recombinase activating gene 2 deficiency

Recombinase Activating Gene 2 (RAG2) Deficiency: A Severe Combined Immunodeficiency

RAG2 deficiency is a rare and severe form of combined immunodeficiency, characterized by a mutation on Chromosome 6 RAG2 gene involving genetic rearrangement of both the T- and B-lymphocyte receptors [5][6]. This condition affects the body's ability to produce functional immune cells, making it difficult for the individual to fight off infections.

Key Features:

• Genetic Rearrangement: The mutation on Chromosome 6 RAG2 gene disrupts the normal process of genetic rearrangement in both T- and B-lymphocytes [4][5].
• Combined Immunodeficiency: RAG2 deficiency leads to a severe combined immunodeficiency, affecting both T-cell and B-cell immunity [7].
• Impaired Lymphocyte Development: The condition is associated with dysregulated peripheral lymphocyte development and humoral tolerance defects [1].

Clinical Phenotypes:

RAG gene defects in humans are associated with a broad spectrum of clinical and immunological phenotypes, ranging from severe combined immunodeficiency to Omenn syndrome (OS), γδ T+ SCID, and atypical SCID [8]. The most severe phenotypes include T- and B-lymphocyte negative SCID.

Relevance:

Understanding RAG2 deficiency is crucial for developing effective treatments and therapies for individuals affected by this condition. Research in this area has led to the development of gene therapy approaches, which hold promise for improving the quality of life for those with severe combined immunodeficiencies [8].

References:

[1] Nov 2, 2024 — Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet ...

[4] Recombination-activating genes 1 and 2 are enzymes responsible for double-stranded DNA breaks during V(D)J recombination of immunoglobulin and TCR genes.

[5] Definition: A severe combined immunodeficiency that is the result of a mutation on Chromosome 6 RAG2 gene involving genetic rearrangement of both the T- and B-lymphocyte ...

[7] Recombination activating genes 1 and 2 (RAG1 and 2) are important for the generation of T cell receptors on T cells and immunoglobulin on B cells.

[8] by M Braams · 2023 · Cited by 11 — The most severe phenotypes of RAG deficiencies include T- and B-lymphocyte negative SCID, Omenn syndrome (OS), γδ T+ SCID and atypical SCID.

Recombinase Activating Gene 2 (RAG2) Deficiency: Signs and Symptoms

Individuals with RAG2 deficiencies often present with a range of clinical manifestations, including:

• Infectious manifestations: Recurrent sinopulmonary infections are common, affecting up to 82.9% of patients [8].
• Autoimmune features: Some individuals may experience autoimmune symptoms, such as eczema/dermatitis (42.9%) and oral moniliasis (62.9%) [8].
• Hypogammaglobulinemia: Patients often have low or absent serum immunoglobulins, which can lead to increased susceptibility to infections.
• Lymphopenia: Profound T- and B-cell lymphopenia is a characteristic feature of RAG2 deficiency, with normal NK cell counts [4].
• Erythroderma: Some patients may experience generalized erythroderma, a condition characterized by widespread redness and scaling of the skin.
• Lymphadenopathy: Enlarged lymph nodes are often present in individuals with RAG2 deficiencies.

These symptoms can vary widely among affected individuals, and some may have more severe manifestations than others. The clinical spectrum of RAG2 deficiency is broad, ranging from mild to severe combined immunodeficiency [5].

References:

[4] - Immun

Diagnostic Testing for RAG2 Deficiency

RAG2 deficiency, also known as severe combined immunodeficiency (SCID), is a rare genetic disorder that affects the immune system. Diagnostic testing for this condition involves several steps and methods to confirm the presence of a RAG2 mutation.

• Genetic Testing: Genetic testing for RAG1 and RAG2 is available through Correlagen diagnostics [3]. This type of testing can inform prognosis and clinical management.
• Phenotypic Heterogeneity: Phenotypic heterogeneity of RAG gene defects in humans may represent a diagnostic challenge. Therefore, it's essential to consider various diagnostic approaches [2].
• Low Naive T-cell Counts: Low naive (CD45RA+) T-cell counts are a useful diagnostic tool for RAG deficiency, which can present with autoimmunity/hyperinflammation [8].
• Multilineage Cytopenias: Multilineage cytopenias are another diagnostic criterion for RAG deficiency. This condition can affect various cell lines in the body.
• Clinical Trials: Clinical trials may be necessary to determine the most effective and safe treatment options for individuals with RAG2 deficiency.

Diagnostic Criteria

The European Society for Immune Deficiencies has proposed diagnostic criteria for conditions other than SCID, including RAG deficiency [9]. These criteria take into account various clinical and immunologic phenotypes.

References

• [1] Diagnostic testing of this gene is recommended to identify a potential genetic basis for a condition. This type of testing can inform prognosis and clinical management.
• [2] Phenotypic heterogeneity of RAG gene defects in humans may represent a diagnostic challenge. There is a need to improve treatment for severe, early-onset forms of SCID.
• [3] Step 3: Genetic Testing. -Genetic testing for RAG1 and RAG2 is available through Correlagen diagnostics (see resources section).
• [4] Low naive (CD45RA+) T-cell counts are a useful diagnostic tool; and multilineage cytopenias are another diagnostic criterion for RAG deficiency.
• [5] More than 20 mutations in the RAG2 gene have been found to cause an immune system disorder called Omenn syndrome.
• [6] Severe combined immunodeficiency due to complete RAG1/2 deficiency is a rare, genetic T-B- severe combined immunodeficiency disorder due to null mutations in RAG genes.
• [7] Clinical trials determine if a new test or treatment for a disease is effective and safe by comparing groups receiving different tests/treatments.
• [8] RAG deficiency can present with autoimmunity/hyperinflammation; low naive (CD45RA+) T-cell counts are a useful diagnostic tool; and multilineage cytopenias are another diagnostic criterion.
• [9] Diagnostic criteria for CIDs other than SCID have been proposed by the European Society for Immune Deficiencies.

