Skip to main content

Molecular basis and therapy of disorders associated with chronic neutropenia

Abstract

There have been many recent advances in our understanding of the molecular basis of neutropenia disorders, primarily through advances in genetic analysis of inherited disorders. Molecular and cellular studies now suggest that accelerated apoptosis of neutrophil precursors in the bone marrow is the common pathophysiologic mechanism. Severe congenital neutropenia and cyclic neutropenia, both usually inherited as autosomal-dominant disorders, are caused by mutations in the neutrophil elastase gene. Myelokathexis is attributed to the downregulation of the bcl-x protein, but the genetic basis is not yet known. The genes for several diseases with more complex phenotypes (eg, glycogen storage disease type 1b, Chediak-Higashi syndrome, Shwachman-Diamond syndrome, dyskeratosis congenita, Griscelli syndrome, Barth syndrome, and Wiskott-Aldrich syndrome) have all been identified recently. The molecular mechanisms for most acquired disorders causing neutropenia (eg, idiopathic neutropenia, pure white-cell aplasia, myelodysplasia, and aplastic anemia) are not yet known. Granulocyte colony stimulating factor (G-CSF) is effective treatment for several of these conditions. Through better understanding of these disorders, we anticipate that better treatments will be found in the future.

This is a preview of subscription content, access via your institution.

References and Recommended Reading

  1. 1.

    Kostmann R: Infantile genetic agranulocytosis. Acta Paediatr Scand 1956, 105(Suppl):1–78.

    Google Scholar 

  2. 2.

    Briar GL, Parry HF, Ansari BM: Dominantly inherited severe congenital neutropenia. J Infect 1996, 33:123–126.

    Article  Google Scholar 

  3. 3.

    Aprikyan AG, Dale DC: Mutations in the neutrophil elastase gene in cyclic and congenital neutropenia. Curr Opin Immunol 2001, 13:535–538. The pattern of mutations in the neutrophil elastase gene associated with cyclic and congenital neutropenia is described.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Dale DC, Bolyard AA, Aprikyan A: Cyclic neutropenia. Semin Hematol 2002, 39:89–94. An excellent review of cyclic neutropenia, this issue also reviews other disorders that are discussed in this paper.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Horwitz M, Benson KF, Person RE, et al.: Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genetics 1999, 23:433–436.

    Article  CAS  Google Scholar 

  6. 6.

    Zuelzer WW: "Myelokathexis": a new form of chronic granulocytopenia. N Engl J Med 1964, 270:699–704. Original report of this unusual syndrome.

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    Aprikyan AAG, Liles CW, Dale DC: Myelokathexis, a congenital disorder of severe neutropenia characterized by accelerated apoptosis and defective expression of bcl-x in neutrophil precursors. Blood 2000, 95:320–327. First report on the cellular mechanism for myelokathexis.

    PubMed  CAS  Google Scholar 

  8. 8.

    Chou JY, Mansfield BC: Molecular genetics of type 1 glycogen storage disease. TEM 1999, 10:104–113.

    CAS  Google Scholar 

  9. 9.

    Calderwood S, Kilpatrick L, Douglas SD, et al.: Recombinant human granulocyte colony-stimulating factor therapy for patients with neutropenia and/or neutrophil dysfunction secondary to glycogen storage disease type 1b. Blood 2001, 97:376–382. This paper describes the use of G-CSF to treat this form of glycogen storage disease, which affects both the number and function of neutrophils.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Ward DM, Shiflett SL, Kaplan J: Chediak-Higashi syndrome: a clinical and molecular view of a rare lysosomal storage disorder. Curr Mol Med 2002, 2:469–477.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Shiflett SL, Kaplan J, Ward DM: Chediak-Higashi syndrome: a rare disorder of lysosomes and lysosome-related organelles. Pigment Cell Res 2002, 15:251–257.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Dror Y, Freedman M: Shwachman-Diamond syndrome review. Br J Haematol 2002, 118:701–713.

    PubMed  Article  Google Scholar 

  13. 13.

    Dror Y, Freedman MH: Shwachman-Diamond syndrome marrow cells show abnormally increased apoptosis mediated through the Fas pathway. Blood 2001, 97:3011–3016. An important paper describing a cellular mechanism for the Schwachman-Diamond syndrome.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Goobie S, Popovic M, Morrison J, et al.: Shwachman-Diamond syndrome with exocrine pancreatic dysfunction and bone marrow failure maps to the centromeric region of chromosome 7. Am J Hum Gen 2001, 68:1048–1054.

    Article  CAS  Google Scholar 

  15. 15.

    Yilmaz K, Inaloz S, Unal B, et al.: Dyskeratosis congenita with isolated neutropenia and granulocyte colony-stimulating factor treatment. Int J Dermatol 2002, 41:170.

    PubMed  Article  Google Scholar 

  16. 16.

    Dokal I: Dyskeratosis congenita: recent advances and future directions. J Pediatr Hematol Oncol 1999; 21:344–355.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Arico M, Zecca M, Santoro N, et al.: Successful treatment of Griscelli syndrome with unrelated donor allogenic hematopoietic stem cell transplantation. Bone Marrow Transplant 2002, 29:995–998.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Barral DC, Ramalho JS, Anders R, et al.: Functional redundancy of rab27 proteins and the pathogenesis of Griscelli syndrome. J Clin Invest 2002, 110:247–257.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Mazzocco MMM, Kelley RI: Preliminary evidence for a cognitive phenotype in Barth syndrome. Am J Med Gen 2001, 102:372–378.

    Article  CAS  Google Scholar 

  20. 20.

    Derry JM, Ochs HD, Francke U: Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell 1994, 79:635–644.

    Article  Google Scholar 

  21. 21.

    Rengan R, Ochs HD: Molecular biology of the Wiskott-Aldrich syndrome. Rev Immunogenet 2000, 2:243–255. An excellent review of the Wiskott-Aldrich syndrome with insightful clinical details of the disease.

    PubMed  CAS  Google Scholar 

  22. 22.

    Jones LN, Lutskiy MI, Cooley J, et al.: A novel protocol to identify mutations in patients with Wiskott-Aldrich syndrome. Blood Cells Mol Dis 2002, 28:392–398.

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stein, S.M., Dale, D.C. Molecular basis and therapy of disorders associated with chronic neutropenia. Curr Allergy Asthma Rep 3, 385–388 (2003). https://doi.org/10.1007/s11882-003-0071-0

Download citation

Keywords

  • Neutropenia
  • Glycogen Storage Disease
  • Barth Syndrome
  • Dyskeratosis Congenita
  • Severe Congenital Neutropenia