underlying defect is corrected.  
* Early diagnosis through population-wide newborn screening and early transplantation in the absence of infectious complications may improve [[hematopoietic cell]] [[Organ transplant|transplantation]] (HCT) outcomes.  
* Among patients transplanted under 3.5 months of age without infection, survival post-transplant is about 95 percent, and overall survival is 90 percent.<ref>{{Cite journal
| author = [[Jennifer Heimall]], [[Brent R. Logan]], [[Morton J. Cowan]], [[Luigi D. Notarangelo]], [[Linda M. Griffith]], [[Jennifer M. Puck]], [[Donald B. Kohn]], [[Michael A. Pulsipher]], [[Suhag Parikh]], [[Caridad Martinez]], [[Neena Kapoor]], [[Richard O'Reilly]], [[Michael Boyer]], [[Sung-Yun Pai]], [[Frederick Goldman]], [[Lauri Burroughs]], [[Sharat Chandra]], [[Morris Kletzel]], [[Monica Thakar]], [[James Connelly]], [[Geoff Cuvelier]], [[Blachy J. Davila Saldana]], [[Evan Shereck]], [[Alan Knutsen]], [[Kathleen E. Sullivan]], [[Kenneth DeSantes]], [[Alfred Gillio]], [[Elie Haddad]], [[Aleksandra Petrovic]], [[Troy Quigg]], [[Angela R. Smith]], [[Elizabeth Stenger]], [[Ziyan Yin]], [[William T. Shearer]], [[Thomas Fleisher]], [[Rebecca H. Buckley]] & [[Christopher C. Dvorak]]
| title = Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study
| journal = [[Blood]]
| volume = 130
| issue = 25
| pages = 2718–2727
| year = 2017
| month = December
| doi = 10.1182/blood-2017-05-781849
| pmid = 29021228
}}</ref>


==Diagnosis==
==Diagnosis==
===Diagnostic Criteria===
===Diagnostic Criteria===
The diagnosis of adenosine deaminase deficiency is made by finding lymphopenia, with low numbers of CD3+ and CD4+ cells, poor in vitro lymphocyte mitogenic and antigenic responses, and absent mixed lymphocyte reactions (MLRs).
* The diagnosis of adenosine deaminase deficiency is made by following finding:<ref>{{Cite journal
| author = [[Capucine Picard]], [[Waleed Al-Herz]], [[Aziz Bousfiha]], [[Jean-Laurent Casanova]], [[Talal Chatila]], [[Mary Ellen Conley]], [[Charlotte Cunningham-Rundles]], [[Amos Etzioni]], [[Steven M. Holland]], [[Christoph Klein]], [[Shigeaki Nonoyama]], [[Hans D. Ochs]], [[Eric Oksenhendler]], [[Jennifer M. Puck]], [[Kathleen E. Sullivan]], [[Mimi L. K. Tang]], [[Jose Luis Franco]] & [[H. Bobby Gaspar]]
| title = Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015
| journal = [[Journal of clinical immunology]]
| volume = 35
| issue = 8
| pages = 696–726
| year = 2015
| month = November
| doi = 10.1007/s10875-015-0201-1
| pmid = 26482257
}}</ref>
 
** [[Lymphocytopenia|Lymphopenia]], with low numbers of [[CD3 (immunology)|CD3+]] and [[CD4|CD4+]] cells
** Poor in vitro [[lymphocyte]] [[Mitogen|mitogenic]] and [[Antigen|antigenic]] responses
** Absent mixed lymphocyte reactions (MLRs)


