Reticular dysgenesis

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]

Reticular dysgenesis
Other namesAK2 deficiency, Congenital aleukocytosis, De Vaal disease, Generalized hematopoietic hypoplasia, SCID with leukopenia
Reticular dysgenesis is inherited in an autosomal recessive manner
SpecialtyHematology 

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] The annual incidence has been estimated at 1/3,000,000-1/5,000,000 and both females and males are affected.[5]

Signs and symptoms
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%

[6]

Risk factors
  • Condition follows an autosomal recessive pattern[7]
    • The mutated gene must be inherited from both the mother and father[7]
    • Both males and females must have an equal frequency of inheritance[7]

Diagnosis

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]

Treatment

RD can only be treated temporarily through hematopoietic stem cell transplantation (HSCT) and cytokine therapy.[4][8][9]

Hematopoietic stem cell transplantation

Transplantation of stem cells are taken from the bone marrow, peripheral blood or umbilical cord of healthy, matched donors.[10] 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][10] Transplantation is a simple process. Bone marrow product is infused through a central vein over a period of several hours.[10] The hematopoietic cells are able to go to the bone marrow through tracking mechanisms.[10] Patients who suffer from RD will now have more stem cells that can differentiate into immune cells.

Cytokine Therapy

Recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) can be used as a temporary cure.[8] GM-CSF stimulates production of white blood cells.[8] This cure is commonly used in patients who are awaiting bone marrow transplantation.[8] Response to this cure can vary.[8] Those with a more severe combined immunodeficiency may have no response to this therapy.[8]

Prognosis

The survival range is estimated to be 3 days to 17 weeks without treatment.[8] Patients die due to bacterial or viral infections.[8] Aggressive treatment with antibiotics is required and bone marrow transplant is common.[8] 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.[10]

Research

Gene Therapy

Gene therapy is a relatively new concept in the field of SCID.[11] This therapy is currently undergoing clinical trial and has cured a small number of children suffering from X-linked SCID and recessive allele SCID.[11] Gene therapy aims to correct the underlying genetic abnormality in SCID.[11] 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.[11] Then in laboratory conditions the stem cells are manipulated and corrected with gene technology.[11] They are then injected back into the patient.[11] Similarly, in bone transplant, stem cells are able to find their way back through tracking mechanisms.[10][11]

References
  1. Pannicke, Ulrich; Hönig, Manfred; Hess, Isabell; Friesen, Claudia; Holzmann, Karlheinz; Rump, Eva-Maria; Barth, Thomas F; Rojewski, Markus T; Schulz, Ansgar (2009). "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. PMID 19043417. S2CID 205347130.
  2. 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 4558504. PMID 26270350.
  3. "The Immune System and Primary Immunodeficiency | Immune Deficiency Foundation". primaryimmune.org. Retrieved 2016-11-20.
  4. 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: epidemiology". rarediseases. Genetic and rare diseases information center. Retrieved 17 April 2018.
  6. "Reticular dysgenesis". GARD.
  7. "Severe Combined Immunodeficiency - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2016-11-20.
  8. Calhoun, Christensen, DA, RD (1998). "Recent advances in the pathogenesis and treatment of nonimmune neutropenias in the neonate". Current Opinion in Hematology. 5 (1): 37–41. doi:10.1097/00062752-199801000-00007. PMID 9515201. S2CID 37329390.
  9. Scheinfeld, Noah (2019-08-05). "Intravenous Immunoglobulin". Intravenous Immunoglobulin. Medscape.
  10. Perumbeti, Ajay (2018-08-06). "Hematopoietic Stem Cell Transplantation". Medscape.
  11. "Severe combined immunodeficiency (SCID)". Retrieved 2016-11-20.
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