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    Topic review

    IRAK-4 Deficiency

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    Submitted by: Camila Xu
    (This entry belongs to Entry Collection "MedlinePlus ")

    Definition

    IRAK-4 deficiency is an inherited disorder of the immune system (primary immunodeficiency). This immunodeficiency leads to recurrent infections by a subset of bacteria known as pyogenic bacteria but not by other infectious agents. (Infection with pyogenic bacteria causes the production of pus.)

    1. Introduction

    The most common infections in IRAK-4 deficiency are caused by the Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa bacteria. Most people with this condition have their first bacterial infection before age 2, and the infections can be life-threatening in infancy and childhood. Infections become less frequent with age.

    Most people with IRAK-4 deficiency have invasive bacterial infections, which can involve the blood (septicemia), the membrane covering the brain and spinal cord (meningitis), or the joints (leading to inflammation and arthritis). Invasive infections can also cause areas of tissue breakdown and pus production (abscesses) on internal organs. In addition, affected individuals can have localized infections of the upper respiratory tract, skin, or eyes. Although fever is a common reaction to bacterial infections, many people with IRAK-4 deficiency do not at first develop a high fever in response to these infections, even if the infection is severe.

    2. Frequency

    IRAK-4 deficiency is a very rare condition, although the exact prevalence is unknown. At least 49 individuals with this condition have been described in the scientific literature.

    3. Causes

    IRAK-4 deficiency is caused by mutations in the IRAK4 gene, which provides instructions for making a protein that plays an important role in stimulating the immune system to respond to infection. The IRAK-4 protein is part of a signaling pathway that is involved in early recognition of foreign invaders (pathogens) and the initiation of inflammation to fight infection. This signaling pathway is part of the innate immune response, which is the body's early, nonspecific response to pathogens.

    Mutations in the IRAK4 gene lead to the production of a nonfunctional protein or no protein at all. The loss of functional IRAK-4 protein prevents the immune system from triggering inflammation in response to pathogens that would normally help fight the infections. Because the early immune response is insufficient, bacterial infections occur often and become severe and invasive.

    4. Inheritance

    This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

    5. Other Names for This Condition

    • interleukin-1 receptor-associated kinase 4 deficiency

    • IRAK4 deficiency

    This entry is adapted from https://medlineplus.gov/genetics/condition/irak-4-deficiency

    References

    1. Ku CL, von Bernuth H, Picard C, Zhang SY, Chang HH, Yang K, Chrabieh M,Issekutz AC, Cunningham CK, Gallin J, Holland SM, Roifman C, Ehl S, Smart J, TangM, Barrat FJ, Levy O, McDonald D, Day-Good NK, Miller R, Takada H, Hara T,Al-Hajjar S, Al-Ghonaium A, Speert D, Sanlaville D, Li X, Geissmann F, Vivier E, Maródi L, Garty BZ, Chapel H, Rodriguez-Gallego C, Bossuyt X, Abel L, Puel A,Casanova JL. Selective predisposition to bacterial infections in IRAK-4-deficientchildren: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. JExp Med. 2007 Oct 1;204(10):2407-22.
    2. Maglione PJ, Simchoni N, Black S, Radigan L, Overbey JR, Bagiella E, BusselJB, Bossuyt X, Casanova JL, Meyts I, Cerutti A, Picard C, Cunningham-Rundles C.IRAK-4 and MyD88 deficiencies impair IgM responses against T-independentbacterial antigens. Blood. 2014 Dec 4;124(24):3561-71. doi:10.1182/blood-2014-07-587824.
    3. Medvedev AE, Lentschat A, Kuhns DB, Blanco JC, Salkowski C, Zhang S, Arditi M,Gallin JI, Vogel SN. Distinct mutations in IRAK-4 confer hyporesponsiveness tolipopolysaccharide and interleukin-1 in a patient with recurrent bacterialinfections. J Exp Med. 2003 Aug 18;198(4):521-31.
    4. Picard C, Casanova JL, Puel A. Infectious diseases in patients with IRAK-4,MyD88, NEMO, or IκBα deficiency. Clin Microbiol Rev. 2011 Jul;24(3):490-7. doi:10.1128/CMR.00001-11. Review.
    5. Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, Soudais C, Dupuis S, Feinberg J, Fieschi C, Elbim C, Hitchcock R, Lammas D, Davies G, Al-Ghonaium A,Al-Rayes H, Al-Jumaah S, Al-Hajjar S, Al-Mohsen IZ, Frayha HH, Rucker R, Hawn TR,Aderem A, Tufenkeji H, Haraguchi S, Day NK, Good RA, Gougerot-Pocidalo MA,Ozinsky A, Casanova JL. Pyogenic bacterial infections in humans with IRAK-4deficiency. Science. 2003 Mar 28;299(5615):2076-9.
    6. Picard C, von Bernuth H, Ghandil P, Chrabieh M, Levy O, Arkwright PD, McDonaldD, Geha RS, Takada H, Krause JC, Creech CB, Ku CL, Ehl S, Maródi L, Al-Muhsen S, Al-Hajjar S, Al-Ghonaium A, Day-Good NK, Holland SM, Gallin JI, Chapel H, Speert DP, Rodriguez-Gallego C, Colino E, Garty BZ, Roifman C, Hara T, Yoshikawa H,Nonoyama S, Domachowske J, Issekutz AC, Tang M, Smart J, Zitnik SE, Hoarau C,Kumararatne DS, Thrasher AJ, Davies EG, Bethune C, Sirvent N, de Ricaud D,Camcioglu Y, Vasconcelos J, Guedes M, Vitor AB, Rodrigo C, Almazán F, Méndez M,Aróstegui JI, Alsina L, Fortuny C, Reichenbach J, Verbsky JW, Bossuyt X,Doffinger R, Abel L, Puel A, Casanova JL. Clinical features and outcome ofpatients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore). 2010Nov;89(6):403-25. doi: 10.1097/MD.0b013e3181fd8ec3.
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