===History and Symptoms===
===History and Symptoms===
The hallmark of findings among patients affected with adenosine deaminase (ADA) deficiency with severe combined immunodeficiency SCID phenotype are life-threatening infections, chronic persistent diarrhea, and failure to thrive in the first months of life. Some neonates may present with prolonged hyperbilirubinemia and hepatitis
* The hallmark of findings among patients affected with adenosine deaminase (ADA) deficiency with [[severe combined immunodeficiency]] [[phenotype]] are:
* Life-threatening [[Infection|infections]]
* [[Chronic diarrhea|Chronic persistent diarrhea]]
* [[Failure to thrive]] in the first months of life
* Recurrent [[Skin and soft-tissue infections|skin abscesses]] and/or other severe skin infections
* Some neonates may present with prolonged [[Jaundice|hyperbilirubinemia]] and [[hepatitis]].<ref>{{Cite journal
| author = [[M. E. Bollinger]], [[F. X. Arredondo-Vega]], [[I. Santisteban]], [[K. Schwarz]], [[M. S. Hershfield]] & [[H. M. Lederman]]
| title = Brief report: hepatic dysfunction as a complication of adenosine deaminase deficiency
| journal = [[The New England journal of medicine]]
| volume = 334
| issue = 21
| pages = 1367–1371
| year = 1996
| month = May
| doi = 10.1056/NEJM199605233342104
| pmid = 8614422
}}</ref>


===Physical Examination===
===Physical Examination===
Physical findings are multisystemic. The patient may present with the following:
Physical findings are multisystemic. The patient may present with the following:<ref>{{Cite journal
* Fever
  | author = [[Magda Carneiro-Sampaio]], [[Cristina Miuki Abe Jacob]] & [[Clea Rodrigues Leone]]
* Failure to thrive
  | title = A proposal of warning signs for primary immunodeficiencies in the first year of life
* Dehydration due to chronic diarrhea
  | journal = [[Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology]]
* Acute otitis media
  | volume = 22
* Absent lymphatic tissue
  | issue = 3
* Extensive candidiasis in the mouth and diaper area
  | pages = 345–346
* Recurrent skin abscesses and/or other severe skin infections
  | year = 2011
* Neurologic abnormalities include cognitive deficits, behavioral problems, gait abnormalities, hypo- and hypertonia, and sensorineural hearing loss are prominent in ADA deficiency.<ref>{{Cite journal
  | month = May
  | author = [[Manfred Honig]], [[Michael H. Albert]], [[Ansgar Schulz]], [[Monika Sparber-Sauer]], [[Catharina Schutz]], [[Bernd Belohradsky]], [[Tayfun Gungor]], [[Markus T. Rojewski]], [[Harald Bode]], [[Ulrich Pannicke]], [[Dominique Lippold]], [[Klaus Schwarz]], [[Klaus-Michael Debatin]], [[Michael S. Hershfield]] & [[Wilhelm Friedrich]]
  | doi = 10.1111/j.1399-3038.2010.01084.x
  | title = Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications
  | pmid = 21457340
  | journal = [[Blood]]
  | volume = 109
  | issue = 8
  | pages = 3595–3602
  | year = 2007
  | month = April
  | doi = 10.1182/blood-2006-07-034678
  | pmid = 17185467
}}</ref>
}}</ref>
* [[Fever]]
* [[Failure to thrive]]
* [[Dehydration]] due to [[chronic diarrhea]]
* [[Acute (medicine)|Acute]] [[otitis media]]
* Absent [[Lymphatic tissues|lymphatic tissue]]
* Signs of extensive [[candidiasis]] in the mouth and diaper area
* Recurrent [[Skin and soft-tissue infections|skin abscesses]] and/or other severe skin infections
* Neurologic abnormalities include
**[[Cognitive deficit|Cognitive deficits]]
**Behavioral problems
**[[Gait abnormality|Gait abnormalities]]
**[[Hypotonia|Hypo]]- and [[hypertonia]]
**[[Sensorineural hearing loss]]


