Activated PI3K delta syndrome explained

Activated PI3K delta syndrome
Synonyms:	immunodeficiency 14, p110δ-activating mutation causing senescent T cells, PASLI
Symptoms:	Immunodeficiency, Lymphadenopathy
Causes:	Mutation in phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
Diagnosis:	Genetic testing
Treatment:	Antiviral therapy

Activated PI3K delta syndrome (APDS) is a primary immunodeficiency disease caused by activating gain of function mutations in the PIK3CD gene.^{[1] [2]}

Symptoms and signs

The signs and symptoms of activated PI3K Delta Syndrome are consistent with the following:^[3]

• Immunodeficiency
• Lymphadenopathy
• Sinopulmonary infections
• Bronchiectasis

Cause

In terms of genetics, activated PI3K Delta Syndrome is autosomal dominant, a mutation in phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform is the reason for this condition (located at chromosome 1p36.) ^{[4] [5]}

Mechanism

The pathophysiology of activated PI3K delta syndrome has several aspects.^[4] The normal function has P110δ (PI3K) involved in immune system regulation.^[6]

P110δ effect is not limited to the immune system; P110δ has a presence in transformed epithelial cells and cell adhesion molecules (airway inflammation), and research has been done on the possibility of P110δ in the nervous system.^[7]

Activated PI3K delta syndrome effect indicates affected individuals are likely to have activation-induced cell death.^[4] Normally, PI3K-delta signaling assists B cells and T cells to mature; however, overactive PI3K-delta has an effect on the B and T cell differentiation (the process by which cells eventually are different from one another^[8]).

Consequently, there is an inability to confront an infection, as well as early cell death. Furthermore, overproduction of said signal can cause lymphadenopathy (which is an enlargement of lymph nodes^[9]) due to excess white blood cells.^[1]

Diagnosis

In order to ascertain if an individual has activated PI3K delta syndrome, usually one finds atypical levels of immunoglobulins. Methods to determine the condition are the following:^[10]

• Genetic testing
• Laboratory findings
• Symptoms exhibited

Treatment

Infections for this condition, are treated or prevented in the following general ways:^{[11] [12]}

• Bacterial infection should be treated rapidly (with antibiotics)
• Antiviral therapy
• Modify lifestyle (exposure to pathogens need to be minimized)

Leniolisib (Joenja) was approved for medical use in the United States in March 2023.^{[13] [14] [15]} It is the first approved drug in the US for activated PI3K delta syndrome.

Further reading

• Arjunaraja S, Snow AL . Gain-of-function mutations and immunodeficiency: at a loss for proper tuning of lymphocyte signaling . Current Opinion in Allergy and Clinical Immunology . 15 . 6 . 533–538 . December 2015 . 26406182 . 4672729 . 10.1097/ACI.0000000000000217 .
• Okkenhaug K, Ali K, Vanhaesebroeck B . Antigen receptor signalling: a distinctive role for the p110delta isoform of PI3K . Trends in Immunology . 28 . 2 . 80–87 . February 2007 . 17208518 . 2358943 . 10.1016/j.it.2006.12.007 .

