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| | {{Short description|A rare genetic disorder affecting the immune system}} |
| {{Infobox medical condition (new) | | {{Infobox medical condition (new) |
| | name = Reticular dysgenesis | | | name = Reticular dysgenesis |
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| | caption = Reticular dysgenesis is inherited in an autosomal recessive manner | | | caption = Reticular dysgenesis is inherited in an autosomal recessive manner |
| | pronounce = | | | pronounce = |
| | field = | | | field = [[Immunology]], [[Hematology]], [[Medical genetics]] |
| | symptoms = | | | symptoms = Severe combined immunodeficiency, profound neutropenia, sensorineural deafness, failure to thrive |
| | complications = | | | complications = Life-threatening infections, sepsis, hearing loss |
| | onset = | | | onset = At birth or within the first few weeks of life |
| | duration = | | | duration = Lifelong without treatment |
| | types = | | | types = A form of [[Severe combined immunodeficiency]] (SCID) |
| | causes = | | | causes = Mutations in the ''AK2'' gene affecting mitochondrial energy metabolism in hematopoietic stem cells |
| | risks = | | | risks = Autosomal recessive inheritance; consanguinity |
| | diagnosis = | | | diagnosis = [[Newborn screening]], [[flow cytometry]], [[genetic testing]], [[bone marrow biopsy]] |
| | differential = | | | differential = Other forms of SCID, congenital neutropenia, hematopoietic disorders |
| | prevention = | | | prevention = Genetic counseling for at-risk families |
| | treatment = | | | treatment = [[Hematopoietic stem cell transplantation]] (HSCT) |
| | medication = | | | medication = Prophylactic antibiotics, antifungals, and antiviral agents; [[immunoglobulin therapy]] |
| | prognosis = | | | prognosis = Poor without treatment; significantly improved outcomes with early HSCT |
| | frequency = | | | frequency = Very rare |
| | deaths = | | | deaths = High mortality rate without early diagnosis and transplantation |
| }} | | }} |
| '''Reticular dysgenesis (RD)''' is a rare, inherited [[autosomal recessive]] disease that results in immunodeficiency.<ref name=":0">{{Cite journal|last=Pannicke|first=Ulrich|last2=Hönig|first2=Manfred|last3=Hess|first3=Isabell|last4=Friesen|first4=Claudia|last5=Holzmann|first5=Karlheinz|last6=Rump|first6=Eva-Maria|last7=Barth|first7=Thomas F|last8=Rojewski|first8=Markus T|last9=Schulz|first9=Ansgar|title=Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2|journal=Nature Genetics|volume=41|issue=1|pages=101–105|doi=10.1038/ng.265|pmid=19043417|year=2009|url=https://www.semanticscholar.org/paper/d85489fba98af7b5ace6524cbb54a657be721466}}</ref> Individuals with RD have mutations in both copies of the [[AK2|AK2 gene]].<ref name=":0" /> Mutations in this gene lead to absence of AK2 protein.<ref name=":4">{{Cite journal|last=Six|first=E.|last2=Lagresle-Peyrou|first2=C.|last3=Susini|first3=S.|last4=De Chappedelaine|first4=C.|last5=Sigrist|first5=N.|last6=Sadek|first6=H.|last7=Chouteau|first7=M.|last8=Cagnard|first8=N.|last9=Fontenay|first9=M.|date=2015-08-13|title=AK2 deficiency compromises the mitochondrial energy metabolism required for differentiation of human neutrophil and lymphoid lineages|journal=Cell Death & Disease|language=en|volume=6|issue=8|pages=e1856|doi=10.1038/cddis.2015.211|pmc=4558504|pmid=26270350}}</ref> AK2 protein allows [[hematopoietic stem cell]]s to differentiate and proliferate.<ref name=":4" /> Hematopoietic stem cells give rise to blood cells.<ref name=":4" />
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| Differentiation and proliferation of hematopoietic stem cells require a lot of energy and this energy is supplied by the [[Mitochondrion|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 [[Cellular differentiation|differentiate]] or [[Cell growth|proliferate]].<ref name=":4" />
| | '''Reticular dysgenesis''' is a rare and severe form of [[severe combined immunodeficiency]] (SCID), characterized by the absence of both [[lymphocytes]] and [[granulocytes]], leading to a profound immunodeficiency. It is considered one of the most severe forms of SCID due to the lack of both adaptive and innate immune responses. |