===Laboratory Findings===
===Laboratory Findings===
The major diagnostic metabolic laboratory findings specific for ADA deficiency, which are also used to monitor treatment results, are the following:
Laboratory findings consistent with the diagnosis of ADA deficiency include :<ref>{{Cite journal
* Absent ADA levels in lysed erythrocytes
| author = [[J. Donofrio]], [[M. S. Coleman]], [[J. J. Hutton]], [[A. Daoud]], [[B. Lampkin]] & [[J. Dyminski]]
* A marked increase in deoxyadenosine triphosphate (dATP) levels in erythrocyte lysates (with levels that vary by laboratory)
| title = Overproduction of adenine deoxynucleosides and deoxynucletides in adenosine deaminase deficiency with severe combined immunodeficiency disease
* A significant decrease in ATP concentration in red blood cells
| journal = [[The Journal of clinical investigation]]
* Absent or extremely low levels of N adenosylhomocysteine hydrolase in red blood cells
| volume = 62
* Increase in 2'-deoxyadenosine in urine and plasma
| issue = 4
| pages = 884–887
| year = 1978
| month = October
| doi = 10.1172/JCI109201
| pmid = 308954
}}</ref>
* Absent ADA levels in lysed [[Red blood cell|erythrocytes]]
* A significant decrease in [[Adenosine triphosphate|ATP]] concentration in [[Red blood cell|red blood cells]]
* Absent or extremely low levels of N [[Adenosylhomocysteine nucleosidase|adenosylhomocysteine]] hydrolase in red blood cells
* A marked increase in [[deoxyadenosine triphosphate]] ([[Deoxyadenosine triphosphate|dATP]]) levels in erythrocyte lysates
* Increase in 2'-deoxyadenosine in [[urine]] and [[Blood plasma|plasma]]


===Imaging Findings===
===Imaging Findings===
A chest x-ray may be helpful in the diagnosis of adenosine deaminase deficiency . The thymic shadow is absent on chest radiography among the majority of patients with adenosine deaminase deficiency, thus, a chest x-ray may be helpful in the newborn suspected of adenosine deaminase deficiency. chest x-ray reveals the flaring of the anterior ribs, pelvic dysplasia, and shortening of the transverse vertebral processes with flattening of their ends and thick growth arrest lines. In addition, obtaining a chest x-ray may be helpful to assess pneumonia secondary to adenosine deaminase deficiency.
* A [[Chest X-ray|chest x-ray]] may be helpful in the diagnosis of adenosine deaminase deficiency. The thymic shadow is absent on chest radiography among the majority of patients with adenosine deaminase deficiency, thus, a chest x-ray may be helpful in the newborn suspected of adenosine deaminase deficiency.  
 
* Chest x-ray reveals the flaring of the anterior [[Rib|ribs]], pelvic dysplasia, and shortening of the transverse vertebral processes with flattening of their ends and thick growth arrest lines. In addition, obtaining a chest x-ray may be helpful to assess [[pneumonia]] secondary to adenosine deaminase deficiency.<ref>{{Cite journal
===Other Diagnostic Studies===
| author = [[Kathryn V. Whitmore]] & [[Hubert B. Gaspar]]
| title = Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency
| journal = [[Frontiers in immunology]]
| volume = 7
| pages = 314
| year = 2016
| month =  
| doi = 10.3389/fimmu.2016.00314
| pmid = 27579027
}}</ref>


==Treatment==
==Treatment==
===Medical Therapy===
===Medical Therapy===
The mainstay of treatment for adenosine deaminase (ADA) deficiency with severe combined immunodeficiency SCID phenotype is hematopoietic cell transplantation (HCT) from a human leukocyte antigen (HLA)-identical sibling, or if not available, a matched family donor. If a matched sibling or family donor is not an option, then we suggest gene therapy, if available and not cost prohibitive, for an infant or young child with ADA-deficient SCID. The majority of cases of adenosine deaminase deficiency require enzyme replacement therapy (polyethylene glycol-adenosine deaminase [PEG-ADA]).
* The mainstay of treatment for adenosine deaminase (ADA) deficiency with [[severe combined immunodeficiency]] [[phenotype]] is [[Hematopoietic cell|hematopoietic cell transplantation]](HCT) from a [[human leukocyte antigen]] ([[Human leukocyte antigen|HLA]])-identical sibling, or if not available, a matched family donor.
* If a matched sibling or family donor is not an option, then [[gene therapy]] is suggested, if available and not cost prohibitive, for an infant or young child with ADA-deficient SCID.  
* The majority of cases of adenosine deaminase deficiency require enzyme replacement therapy with polyethylene glycol-adenosine deaminase [PEG-ADA].<ref>{{Cite journal
| author = [[H. Bobby Gaspar]]
| title = Bone marrow transplantation and alternatives for adenosine deaminase deficiency
| journal = [[Immunology and allergy clinics of North America]]
| volume = 30
| issue = 2
| pages = 221–236
| year = 2010
| month = May
| doi = 10.1016/j.iac.2010.01.002
| pmid = 20493398
}}</ref>