Notes and References

1. Web site: Activated PI3K-delta syndrome. MedlinePlus. 2017-06-09. 28 November 2022. https://web.archive.org/web/20221128142354/https://medlineplus.gov/genetics/condition/activated-pi3k-delta-syndrome/. live.
2. Book: Interstitial Lung Disease E-Book. Collard. Harold R.. Richeldi. Luca. 2017-02-18. Elsevier Health Sciences. 9. 9780323480253. 27 November 2021. 26 March 2023. https://web.archive.org/web/20230326201550/https://books.google.com/books?id=yvYoDgAAQBAJ&dq=Activated+PI3K+Delta+Syndrome+diagnosis&pg=PA9. live.
3. Web site: PASLI disease Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. rarediseases.info.nih.gov. 2017-06-09. 2 January 2018. https://web.archive.org/web/20180102013348/https://rarediseases.info.nih.gov/diseases/11983/index. live.
4. Web site: IMMUNODEFICIENCY 14A WITH LYMPHOPROLIFERATION, AUTOSOMAL DOMINANT; IMD14A. Online Mendelian Inheritance in Man (OMIM). 2017-06-10. 4 July 2017. https://web.archive.org/web/20170704121540/http://omim.org/entry/615513. live.
5. Web site: PIK3CD gene . MedlinePlus . 2017-06-10 . 31 May 2022 . https://web.archive.org/web/20220531213604/https://medlineplus.gov/genetics/gene/pik3cd/ . live .
6. Web site: PIK3CD phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [Homo sapiens (human)]]. National Library of Medicine. 2017-06-11. 6 November 2018. https://web.archive.org/web/20181106171922/https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=5293. live.
7. Book: Crossroads Between Innate and Adaptive Immunity V. Schoenberger. Stephen P.. Katsikis. Peter D.. Pulendran. Bali. 2015-08-31. Springer. 121. 9783319157740. 27 November 2021. 26 March 2023. https://web.archive.org/web/20230326201554/https://books.google.com/books?id=fFl4CgAAQBAJ&dq=P110%CE%B4&pg=PA121. live.
8. Book: Prasad, Keder N.. Regulation of Differentiation in Mammalian Nerve Cells. 2012-12-06. Springer Science & Business Media. 2. 9781468481129. 27 November 2021. 26 March 2023. https://web.archive.org/web/20230326201558/https://books.google.com/books?id=yXzdBwAAQBAJ&dq=differentiation+cells+definition&pg=PA2. live.
9. Book: Textbook of Pediatric Emergency Medicine. Fleisher. Gary R.. Ludwig. Stephen. 2010. Lippincott Williams & Wilkins. 378. 9781605471594. 27 November 2021. 26 March 2023. https://web.archive.org/web/20230326201612/https://books.google.com/books?id=a7CqcE1ZrFkC&dq=lymphadenopathy&pg=PA799. live.
10. Web site: PI3 Kinase Disease. National Institute of Allergy and Infectious Diseases. 2017-06-10. 28 June 2017. https://web.archive.org/web/20170628043131/https://www.niaid.nih.gov/diseases-conditions/pi3-kinase-disease. live.
11. Web site: Immunodeficiency (Primary and Secondary). Information.. patient.info. 2017-06-11. 21 December 2022. https://web.archive.org/web/20221221090119/https://patient.info/doctor/immunodeficiency-primary-and-secondary. live.
12. Web site: 2017-02-17. Bronchiectasis Treatment & Management: Approach Considerations, Supportive Treatment, Antibiotic Therapy. registration. 11 June 2017. 8 June 2017. https://web.archive.org/web/20170608193158/http://emedicine.medscape.com/article/296961-treatment#showall. live.
13. FDA approves first treatment for activated phosphoinositide 3-kinase delta syndrome . U.S. Food and Drug Administration (FDA) . 24 March 2023 . 24 March 2023 . 25 March 2023 . https://web.archive.org/web/20230325032644/https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-activated-phosphoinositide-3-kinase-delta-syndrome . live .
14. News: US FDA approves Pharming's immune disorder drug . 24 March 2023 . Reuters . 24 March 2023 . https://web.archive.org/web/20230324190543/https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-approves-pharmings-immune-disorder-drug-2023-03-24/ . live .
15. Pharming announces US FDA approval of Joenja (leniolisib) as the first and only treatment indicated for APDS . Pharming Group N.V. . 24 March 2023 . 25 March 2023 . 26 March 2023 . https://web.archive.org/web/20230326201459/https://www.pharming.com/sites/default/files/imce/Press%20releases/Leniolisib%20PDUFA%20Approval%20_EN_24MAR23.pdf . live .