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| The immune system consists of specialized cells that work together to fight off bacteria, fungi and viruses.<ref name=":7">{{Cite web|url=http://primaryimmune.org/about-primary-immunodeficiencies/relevant-info/the-immune-system/|title=The Immune System and Primary Immunodeficiency {{!}} Immune Deficiency Foundation|website=primaryimmune.org|access-date=2016-11-20}}</ref> These cells include [[T cell|T lymphocytes]] (T cells), that primarily mediate the immune system, [[B cell|B lymphocytes]] (B cells) and [[Natural killer cell|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">{{Cite journal|last=Bertrand|first=Y.|last2=Müller|first2=S. M.|last3=Casanova|first3=J. L.|last4=Morgan|first4=G.|last5=Fischer|first5=A.|last6=Friedrich|first6=W.|date=2002-05-01|title=Reticular dysgenesis: HLA non-identical bone marrow transplants in a series of 10 patients|journal=Bone Marrow Transplantation|volume=29|issue=9|pages=759–762|doi=10.1038/sj.bmt.1703531|issn=0268-3369|pmid=12040473|doi-access=free}}</ref> Since more than one type of immune cell is affected, this disease is classified as a [[Severe combined immunodeficiency|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>{{cite web|title=Reticular dysgenesis: epidemiology|url=https://rarediseases.info.nih.gov/diseases/8625/reticular-dysgenesis|website=rarediseases|publisher=Genetic and rare diseases information center|accessdate=17 April 2018}}</ref>
| | ==Pathophysiology== |
| | Reticular dysgenesis is caused by mutations in the [[AK2 gene]], which is located on chromosome 1. The AK2 gene encodes the adenylate kinase 2 enzyme, which is crucial for energy metabolism in cells, particularly in the [[mitochondria]]. The deficiency of this enzyme affects the development of [[hematopoietic stem cells]], leading to the failure of [[myeloid]] and [[lymphoid]] cell lineages. |
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| == Signs and symptoms == | | ==Clinical Presentation== |
| {| class="wikitable"
| | Patients with reticular dysgenesis typically present in the neonatal period with severe [[infections]], failure to thrive, and [[neutropenia]]. The absence of [[neutrophils]] and [[lymphocytes]] results in an inability to mount an effective immune response, making affected individuals highly susceptible to bacterial, viral, and fungal infections. |
| !Signs and Symptoms
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| !Approximate Number of Patients Affected
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| |-
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| |Abnormality of mitochondria metabolism
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| |90%
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| |-
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| |Abnormality of Neutrophils
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| |90%
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| |-
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| |Anemia
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| |90%
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| |-
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| |Aplasia/Hypoplasia of the thymus
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| |90%
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| |-
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| |Cellular immunodeficiency
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| |90%
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| |-
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| |Decreased antibody level in blood
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| |90%
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| |-
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| |Diarrhea
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| |90%
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| |-
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| |Hearing Impairment
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| |90%
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| |-
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| |Recurrent respiratory infection
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| |90%
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| |-
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| |Sepsis
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| |90%
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| |-
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| |Abnormality of temperature regulation
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| |50%
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| |-
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| |Malabsorption
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| |50%
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| |-
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| |Weight Loss
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| |50%
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| |-
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| |Dehydration
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| |7.5%
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| |-
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| |Skin rash
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| |7.5%
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| |-