===Primary Prevention===
===Primary Prevention===
There are no established measures for the primary prevention of  
* There are no established measures for the primary prevention of adenosine deaminase deficiency.


=== '''Secondary Prevention''' ===
=== '''Secondary Prevention''' ===
Effective measures for the secondary prevention of  adenosine deaminase deficiency include:
Effective measures for the secondary prevention of  adenosine deaminase deficiency include:<ref>{{Cite journal
| author = [[Linda M. Griffith]], [[Morton J. Cowan]], [[Luigi D. Notarangelo]], [[Jennifer M. Puck]], [[Rebecca H. Buckley]], [[Fabio Candotti]], [[Mary Ellen Conley]], [[Thomas A. Fleisher]], [[H. Bobby Gaspar]], [[Donald B. Kohn]], [[Hans D. Ochs]], [[Richard J. O'Reilly]], [[J. Douglas Rizzo]], [[Chaim M. Roifman]], [[Trudy N. Small]] & [[William T. Shearer]]
| title = Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management
| journal = [[The Journal of allergy and clinical immunology]]
| volume = 124
| issue = 6
| pages = 1152–1160
| year = 2009
| month = December
| doi = 10.1016/j.jaci.2009.10.022
| pmid = 20004776
}}</ref>
* Mothers with a history of a prior affected child with SCID should receive recommended booster [[Vaccine|vaccines]] prior to [[Childbirth|delivery]] to provide [[transplacental]] [[antibodies]]
* Mothers with a history of a prior affected child with SCID should receive recommended booster [[Vaccine|vaccines]] prior to [[Childbirth|delivery]] to provide [[transplacental]] [[antibodies]]
* Protective [[Isolation (health care)|isolation]] for neonates with suspected SCID before receiving definitive treatment
* Protective [[Isolation (health care)|isolation]] for neonates with suspected SCID before receiving definitive treatment
Line 126: Line 351:
* Antiviral agent for prophylaxis against [[Herpes simplex virus|HSV]], [[Cytomegalovirus infection|CMV]], [[Epstein Barr virus|EBV]]
* Antiviral agent for prophylaxis against [[Herpes simplex virus|HSV]], [[Cytomegalovirus infection|CMV]], [[Epstein Barr virus|EBV]]


==External links==
==References==
* Gene Therapy: A Brief History: [http://www.family.org/cforum/fosi/bioethics/genetics/a0032608.cfm]
{{Reflist|2}}
 
{{Immune disorders}}
 
[[Category:Hematology]]
 
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Latest revision as of 00:03, 29 January 2019

Adenosine deaminase deficiency
ICD-10 D81.3
ICD-9 279.2
OMIM 102700
DiseasesDB 260

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2];Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

Synonyms and Keywords: ADA Deficiency; SCID Due to ADA Deficiency; ADA-SCID

Overview

Adenosine deaminase deficiency, or ADA deficiency, is an inherited immunodeficiency syndrome accounting for about 15% of all cases of severe combined immunodeficiency (SCID). This disease is due to a lack of the enzyme adenosine deaminase coded for by a gene on chromosome 20. There is an accumulation of dATP, which causes an increase in S-adenosylhomocysteine; both substances are toxic to immature lymphoid cells, so fail to reach maturity. As a result, the immune system of the afflicted person is severely compromised or completely lacking. The enzyme adenosine deaminase is important for purine metabolism.

