Complement, Inborn Errors, Lymphoid and compliment disorders causing immunodeficiency, Seeing Red, Who's Who
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Adenosine deaminase deficiency (ADA deficiency) was discovered in 1972 and recognized as the first immunodeficiency disorder

Adenosine deaminase deficiency (ADA deficiency) is a metabolic disorder that causes immunodeficiency. It is caused by mutations in the ADA gene. It accounts for about 10–15% of all cases of autosomal recessive forms of severe combined immunodeficiency (SCID) among non-inbred populations.

ADA deficiency can present in infancy, childhood, adolescence, or adulthood. Age of onset and severity is related to some 29 known genotypes associated with the disorder.

It occurs in fewer than one in 100,000 live births worldwide.

Signs and symptoms

The main symptoms of ADA deficiency are pneumonia, chronic diarrhea, and widespread skin rashes. Affected children also grow much more slowly than healthy children and some have developmental delay. Most individuals with ADA deficiency are diagnosed with SCID in the first 6 months of life.[citation needed]

An association with polyarteritis nodosa has been reported.

  • Liebowitz J, Hellmann DB1, Schnappauf O (2019) Thirty years of followup in 3 patients with familial polyarteritis nodosa due to adenosine deaminase 2 deficiency. J Rheumatol

Genetics

The enzyme adenosine deaminase is encoded by the ADA gene on chromosome 20.

ADA deficiency is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome (chromosome 20 is an autosome), and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.[citation needed]

Age of onset and severity is related to some 29 known genotypes associated with the disorder.

Pathophysiology

ADA deficiency is due to a lack of the enzyme adenosine deaminase. This deficiency results in an accumulation of deoxyadenosine, which, in turn, leads to:

Because T cells undergo proliferation and development in the thymus, affected individuals typically have a small, underdeveloped thymus. As a result, the immune system is severely compromised or completely lacking.

  • p347, The Immune System Peter Parham, Garland Science, London and New York, 2009

Diagnosis

The diagnosis is based on clinical features, with a concomitant decreased blood adenosine deaminase level supporting the diagnosis.[citation needed]

Treatment

Treatments include:

  • Booth Claire; Hershfield Mike; Notarangelo Luigi; Buckley Rebecca; Hoenig Manfred; Mahlaoui Nizar; Cavazzana-Calvo Marina; Aiuti Alessandro; Gaspar H. Bobby (2007). “Management options for adenosine deaminase deficiency; proceedings of the EBMT satellite workshop (Hamburg, March 2006)”. Clinical Immunology. 123 (2): 139–147. doi:10.1016/j.clim.2006.12.009. PMID 17300989.

Gene therapy

In September 1990, the first gene therapy to combat this disease was performed by Dr. William French Anderson on a four-year-old girl, Ashanti DeSilva, at the National Institutes of Health, Bethesda, Maryland, U.S.A.

In April 2016 the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed and recommended for approval a stem cell gene therapy called Strimvelis, for children with ADA-SCID for whom no matching bone marrow donor is available.

History

ADA deficiency was discovered in 1972 by Eloise Giblett, a professor at the University of Washington. The ADA gene was used as a marker for bone marrow transplants. A lack of ADA activity was discovered by Giblett in an immunocompromised transplant candidate. After discovering a second case of ADA deficiency in an immunocompromised patient, ADA deficiency was recognized as the first immunodeficiency disorder.

  • Motulsky A, Gartler S. “Biographical Memoirs: Eloise R. Giblett”. National Academy of Sciences.

Eloise Giblett

Eloise “Elo” R. Giblett (January 17, 1921 – September 16, 2009) was a pioneering genetic scientist and hematologist who discovered the first recognized immunodeficiency disease, adenosine deaminase deficiency.

Giblett was a Professor of Medicine at the University of Washington in Seattle and Executive Director of the Puget Sound Blood Center in Seattle.

The author of over 200 research papers, she also wrote an esteemed textbook on genetic markers, Genetic Markers in Human Blood, published in 1969. She was elected to the National Academy of Sciences in 1980.

Giblett’s numerous accomplishments include discovering the first immunodeficiency disease: adenosine deaminase deficiency. She identified and characterized numerous blood group antigens (including the ‘Elo’ antigen, named after her). Her work paved the way for safe red blood cell transfusions. She also applied her understanding of red blood cell protein polymorphisms to genetic linkage analyses, was senior author on the paper that demonstrated the feasibility of unrelated marrow transplantation for leukemia, and was an early supporter of bone marrow donation.