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| |Skin Ulcer
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| |7.5%
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| |}
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| <ref>{{Cite web|url=https://rarediseases.info.nih.gov/diseases/8625/reticular-dysgenesis|title=Reticular dysgenesis|last=|first=|date=|website=GARD|access-date=}}</ref>
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| == Risk factors == | | ==Diagnosis== |
| * Condition follows an autosomal recessive pattern<ref name=":8">{{Cite news|url=https://rarediseases.org/rare-diseases/severe-combined-immunodeficiency/|title=Severe Combined Immunodeficiency - NORD (National Organization for Rare Disorders)|newspaper=NORD (National Organization for Rare Disorders)|language=en-US|access-date=2016-11-20}}</ref>
| | The diagnosis of reticular dysgenesis is based on clinical presentation, laboratory findings, and genetic testing. Laboratory tests reveal severe [[lymphopenia]] and [[neutropenia]]. Genetic testing can confirm mutations in the AK2 gene, which is diagnostic of the condition. |
| ** The mutated gene must be inherited from both the mother and father<ref name=":8" />
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| ** Both males and females must have an equal frequency of inheritance<ref name=":8" />
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| == Diagnosis == | | ==Treatment== |
| 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" />
| | The primary treatment for reticular dysgenesis is [[hematopoietic stem cell transplantation]] (HSCT), which can restore immune function. Prior to transplantation, patients may require supportive care, including [[antibiotics]], [[antifungal]]s, and [[immunoglobulin replacement therapy]]. |
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| == Treatment == | | ==Prognosis== |
| RD can only be treated temporarily through [[Hematopoietic stem cell transplantation]] (HSCT) and Cytokine Therapy.<ref name=":1" /><ref name=":5" /><ref name=":2">{{Cite journal|url=http://emedicine.medscape.com/article/210367-overview?pa=PmDve%2FalcQVFwj6gs9oO35bXOkN3F7qRBlYh4a9jWMjretDc%2F9eVnMnljEwh2N9BCireY%2BwZp%2FVchUGrFPrk1CchrzF%2F7vlnSF6AEX%2F09M8%3D|title=Intravenous Immunoglobulin|last=Scheinfeld|first=Noah|date=2019-08-05|website=Intravenous Immunoglobulin|publisher=Medscape|access-date=}}</ref>
| | Without treatment, reticular dysgenesis is fatal in infancy due to overwhelming infections. However, with successful hematopoietic stem cell transplantation, long-term survival is possible, and immune function can be restored. |
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| === Hematopoietic Stem Cell Transplantation === | | ==Related pages== |
| 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.
| | * [[Severe combined immunodeficiency]] |
| | * [[Hematopoietic stem cell transplantation]] |
| | * [[Neutropenia]] |
| | * [[Lymphopenia]] |
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| === Cytokine Therapy ===
| | [[Category:Genetic disorders]] |
| Recombinant [[Granulocyte macrophage colony-stimulating factor|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" />
| | [[Category:Immunodeficiency]] |
| | | [[Category:Hematology]] |
| == Prognosis ==
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| The survival range is estimated to be 3 days to 17 weeks without treatment.<ref name=":5">{{Cite journal|last=Calhoun, Christensen|first=DA, RD|year=1998|title=Recent advances in the pathogenesis and treatment of nonimmune neutropenias in the neonate|url=|journal=Current Opinion in Hematology|volume=5|issue=1|pages=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">{{Cite journal|url=http://emedicine.medscape.com/article/208954-overview|title=Hematopoietic Stem Cell Transplantation|last=Perumbeti|first=Ajay|date=2018-08-06|website=Medscape|access-date=}}</ref>
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| == Research ==
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| === Gene Therapy ===
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| [[Gene therapy]] is a relatively new concept in the field of SCID.<ref name=":6">{{Cite news|url=http://www.gosh.nhs.uk/medical-information-0/search-medical-conditions/severe-combined-immunodeficiency-scid|title=Severe combined immunodeficiency (SCID)|access-date=2016-11-20}}</ref> This therapy is currently undergoing clinical trial and has cured a small number of children suffering from [[X-linked severe combined immunodeficiency|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" />
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| == References ==
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| {{Reflist}}
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| == External links ==
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| {{Medical resources