Historical Perspective

  • Adenosine deaminase (ADA) deficiency was first discovered by Dr. Eloise Giblett in 1972, when she received samples from a patient with severe combined immunodeficiency (SCID) that was a candidate for bone marrow transplantation; examination of blood samples presented that the patients have no ADA activity.
  • With discovering the second case with ADA deficiency and immunodeficiency, ADA deficiency was the first immunodeficiency in which the specific molecular defect was described.[1]

Classification

  • There is no established system for the classification of adenosine deaminase deficiency.

Pathophysiology

Causes

  • Adenosine deaminase deficiency is a disorder arising from a mutation in the ADA1 gene at 20q13.11.

Differentiating Adenosine deaminase deficiency from Other Diseases

  • Adenosine deaminase deficiency must be differentiated from other diseases that cause clinical features of severe combined immunodeficiency , and complete DiGeorge syndrome. Although DiGeorge syndrome is associated with facial and cardiac anomalies which are not seen with ADA deficiency.[5]

Epidemiology and Demographics

Risk Factors

  • There are no established risk factors for adenosine deaminase deficiency.

Screening

  • ADA deficiency can be diagnosed in a newborn before the beginning of infections, with one well-documented example by screening of T-cell–receptor excision circles(TRECs).TRECs, formed during the differentiation of T cells in the thymus.
  • A quantitative real-time polymerase chain reaction(PCR) test can measure T cell receptor excision circles. TRECs serve as a biomarker of naïve T cells, which is a sensitive and specific, as well as cost effective method for ADA deficiency newborn screening.[8]

Natural History, Complications, and Prognosis

Natural History

Complications

  • Patients are at risk for opportunistic infections usually follow more common infections. P. jiroveci and fungal pneumonias cause death in classic cases.
  • CMV, VZV, and HSV infections typically occur in infants who have already had treatable infections. Neurologic compromise from polio and other enteroviruses impede stem cell reconstitution.[12]
  • Lymphoma is an invariably fatal complication that occurs among patients with a later onset and in patients treated successfully with enzyme replacement therapy.[13]

Prognosis

  • ADA deficiency is fatal, generally within the first year of life, unless the underlying defect is corrected.
  • Early diagnosis through population-wide newborn screening and early transplantation in the absence of infectious complications may improve hematopoietic cell transplantation (HCT) outcomes.
  • Among patients transplanted under 3.5 months of age without infection, survival post-transplant is about 95 percent, and overall survival is 90 percent.[14]

Diagnosis

Diagnostic Criteria

  • The diagnosis of adenosine deaminase deficiency is made by following finding:[15]

History and Symptoms

Physical Examination

Physical findings are multisystemic. The patient may present with the following:[17]

Laboratory Findings

Laboratory findings consistent with the diagnosis of ADA deficiency include :[18]

Imaging Findings

  • A chest x-ray may be helpful in the diagnosis of adenosine deaminase deficiency. The thymic shadow is absent on chest radiography among the majority of patients with adenosine deaminase deficiency, thus, a chest x-ray may be helpful in the newborn suspected of adenosine deaminase deficiency.
  • Chest x-ray reveals the flaring of the anterior ribs, pelvic dysplasia, and shortening of the transverse vertebral processes with flattening of their ends and thick growth arrest lines. In addition, obtaining a chest x-ray may be helpful to assess pneumonia secondary to adenosine deaminase deficiency.[19]

Treatment

Medical Therapy

  • The mainstay of treatment for adenosine deaminase (ADA) deficiency with severe combined immunodeficiency phenotype is hematopoietic cell transplantation(HCT) from a human leukocyte antigen (HLA)-identical sibling, or if not available, a matched family donor.
  • If a matched sibling or family donor is not an option, then gene therapy is suggested, if available and not cost prohibitive, for an infant or young child with ADA-deficient SCID.
  • The majority of cases of adenosine deaminase deficiency require enzyme replacement therapy with polyethylene glycol-adenosine deaminase [PEG-ADA].[20]

Primary Prevention

  • There are no established measures for the primary prevention of adenosine deaminase deficiency.