Giblett graduated from Lewis and Clark High School in 1938. She was only 16 when she earned a scholarship to Mills College in Oakland, California. After two years, she transferred to the University of Washington in Seattle where she earned a degree in bacteriology (now microbiology) in 1942. From 1944 to 1946, she served in the Navy WAVES. Through this program, she worked as a technician at the clinical laboratory of the U.S. Naval Hospital in San Diego, California. In 1947, she returned to the University of Washington to earn her Master of Science in microbiology. Her master’s thesis focused on physiology of fungi in the genus Microsporum.

After completing her master’s degree, Giblett attended the University of Washington Medical School. One of five women in her year, she graduated first in her class in 1951. From 1951 to 1953, Giblett served as an intern, then resident in Internal Medicine, at King County Hospital (now Harborview Hospital).

Early career

In 1953, Giblett was awarded a two year fellowship for post-doctoral research in hematology. During this time, Giblett worked under Clement Finch, a renowned hematologist interested in iron metabolism. Giblett primarily assisted with his research on erythrokinetics, the dynamic study of the production and destruction of red blood cells.

  • Counts, Richard B. (April 2010). “Eloise R. Giblett: 1921-2009”. Transfusion. 50 (4): 952–954. doi:10.1111/j.1537-2995.2010.02594.x.
  • Dorland’s Medical Dictionary for Health Consumers. © 2007 by Saunders, an imprint of Elsevier, Inc. All rights reserved.

In her first year working for Finch, Giblett published five papers, including a highly-cited paper describing red blood cell lifetime and hemolysis.

Giblett also worked with geneticist Arno Motulsky studying erythrokinetics in splenomegaly, kicking off a decades-long collaboration.

After completing her fellowship, Giblett traveled to London to train under Patrick Mollison at the Medical Research Council’s Blood Transfusion Research Unit. In this research unit, Giblett gained the laboratory experience necessary to co-direct Puget Sound Blood Center (then King County Blood Bank), a position she assumed upon her return to Seattle in 1955.

  • Motulsky A, Gartler S. “Biographical Memoirs: Eloise R. Giblett”. National Academy of Sciences.

Giblett remained at the Blood Center as Associate Director until her promotion to Executive Director in 1979. She retired in 1987.

Scientific discoveries

Giblett focused the majority of her career on academic research. In 1955, she was appointed Clinical Associate in Medicine at the University of Washington. Giblett’s lab focused on studying blood groups, with particular attention to genetic markers in human blood. She identified several blood group antigens. Her research assisted in refuting the standard practice at the time of segregating blood donations based on the race of the donor.

In 1958, Giblett began research studying polymorphisms of the human plasma proteins haptoglobin and transferrin using starch gel electrophoresis.

As a result of her studies on genetic variation, Giblett documented the first case of a mosaic individual conceived from dispermic fertilization of two eggs followed by cell fusion.

Giblett actively collaborated with Arno Motulsky, a fellow professor at the University of Washington. Giblett analyzed blood samples from a population study Motulsky carried out in the Congo in 1960. The resulting paper, published in 1966, described many novel genetic variants.

Decades later, scientists discovered that one of these samples contained first known case of HIV. The viral sequence from this sample is still used to date in studies of HIV.

  • Motulsky A, Gartler S. “Biographical Memoirs: Eloise R. Giblett”. National Academy of Sciences.

Starting in 1971, Giblett began researching bone marrow transplants with E. Donnall Thomas.

  • Motulsky A, Gartler S. “Biographical Memoirs: Eloise R. Giblett”. National Academy of Sciences.

Bone marrow transplantations were a pioneering technique used to treat blood cancers. At the time, if the donor and acceptor were the same sex, doctors could not confirm the success of the graft. Giblett assisted in discovering genetic markers that could confirm graft success, regardless of donor sex, using polymorphic blood proteins.

Giblett eventually expanded her research into the activity of polymorphic proteins in human plasma and blood cells, leading to her famous discovery of the first immunodeficiency disease. One polymorphic protein used as a routine a genetic marker for transplants was adenosine deaminase (ADA) located in red blood cells. In 1972, Giblett received samples from a patient with severe combined immunodeficiency disease (SCID). The patient was a candidate for bone marrow transplantation from her mother; analysis of blood samples surprisingly revealed that the child exhibited no ADA activity. Giblett soon discovered a second case where ADA deficiency underlaid immune dysfunction, leading her to conclude that the two may be related.

  • Motulsky A, Gartler S. “Biographical Memoirs: Eloise R. Giblett”. National Academy of Sciences.

Giblett named this disease adenosine deaminase immunodeficiency, and it was recognized as the first official immunodeficiency disease.