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| | ICD10 = D81.0
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| | ICD9 = <!--{{ICD9|xxx}}-->
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| | ICDO =
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| | OMIM =
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| | DiseasesDB =
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| | MedlinePlus =
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| | eMedicineSubj =
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| | eMedicineTopic =
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| | MeSH = C538361
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| | GeneReviewsNBK =
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| | GeneReviewsName =
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| | Orphanet = 33355
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| }}
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| [[Category:Rare diseases]]
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| [[Category:Genetic disorders by system]] | |
| [[Category:Combined T and B–cell immunodeficiencies]] | |
| [[Category:Noninfectious immunodeficiency-related cutaneous conditions]] | |
| {{dictionary-stub1}}
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| <gallery>
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| File:Autosomal recessive - en.svg|Reticular dysgenesis
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| </gallery>
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A rare genetic disorder affecting the immune system
| Reticular dysgenesis
|
|
| Synonyms
|
AK2 deficiency, Congenital aleukocytosis, De Vaal disease, Generalized hematopoietic hypoplasia, SCID with leukopenia
|
| Pronounce
|
|
| Field
|
Immunology, Hematology, Medical genetics
|
| Symptoms
|
Severe combined immunodeficiency, profound neutropenia, sensorineural deafness, failure to thrive
|
| Complications
|
Life-threatening infections, sepsis, hearing loss
|
| Onset
|
At birth or within the first few weeks of life
|
| Duration
|
Lifelong without treatment
|
| Types
|
A form of Severe combined immunodeficiency (SCID)
|
| Causes
|
Mutations in the AK2 gene affecting mitochondrial energy metabolism in hematopoietic stem cells
|
| Risks
|
Autosomal recessive inheritance; consanguinity
|
| Diagnosis
|
Newborn screening, flow cytometry, genetic testing, bone marrow biopsy
|
| Differential diagnosis
|
Other forms of SCID, congenital neutropenia, hematopoietic disorders
|
| Prevention
|
Genetic counseling for at-risk families
|
| Treatment
|
Hematopoietic stem cell transplantation (HSCT)
|
| Medication
|
Prophylactic antibiotics, antifungals, and antiviral agents; immunoglobulin therapy
|
| Prognosis
|
Poor without treatment; significantly improved outcomes with early HSCT
|
| Frequency
|
Very rare
|
| Deaths
|
High mortality rate without early diagnosis and transplantation
|
Reticular dysgenesis is a rare and severe form of severe combined immunodeficiency (SCID), characterized by the absence of both lymphocytes and granulocytes, leading to a profound immunodeficiency. It is considered one of the most severe forms of SCID due to the lack of both adaptive and innate immune responses.
Pathophysiology[edit]
Reticular dysgenesis is caused by mutations in the AK2 gene, which is located on chromosome 1. The AK2 gene encodes the adenylate kinase 2 enzyme, which is crucial for energy metabolism in cells, particularly in the mitochondria. The deficiency of this enzyme affects the development of hematopoietic stem cells, leading to the failure of myeloid and lymphoid cell lineages.
Clinical Presentation[edit]
Patients with reticular dysgenesis typically present in the neonatal period with severe infections, failure to thrive, and neutropenia. The absence of neutrophils and lymphocytes results in an inability to mount an effective immune response, making affected individuals highly susceptible to bacterial, viral, and fungal infections.
Diagnosis[edit]
The diagnosis of reticular dysgenesis is based on clinical presentation, laboratory findings, and genetic testing. Laboratory tests reveal severe lymphopenia and neutropenia. Genetic testing can confirm mutations in the AK2 gene, which is diagnostic of the condition.
Treatment[edit]
The primary treatment for reticular dysgenesis is hematopoietic stem cell transplantation (HSCT), which can restore immune function. Prior to transplantation, patients may require supportive care, including antibiotics, antifungals, and immunoglobulin replacement therapy.
Prognosis[edit]
Without treatment, reticular dysgenesis is fatal in infancy due to overwhelming infections. However, with successful hematopoietic stem cell transplantation, long-term survival is possible, and immune function can be restored.
Related pages[edit]
