Reticular dysgenesis

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Reticular dysgenesis (RD) is a rare, inherited autosomal recessive disease that results in immunodeficiency.[1] Individuals with RD have mutations in both copies of the AK2 gene.[1] Mutations in this gene lead to absence of AK2 protein.[2] AK2 protein allows hematopoietic stem cells to differentiate and proliferate.[2] Hematopoietic stem cells give rise to blood cells.[2]

Differentiation and proliferation of hematopoietic stem cells require a lot of energy and this energy is supplied by the mitochondria.[2] The energy metabolism of mitochondria is regulated by the AK2 protein.[2] If there is a mutation in the protein, that means that the mitochondria metabolism most likely will be altered and will not be able to provide enough energy to the hematopoietic stem cells.[2] As a result, hematopoietic stem cells will not be able to differentiate or proliferate.[2]

The immune system consists of specialized cells that work together to fight off bacteria, fungi and viruses.[3] These cells include T lymphocytes (T cells), that primarily mediate the immune system, B lymphocytes (B cells) and Natural Killer cells.[3] Patients with RD have a genetic defect that affects the T cells and at least one other type of immune cell.[4] Since more than one type of immune cell is affected, this disease is classified as a severe combined immunodeficiency disease (SCID).[3] A weakened immune system leaves patients susceptible to different kinds of infection. Commonly, patients who are diagnosed with RD also have bacterial sepsis and/or pneumonia.[4]

Signs and symptoms[edit]

Signs and Symptoms Approximate Number of Patients Affected
Abnormality of mitochondria metabolism 90%
Abnormality of Neutrophils 90%
Anemia 90%
Aplasia/Hypoplasia of the thymus 90%
Cellular immunodeficiency 90%
Decreased antibody level in blood 90%
Diarrhea 90%
Hearing Impairment 90%
Recurrent respiratory infection 90%
Sepsis 90%
Abnormality of temperature regulation 50%
Malabsorption 50%
Weight Loss 50%
Dehydration 7.5%
Skin rash 7.5%
Skin Ulcer 7.5%


Risk Factors[edit]

  • Condition follows an autosomal recessive pattern[6]
    • The mutated gene must be inherited from both the mother and father[6]
    • Both males and females must have an equal frequency of inheritance[6]


Health professionals must look at a person's history, symptoms, physical exam and laboratory test in order to make a diagnosis. If the results show patients with low levels of lymphocytes, absence of granulocytes or absence of thymus then the patient may be suspected to have RD.[4]


The survival range is estimated to be 3 days to 17 weeks without treatment.[7] Patients die due to bacterial or viral infections.[7] Aggressive treatment with antibiotics is required and bone marrow transplant is common.[7] Patients undergoing bone marrow transplant, specifically from a matched sibling, have a higher 5 year survival rate than those receiving a transplant from other donors.[8]


RD can only be treated temporarily through Hematopoietic stem cell transplantation (HSCT) and Cytokine Therapy.[4][7][9]

Hematopoietic Stem Cell Transplantation[edit]

Transplantation of stem cells are taken from the bone marrow, peripheral blood or umbilical cord of healthy, matched donors.[8] Hematopoietic Stem Cell Transplantation (HSCT) involves intravenous infusion of stem cells to those who have either a damaged bone marrow or defective immune system.[4][8] Transplantation is a simple process. Bone marrow product is infused through a central vein over a period of several hours.[8] The hematopoietic cells are able to go to the bone marrow through tracking mechanisms.[8] Patients who suffer from RD will now have more stem cells that can differentiate into immune cells.

Cytokine Therapy[edit]

Recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) can be used as a temporary cure.[7] GM-CSF stimulates production of white blood cells.[7] This cure is commonly used in patients who are awaiting bone marrow transplantation.[7] Response to this cure can vary.[7] Those with a more severe combined immunodeficiency may have no response to this therapy.[7]


Gene Therapy[edit]

Gene therapy is a relatively new concept in the field of SCID.[10] This therapy is currently undergoing clinical trial and has cured a small number of children suffering from X-linked SCID and recessive allele SCID.[10] Gene therapy aims to correct the underlying genetic abnormality in SCID.[10] In the case of RD, the genetic abnormality would be AK2 malfunction.[2] Stem cells are taken from an affected child's blood or bone marrow.[10] Then in laboratory conditions the stem cells are manipulated and corrected with gene technology.[10] They are then injected back into the patient.[10] Similarly, in bone transplant, stem cells are able to find their way back through tracking mechanisms.[8][10]


  1. ^ a b Pannicke, Ulrich; Hönig, Manfred; Hess, Isabell; Friesen, Claudia; Holzmann, Karlheinz; Rump, Eva-Maria; Barth, Thomas F; Rojewski, Markus T; Schulz, Ansgar. "Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2". Nature Genetics. 41 (1): 101–105. doi:10.1038/ng.265. 
  2. ^ a b c d e f g h Six, E.; Lagresle-Peyrou, C.; Susini, S.; De Chappedelaine, C.; Sigrist, N.; Sadek, H.; Chouteau, M.; Cagnard, N.; Fontenay, M. (2015-08-13). "AK2 deficiency compromises the mitochondrial energy metabolism required for differentiation of human neutrophil and lymphoid lineages". Cell Death & Disease. 6 (8): e1856. doi:10.1038/cddis.2015.211. PMC 4558504Freely accessible. PMID 26270350. 
  3. ^ a b c "The Immune System and Primary Immunodeficiency | Immune Deficiency Foundation". Retrieved 2016-11-20. 
  4. ^ a b c d e Bertrand, Y.; Müller, S. M.; Casanova, J. L.; Morgan, G.; Fischer, A.; Friedrich, W. (2002-05-01). "Reticular dysgenesis: HLA non-identical bone marrow transplants in a series of 10 patients". Bone Marrow Transplantation. 29 (9): 759–762. doi:10.1038/sj.bmt.1703531. ISSN 0268-3369. PMID 12040473. 
  5. ^ "Reticular dysgenesis". GARD. 
  6. ^ a b c "Severe Combined Immunodeficiency - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2016-11-20. 
  7. ^ a b c d e f g h i Calhoun, Christensen, DA, RD (1998). "Recent advances in the pathogenesis and treatment of nonimmune neutropenias in the neonate". Current Opinion in Hematology. 5: 37–41. 
  8. ^ a b c d e f Perumbeti, Ajay. "Hematopoietic Stem Cell Transplantation". Medscape. 
  9. ^ Scheinfeld, Noah. "Intravenous Immunoglobulin". Intravenous Immunoglobulin. Medscape. 
  10. ^ a b c d e f g "Severe combined immunodeficiency (SCID)". Retrieved 2016-11-20.