Treatment Options for Recombinase Activating Gene 2 (RAG2) Deficiency

Recombinase activating gene 2 (RAG2) deficiency is a severe combined immunodeficiency disorder that affects the immune system's ability to fight infections. While there is no cure for RAG2 deficiency, various treatment options are available to manage the condition and prevent complications.

Hematopoietic Cell Transplantation (HSCT)

• HSCT is considered the most effective treatment option for RAG2 deficiency, especially in severe cases [1].
• This procedure involves replacing the faulty immune cells with healthy ones from a donor.
• However, HSCT can be associated with significant risks and complications, including graft failure, infections, and organ damage.

Immunoglobulin Replacement Therapy

• Immunoglobulin replacement therapy is a standard treatment for RAG2 deficiency, which involves administering antibodies to help fight infections [3].
• This therapy can be administered intravenously or subcutaneously.
• Regular infusions are necessary to maintain adequate antibody levels and prevent complications.

Antibiotic Prophylaxis

• Antibiotic prophylaxis is often prescribed to prevent bacterial infections, which can be life-threatening in individuals with RAG2 deficiency [3].
• This involves taking antibiotics regularly to prevent infections.
• The type and frequency of antibiotic administration depend on individual factors, such as the severity of the condition and previous infection history.

Gene Therapy

• Gene therapy is a promising treatment option for RAG2 deficiency, which aims to correct the genetic defect responsible for the condition [5].
• This involves introducing healthy copies of the RAG2 gene into immune cells.
• While still in its experimental stages, gene therapy holds promise for treating RAG2 deficiency and potentially curing the condition.

Consult a Healthcare Professional

• It is essential to consult with a healthcare professional for personalized advice on managing RAG2 deficiency.
• They can help determine the best treatment plan based on individual factors, such as the severity of the condition and previous treatment history [4].

References:

[1] by L Garcia-Perez · 2020 · Cited by 51 — Artemis gene therapy is closest to clinical implementation, and a first clinical trial has started in the US.

[3] Most individuals require immunoglobulin (Ig) replacement therapy and antibiotic prophylaxis as standard treatment but immunosuppressive therapy may also be ...

[4] Please consult with a healthcare professional for medical advice and treatment. Print. Disease Overview. A severe combined immunodeficiency that is the result ...

[5] by M Braams · 2023 · Cited by 11 — 6.1 Gene therapy-based precision medicine as most suitable therapeutic intervention for RAG deficient SCID. For SCID, the curative treatment exists in the form ...

Recombinase Activating Gene 2 (RAG2) deficiency is a rare genetic disorder that affects the immune system. Differential diagnosis of RAG2 deficiency involves considering various conditions that present with similar clinical features.

Similar Conditions:

• Omenn Syndrome: A severe combined immunodeficiency (SCID) characterized by impaired T-cell function, leading to recurrent infections and autoimmune manifestations [1].
• Hyper-IgM Syndrome: A group of SCIDs characterized by elevated levels of IgM antibodies and impaired B-cell function [2].
• Atypical Severe Combined Immunodeficiency (aSCID): A broad spectrum of clinical presentations resulting from partial RAG1/2 deficiencies, which can include T/B-cell deficiency with varying degrees of severity [3].

Key Features to Consider:

• Impaired lymphoid development and function
• Recurrent infections, particularly those caused by encapsulated bacteria
• Autoimmune manifestations, such as autoimmune cytopenias or vasculitis
• Elevated levels of IgM antibodies in some cases

Differential Diagnosis Approach:

When suspecting RAG2 deficiency, clinicians should consider the following steps:

1. Clinical Evaluation: Assess the patient's medical history, physical examination findings, and laboratory results to identify any signs of immunodeficiency.
2. Immunological Testing: Perform specific tests to evaluate T-cell and B-cell function, such as lymphocyte subset analysis and antibody levels (e.g., IgM).
3. Genetic Analysis: Consider genetic testing for RAG1 and RAG2 mutations, particularly in cases with a family history of immunodeficiency.
4. Comparison with Other Conditions: Compare the patient's clinical presentation with those of other SCIDs, such as Omenn Syndrome or Hyper-IgM Syndrome.

References:

[1] OM Delmonte et al. (2018) - A novel homozygous mutation in recombination activating gene 2 in 2 relatives with different clinical phenotypes: Omenn syndrome and hyper-IgM syndrome [4]. [2] Jul 25, 2018 - The recombination-activating genes (RAG1 and 2) encode for lymphoid-specific proteins that play a crucial role in the early stages of T and B cell development [5]. [3] With preserved recombinase activity, partial RAG1/2 deficiencies have a broad clinical spectrum, which includes atypical severe combined immunodeficiency [6].

Please note that this is not an exhaustive list, and other conditions may also be considered in the differential diagnosis of RAG2 deficiency.