The discovery of ADA deficiency lead to a breakthrough in understanding immunodeficiency. Based on the function of ADA in purine metabolism, Giblett hypothesized that mutations in other proteins involved in purine metabolism or related pyrimidine metabolism might underlie additional forms of immune dysfunction. Her hypothesis was confirmed in 1975 upon analysis of an immunocompromised patient exhibiting normal ADA activity but defective purine nucleoside phosphorylase (PNP) activity.

  • Giblett ER, Ammann AJ, Wara DW, Sandman R, Diamond LK (May 1975). “Nucleoside-phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity”. Lancet. 1 (7914): 1010–3. doi:10.1016/s0140-6736(75)91950-9. PMID 48676. S2CID 21835540

Within several years, ten more cases of immune deficiency linked to PNP mutations were described, leading to the classification of the disorder as purine nucleoside phosphorylase deficiency.

  • Motulsky A, Gartler S. “Biographical Memoirs: Eloise R. Giblett”. National Academy of Sciences.

Giblett’s other notable discoveries include T cell immunodeficiency.

Throughout her career, Giblett collaborated with some of the most notable and talented scientists of her era, including: Oliver Smithies, Alexander Bearn, James Neel, Curt Stern, Victor McKusick, Ernest Beutler, Stanley Gartler, Walter Bodmer, John Cairns, David Weatherall, Henry Kunkel, H. Hugh Fudenberg, and Newton Morton.

AIDS crisis

In 1978, Giblett closed her research lab to direct the Puget Sound Blood Center. Soon after, in 1981, HIV/AIDS was discovered. Infectious disease experts at the time realized that the disorder might be transmissible by blood, creating complications for blood transfusions. This discovery led to a crisis in blood banking. Giblett attempted to allay fears about the hazard of giving blood and closely followed the incidence of the disease in previously transfused patients.

  •  Motulsky A, Gartler S. “Biographical Memoirs: Eloise R. Giblett”. National Academy of Sciences.

Before HIV could be detected in blood, Giblett developed a screening policy for blood donors at the center.

Honors

In 1967, Giblett was promoted to full professor at the University of Washington. Giblett served as president of the American Society of Human Genetics in 1973. She was a board member of the American Society of Hematology, the Western Association of Physicians and the New York Blood Center Research Advisory Committee. In 1980, Giblett was elected to the National Academy of Sciences. The following year, she became a fellow of the National Association for the Advancement of Science. In 1987, she was the first woman to receive the University of Washington Medical School Alumni Association’s Distinguished Alumni Award.

Upon her retirement, she was awarded emeritus status at the University of Washington School of Medicine and Puget Sound Blood Center.

Legacy

In 1969, Giblett published Genetic Markers in Human Blood, a reference book aimed to increase the accessibility of information about biochemical variation in blood. The book was described by H. E. Sutton as “a remarkable achievement for a single individual.”

  • Motulsky A, Gartler S. “Biographical Memoirs: Eloise R. Giblett”. National Academy of Sciences.

Giblett was a fan of science fiction literature. She is mentioned by name in Robert Heinlein’s novel The Number of the Beast.

In 2010, the Elo Giblett Endowed Professorship in Hematology was established at the University of Washington.