Secondary Prevention

Effective measures for the secondary prevention of adenosine deaminase deficiency include:[21]

Typical prophylaxis against infection includes:

References

  1. Motulsky A, Gartler S. "Biographical Memoirs: Eloise R. Giblett". National Academy of Sciences
  2. D. A. Wiginton, G. S. Adrian, R. L. Friedman, D. P. Suttle & J. J. Hutton (1983). "Cloning of cDNA sequences of human adenosine deaminase". Proceedings of the National Academy of Sciences of the United States of America. 80 (24): 7481–7485. PMID 6200875. Unknown parameter |month= ignored (help)
  3. M. S. Hershfield, N. M. Kredich, D. R. Ownby, H. Ownby & R. Buckley (1979). "In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine in adenosine deaminase-deficient patients". The Journal of clinical investigation. 63 (4): 807–811. doi:10.1172/JCI109367. PMID 312296. Unknown parameter |month= ignored (help)
  4. R. H. Buckley, R. I. Schiff, S. E. Schiff, M. L. Markert, L. W. Williams, T. O. Harville, J. L. Roberts & J. M. Puck (1997). "Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants". The Journal of pediatrics. 130 (3): 378–387. PMID 9063412. Unknown parameter |month= ignored (help)
  5. Fausto Cossu (2010). "Genetics of SCID". Italian journal of pediatrics. 36: 76. doi:10.1186/1824-7288-36-76. PMID 21078154. Unknown parameter |month= ignored (help)
  6. R. H. Buckley, R. I. Schiff, S. E. Schiff, M. L. Markert, L. W. Williams, T. O. Harville, J. L. Roberts & J. M. Puck (1997). "Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants". The Journal of pediatrics. 130 (3): 378–387. PMID 9063412. Unknown parameter |month= ignored (help)
  7. Kee Chan & Jennifer M. Puck (2005). "Development of population-based newborn screening for severe combined immunodeficiency". The Journal of allergy and clinical immunology. 115 (2): 391–398. doi:10.1016/j.jaci.2004.10.012. PMID 15696101. Unknown parameter |month= ignored (help)
  8. John M. Routes, William J. Grossman, James Verbsky, Ronald H. Laessig, Gary L. Hoffman, Charles D. Brokopp & Mei W. Baker (2009). "Statewide newborn screening for severe T-cell lymphopenia". JAMA. 302 (22): 2465–2470. doi:10.1001/jama.2009.1806. PMID 19996402. Unknown parameter |month= ignored (help)
  9. Jennifer M. Puck (2011). "Neonatal screening for severe combined immunodeficiency". Current opinion in pediatrics. 23 (6): 667–673. doi:10.1097/MOP.0b013e32834cb9b0. PMID 22001765. Unknown parameter |month= ignored (help)
  10. Kathryn V. Whitmore & Hubert B. Gaspar (2016). "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency". Frontiers in immunology. 7: 314. doi:10.3389/fimmu.2016.00314. PMID 27579027.
  11. A. Fischer (2000). "Severe combined immunodeficiencies (SCID)". Clinical and experimental immunology. 122 (2): 143–149. PMID 11091267. Unknown parameter |month= ignored (help)
  12. G. Morgan, R. J. Levinsky, K. Hugh-Jones, L. D. Fairbanks, G. S. Morris & H. A. Simmonds (1987). "Heterogeneity of biochemical, clinical and immunological parameters in severe combined immunodeficiency due to adenosine deaminase deficiency". Clinical and experimental immunology. 70 (3): 491–499. PMID 3436096. Unknown parameter |month= ignored (help)
  13. Maitham Husain, Eyal Grunebaum, Ahmed Naqvi, Adelle Atkinson, Bo-Yee Ngan, Alessandro Aiuti & Chaim M. Roifman (2007). "Burkitt's lymphoma in a patient with adenosine deaminase deficiency-severe combined immunodeficiency treated with polyethylene glycol-adenosine deaminase". The Journal of pediatrics. 151 (1): 93–95. doi:10.1016/j.jpeds.2007.03.059. PMID 17586199. Unknown parameter |month= ignored (help)
