Severe Combined Immunodeficiency (SCID)

Severe combined immunodeficiency (SCID), also known as Swiss-type agammaglobulinaemia, is a rare genetic disorder characterised by the defective development of functional T cells and B cells. This condition results from numerous genetic mutations, causing various clinical presentations.

SCID is the most severe form of primary immunodeficiencies, often referred to as "bubble boy disease" or "bubble baby disease" due to the extreme vulnerability of its victims to infections. The immune system in SCID patients is so compromised that it is almost absent.

Signs and Symptoms

SCID patients typically present severe bacterial, viral, or fungal infections early in life and often exhibit symptoms such as interstitial lung disease, chronic diarrhoea, and failure to thrive. Common infections include ear infections, recurrent Pneumocystis jirovecii pneumonia, and profuse oral candidiasis. Without treatment, these infants usually die within one year due to severe, recurrent infections.

Classification

SCID can be classified into several types based on the underlying genetic mutations:

• X-linked severe combined immunodeficiency: Most common form, caused by mutations in the IL2RG gene affecting the common gamma chain (γc) involved in T and B cell development.
• Adenosine deaminase deficiency: Caused by a defective enzyme necessary for purine breakdown, leading to lymphocyte proliferation inhibition.
• Purine nucleoside phosphorylase deficiency: An autosomal recessive disorder causing T-cell toxicity and deficiency due to elevated dGTP levels.
• Reticular dysgenesis: Involves malfunction of mitochondrial adenylate kinase 2 (AK2), affecting granulocyte precursor formation.
• Omenn syndrome: Mutations in RAG-1 or RAG-2 genes prevent V(D)J recombination, essential for immunoglobulin manufacture.
• Bare lymphocyte syndrome: Caused by defective TAP proteins (Type 1) or altered MHC-II gene regulatory proteins (Type 2).
• JAK3: Mutation in Janus kinase-3 (JAK3) enzyme, affecting γc signal transduction.
• DCLRE1C and PRKDC: Genes required for DNA repair and V(D)J recombination, leading to SCID when mutated.

Diagnosis

Early diagnosis of SCID is challenging and often requires advanced screening techniques. Symptoms like a family history of infant death, chronic coughs, hyperinflated lungs, and persistent infections may indicate SCID. A full blood lymphocyte count is reliable but influenced by high childhood lymphocyte counts. Genetic defect-based clinical diagnosis is implemented in some regions. Newborn screening using real-time quantitative PCR to measure T-cell receptor excision circles is routine in several countries, including the U.S., Australia, and parts of Europe and Latin America.

Treatment

The primary treatment for SCID is bone marrow transplantation, which can use matched related, unrelated, or half-matched (haploidentical) donors. Haploidentical transplants require donor marrow to be depleted of mature T cells to avoid graft-versus-host disease (GVHD). Early-life transplants have high success rates, and in utero transplants are also looked at. Gene therapy is an alternative treatment, with notable success in ADA SCID and X-linked SCID. Non-curative treatments include reverse isolation and enzyme replacement therapy for ADA-SCID.

Epidemiology

The prevalence of SCID is typically around one in 100,000 births, although some estimates suggest it may be as high as one in 50,000. Higher prevalence is noted in regions with consanguineous mating. For instance, one in every 2,500 children in the Navajo population inherits SCID, a significant cause of illness and death among Navajo and related Apache children.

SCID in Animals

SCID is used in research, with SCID mice serving as models for disease, vaccine, and transplant studies. Arabian horses and certain dog breeds also exhibit SCID-like conditions, with careful breeding practices and DNA tests employed to manage the disease in animals.

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Self-assessment MCQs (single best answer)

What is the most common form of SCID?

Which gene is affected in X-linked SCID?

What is a common symptom of SCID in infants?

Which enzyme's deficiency causes an autosomal recessive form of SCID by inhibiting purine breakdown?

What diagnostic method is used in newborn screening for SCID in several countries?

Which treatment involves removing mature T cells from donor marrow to avoid GVHD?

Which form of SCID is characterised by mutations in RAG-1 or RAG-2 genes?

What is the estimated prevalence of SCID in the general population?

Which animal is commonly used as a model for SCID in research studies?

What is a notable success of gene therapy in treating SCID?