Reticular dysgenesis

Reticular dysgenesis
Synonyms	AK2 deficiency, Congenital aleukocytosis, De Vaal disease, Generalized hematopoietic hypoplasia, SCID with leukopenia
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Field
Symptoms
Complications
Onset
Duration
Types
Causes
Risks
Diagnosis
Differential diagnosis
Prevention
Treatment
Medication
Prognosis
Frequency
Deaths

Reticular dysgenesis (RD) is a rare, inherited autosomal recessive disease that results in immunodeficiency.<ref name=":0">Pannicke, Ulrich,

 Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2, 
 Nature Genetics, 
 2009,
 Vol. 41(Issue: 1),
 pp. 101–105,
 DOI: 10.1038/ng.265,
 PMID: 19043417,
 
 
 Full text,</ref> Individuals with RD have mutations in both copies of the AK2 gene.<ref name=":0" /> Mutations in this gene lead to absence of AK2 protein.<ref name=":4">Six, E., 
 AK2 deficiency compromises the mitochondrial energy metabolism required for differentiation of human neutrophil and lymphoid lineages, 
 Cell Death & Disease, 
 
 Vol. 6(Issue: 8),
 pp. e1856,
 DOI: 10.1038/cddis.2015.211,
 PMID: 26270350,
 PMC: 4558504,</ref> AK2 protein allows hematopoietic stem cells to differentiate and proliferate.<ref name=":4" /> Hematopoietic stem cells give rise to blood cells.<ref name=":4" />

Differentiation and proliferation of hematopoietic stem cells require a lot of energy and this energy is supplied by the mitochondria.<ref name=":4" /> The energy metabolism of mitochondria is regulated by the AK2 protein.<ref name=":4" /> 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.<ref name=":4" /> As a result, hematopoietic stem cells will not be able to differentiate or proliferate.<ref name=":4" />

The immune system consists of specialized cells that work together to fight off bacteria, fungi and viruses.<ref name=":7">

The Immune System and Primary Immunodeficiency | Immune Deficiency Foundation(link). primaryimmune.org.

Accessed 2016-11-20.

</ref> These cells include T lymphocytes (T cells), that primarily mediate the immune system, B lymphocytes (B cells) and Natural Killer cells.<ref name=":7" /> Patients with RD have a genetic defect that affects the T cells and at least one other type of immune cell.<ref name=":1">Bertrand, Y.,

 Reticular dysgenesis: HLA non-identical bone marrow transplants in a series of 10 patients, 
 Bone Marrow Transplantation, 
 
 Vol. 29(Issue: 9),
 pp. 759–762,
 DOI: 10.1038/sj.bmt.1703531,
 PMID: 12040473,</ref> Since more than one type of immune cell is affected, this disease is classified as a severe combined immunodeficiency disease (SCID).<ref name=":7" /> 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.<ref name=":1" />The annual incidence has been estimated at 1/3,000,000-1/5,000,000 and both females and males are affected.<ref>

Reticular dysgenesis: epidemiology(link). rarediseases. Genetic and rare diseases information center.

</ref>

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%

<ref>

Reticular dysgenesis(link). GARD.

</ref>

Risk factors

• Condition follows an autosomal recessive pattern<ref name=":8">

,

 Severe Combined Immunodeficiency - NORD (National Organization for Rare Disorders) Full text, 
 , 
  
  
  
  
 Accessed on: 2016-11-20.

</ref>

• • The mutated gene must be inherited from both the mother and father<ref name=":8" />
  • Both males and females must have an equal frequency of inheritance<ref name=":8" />

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.<ref name=":1" />

Treatment

RD can only be treated temporarily through Hematopoietic stem cell transplantation (HSCT) and Cytokine Therapy.<ref name=":1" /><ref name=":5" /><ref name=":2">Scheinfeld, Noah,

 Intravenous Immunoglobulin, 
 , 
 
 
 
 
 
 
 
 Full text,</ref>

Hematopoietic Stem Cell Transplantation

Transplantation of stem cells are taken from the bone marrow, peripheral blood or umbilical cord of healthy, matched donors.<ref name=":3" /> Hematopoietic Stem Cell Transplantation (HSCT) involves intravenous infusion of stem cells to those who have either a damaged bone marrow or defective immune system.<ref name=":1" /><ref name=":3" /> Transplantation is a simple process. Bone marrow product is infused through a central vein over a period of several hours.<ref name=":3" /> The hematopoietic cells are able to go to the bone marrow through tracking mechanisms.<ref name=":3" /> 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.<ref name=":5" /> GM-CSF stimulates production of white blood cells.<ref name=":5" /> This cure is commonly used in patients who are awaiting bone marrow transplantation.<ref name=":5" /> Response to this cure can vary.<ref name=":5" /> Those with a more severe combined immunodeficiency may have no response to this therapy.<ref name=":5" />

Prognosis

The survival range is estimated to be 3 days to 17 weeks without treatment.<ref name=":5">Calhoun, Christensen, DA, RD,

 Recent advances in the pathogenesis and treatment of nonimmune neutropenias in the neonate, 
 Current Opinion in Hematology, 
 1998,
 Vol. 5(Issue: 1),
 pp. 37–41,
 DOI: 10.1097/00062752-199801000-00007,
 PMID: 9515201,</ref> Patients die due to bacterial or viral infections.<ref name=":5" /> Aggressive treatment with antibiotics is required and bone marrow transplant is common.<ref name=":5" /> 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.<ref name=":3">Perumbeti, Ajay, 
 Hematopoietic Stem Cell Transplantation, 
 , 
 
 
 
 
 
 
 
 Full text,</ref>

Research

Gene Therapy

Gene therapy is a relatively new concept in the field of SCID.<ref name=":6"> ,

 Severe combined immunodeficiency (SCID) Full text, 
 , 
  
  
  
  
 Accessed on: 2016-11-20.

</ref> This therapy is currently undergoing clinical trial and has cured a small number of children suffering from X-linked SCID and recessive allele SCID.<ref name=":6" /> Gene therapy aims to correct the underlying genetic abnormality in SCID.<ref name=":6" /> In the case of RD, the genetic abnormality would be AK2 malfunction.<ref name=":4" /> Stem cells are taken from an affected child's blood or bone marrow.<ref name=":6" /> Then in laboratory conditions the stem cells are manipulated and corrected with gene technology.<ref name=":6" /> They are then injected back into the patient.<ref name=":6" /> Similarly, in bone transplant, stem cells are able to find their way back through tracking mechanisms.<ref name=":3" /><ref name=":6" />

External links

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