  14. Jennifer Heimall, Brent R. Logan, Morton J. Cowan, Luigi D. Notarangelo, Linda M. Griffith, Jennifer M. Puck, Donald B. Kohn, Michael A. Pulsipher, Suhag Parikh, Caridad Martinez, Neena Kapoor, Richard O'Reilly, Michael Boyer, Sung-Yun Pai, Frederick Goldman, Lauri Burroughs, Sharat Chandra, Morris Kletzel, Monica Thakar, James Connelly, Geoff Cuvelier, Blachy J. Davila Saldana, Evan Shereck, Alan Knutsen, Kathleen E. Sullivan, Kenneth DeSantes, Alfred Gillio, Elie Haddad, Aleksandra Petrovic, Troy Quigg, Angela R. Smith, Elizabeth Stenger, Ziyan Yin, William T. Shearer, Thomas Fleisher, Rebecca H. Buckley & Christopher C. Dvorak (2017). "Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study". Blood. 130 (25): 2718–2727. doi:10.1182/blood-2017-05-781849. PMID 29021228. Unknown parameter |month= ignored (help)
  15. Capucine Picard, Waleed Al-Herz, Aziz Bousfiha, Jean-Laurent Casanova, Talal Chatila, Mary Ellen Conley, Charlotte Cunningham-Rundles, Amos Etzioni, Steven M. Holland, Christoph Klein, Shigeaki Nonoyama, Hans D. Ochs, Eric Oksenhendler, Jennifer M. Puck, Kathleen E. Sullivan, Mimi L. K. Tang, Jose Luis Franco & H. Bobby Gaspar (2015). "Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015". Journal of clinical immunology. 35 (8): 696–726. doi:10.1007/s10875-015-0201-1. PMID 26482257. Unknown parameter |month= ignored (help)
  16. M. E. Bollinger, F. X. Arredondo-Vega, I. Santisteban, K. Schwarz, M. S. Hershfield & H. M. Lederman (1996). "Brief report: hepatic dysfunction as a complication of adenosine deaminase deficiency". The New England journal of medicine. 334 (21): 1367–1371. doi:10.1056/NEJM199605233342104. PMID 8614422. Unknown parameter |month= ignored (help)
  17. Magda Carneiro-Sampaio, Cristina Miuki Abe Jacob & Clea Rodrigues Leone (2011). "A proposal of warning signs for primary immunodeficiencies in the first year of life". Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 22 (3): 345–346. doi:10.1111/j.1399-3038.2010.01084.x. PMID 21457340. Unknown parameter |month= ignored (help)
  18. J. Donofrio, M. S. Coleman, J. J. Hutton, A. Daoud, B. Lampkin & J. Dyminski (1978). "Overproduction of adenine deoxynucleosides and deoxynucletides in adenosine deaminase deficiency with severe combined immunodeficiency disease". The Journal of clinical investigation. 62 (4): 884–887. doi:10.1172/JCI109201. PMID 308954. Unknown parameter |month= ignored (help)
  19. Kathryn V. Whitmore & Hubert B. Gaspar (2016). "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency". Frontiers in immunology. 7: 314. doi:10.3389/fimmu.2016.00314. PMID 27579027.
  20. H. Bobby Gaspar (2010). "Bone marrow transplantation and alternatives for adenosine deaminase deficiency". Immunology and allergy clinics of North America. 30 (2): 221–236. doi:10.1016/j.iac.2010.01.002. PMID 20493398. Unknown parameter |month= ignored (help)
  21. Linda M. Griffith, Morton J. Cowan, Luigi D. Notarangelo, Jennifer M. Puck, Rebecca H. Buckley, Fabio Candotti, Mary Ellen Conley, Thomas A. Fleisher, H. Bobby Gaspar, Donald B. Kohn, Hans D. Ochs, Richard J. O'Reilly, J. Douglas Rizzo, Chaim M. Roifman, Trudy N. Small & William T. Shearer (2009). "Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management". The Journal of allergy and clinical immunology. 124 (6): 1152–1160. doi:10.1016/j.jaci.2009.10.022. PMID 20004776. Unknown parameter |month= ignored (help)

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