References

  1. Flinn AM, Gennery AR (2018). “Adenosine deaminase deficiency: a review”. Orphanet Journal of Rare Diseases. 13 (1): 65. doi:10.1186/s13023-018-0807-5. PMC 5916829. PMID 29690908.
  2. Arredondo-Vega FX, Santisteban I, Daniels S, Toutain S, Hershfield MS (October 1998). “Adenosine deaminase deficiency: genotype–phenotype correlations based on expressed activity of 29 mutant alleles”. American Journal of Human Genetics. 63 (4): 1049–59. doi:10.1086/302054. PMC 1377486. PMID 9758612.
  3. Liebowitz J, Hellmann DB1, Schnappauf O (2019) Thirty years of followup in 3 patients with familial polyarteritis nodosa due to adenosine deaminase 2 deficiency. J Rheumatol
  4. Arredondo-Vega FX, Santisteban I, Daniels S, Toutain S, Hershfield MS (October 1998). “Adenosine deaminase deficiency: genotype–phenotype correlations based on expressed activity of 29 mutant alleles”. American Journal of Human Genetics. 63 (4): 1049–59. doi:10.1086/302054. PMC 1377486. PMID 9758612.
  5. “Adenosine Deaminase (ADA) Deficiency”. Archived from the original on 2008-02-12. Retrieved 2008-02-28.
  6. p347, The Immune System Peter Parham, Garland Science, London and New York, 2009
  7. Booth Claire; Hershfield Mike; Notarangelo Luigi; Buckley Rebecca; Hoenig Manfred; Mahlaoui Nizar; Cavazzana-Calvo Marina; Aiuti Alessandro; Gaspar H. Bobby (2007). “Management options for adenosine deaminase deficiency; proceedings of the EBMT satellite workshop (Hamburg, March 2006)”. Clinical Immunology. 123 (2): 139–147. doi:10.1016/j.clim.2006.12.009. PMID 17300989.
  8. Naam, Ramez (2005-07-03). “‘More Than Human’ – New York Times”. The New York Times. Retrieved 2008-02-28.
  9. House, Douglas W., (1 April 2016) European Ad Comm backs Glaxo’s stem cell therapy Strimvelis for rare autoimmune disorder, Seeking Alpha, Retrieved 13 April 2016
  10. “Summary of opinion1 (initial authorisation) Strimvelis” (PDF). European Medicines Agency. 1 April 2016. pp. 1–2. Retrieved 13 April 2016.
  11. Motulsky A, Gartler S. “Biographical Memoirs: Eloise R. Giblett”. National Academy of Sciences.
  12. Glaser V (23 September 2009). “Eloise R. Giblett, Blood Research Leader, Dies at 88”. New York Times.
  13. “Eloise Giblett: The Rock of Puget Sound Blood Center”. January 2010.
  14. Spokane Public Library (1936). SPL Yearbooks Lewis And Clark 1936 June.
  15. Counts, Richard B. (April 2010). “Eloise R. Giblett: 1921-2009”. Transfusion. 50 (4): 952–954. doi:10.1111/j.1537-2995.2010.02594.x.
  16. Harding A (2010). “Eloise R Giblett”. The Lancet. 375 (9709): 116. doi:10.1016/S0140-6736(10)60038-4. S2CID 54232275.
  17. Giblett ER, Henry BS (May 1950). “Physiological studies on the genus Microsporum”. The Journal of Investigative Dermatology. 14 (5): 377–86. doi:10.1038/jid.1950.46. PMID 15422186.
  18. Advancement, UW Medicine. “Elo Giblett Endowed Professorship in Hematology – Chairs & Professorships | UW Medicine”. depts.washington.edu. Retrieved 2018-08-01.
  19. “UW Medicine | Passages”. depts.washington.edu. Retrieved 2018-08-01.
  20. Giblett ER, Ammann AJ, Wara DW, Sandman R, Diamond LK (May 1975). “Nucleoside-phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity”. Lancet. 1 (7914): 1010–3. doi:10.1016/s0140-6736(75)91950-9. PMID 48676. S2CID 21835540
  21. Akpa OM, Bamgboye EA, Baiyewu O (2015). “The Adolescents’ Psychosocial Functioning Inventory (APFI): scale development and initial validation using Exploratory and Confirmatory Factor Analysis”. African Journal for the Psychological Study of Social Issues. 18 (1): 1–21. PMC 4399859. PMID 25893221.
  22. Kenny MG (October 2006). “A question of blood, race, and politics”. Journal of the History of Medicine and Allied Sciences. 61 (4): 456–91. doi:10.1093/jhmas/jrl003. PMID 16788092.
  23. Giblett ER, Hickman CG, Smithies O (June 1959). “Serum transferrins”. Nature. 183 (4675): 1589–90. Bibcode:1959Natur.183.1589G.
  24.  “Eloise R. “Elo” Giblett”. The Seattle Times.
  25. Giblett ER, Gartler SM, Waxman SH (March 1963). “Blood group studies on the family of an XX/XY hermaphrodite with generalized tissue mosaicism”. American Journal of Human Genetics. 15 (1): 62–8. PMC 1932422. PMID 13947709.
  26. Giblett ER, Motusky AG, Fraser GR (November 1966). “Population genetic studies in the Congo. IV. Haptoglobin and transferrin serum groups in the Congo and in other African population.s”. American Journal of Human Genetics. 18 (6): 553–8. PMC 1706202. PMID 5927875.
  27. Dorland’s Medical Dictionary for Health Consumers. © 2007 by Saunders, an imprint of Elsevier, Inc. All rights reserved.
  28. Giblett ER, Coleman DH, Pirzio-Biroli G, Donohue DM, Motulsky AG, Finch CA (April 1956). “Erythrokinetics: quantitative measurements of red cell production and destruction in normal subjects and patients with anemia”. Blood. 11 (4): 291–309. doi:10.1182/blood.V11.4.291.291. PMID 13304119.

Further reading

External links

ClassificationDICD–10: D81.3ICD–9-CM: 279.2OMIM: 102700DiseasesDB: 260
External resourcesGeneReviews: Adenosine Deaminase Deficiency
Lymphoid and complement disorders causing immunodeficiency
Inborn error of purine–pyrimidine metabolism

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