Contents
Genotypically and phenotypically heterogeneous conditions characterized by a block in T lymphocyte differentiation variably associated with abnormal development of other lymphocyte lineages (B and/or natural killer [NK] cells), leading to death early in life unless treated urgently by hematopoietic stem cell transplant.
- Genes involved: JAK3, RAG1, and IL-7R.
History:
Human SCID was first reported by Glanzmann and Riniker in 1950. Swiss infants with the condition were profoundly lymphopenic and died of infection before their first or second birthdays. In the ensuing years, differences were noted in inheritance patterns for SCID. This indicated that there was more than one cause for this fatal syndrome characterized by an absence of T cells and all adaptive immunity. In many families there was an X-linked recessive mode of inheritance while in others an autosomal recessive mode of inheritance was observed. The first discovered molecular cause of human SCID, adenosine deaminase deficiency, was reported in 1972. However, it was not until 21 years later, in 1993, that a second fundamental cause of the condition was found, i.e., the molecular basis of X-linked human SCID. Advances in molecular biology and the Human Genome Project as well as increased knowledge of various components of the immune system through studies of mutant mice and humans with genetically determined immunodeficiencies have all contributed to this understanding. It is now known that SCID can be caused in humans by mutations in at least 10 different genes and the likelihood is that there are other causes yet to be discovered.
Classification
Molecular classification:
- X-lined SCID (M/C, 50-60%): Mutation in common γ-chain (γc) subunit of cytokine receptors
- Autosomal recessive SCID:
- M/C form: Deficiency of ADA enzyme


Pathophysiology

Clinical features
The clinical presentation is fairly uniform and is characterized by early onset of infections, mainly of the respiratory tract and gut.
Clinical presentation usually includes severe, recurrent, and potentially lethal infections early in infancy such as chronic diarrhoea, failure to thrive, lymphopenia (particularly of T lymphocytes) with profound abnormalities of cell-mediated immunity, and antibody deficiency.

Diagnosis
Newborn screening: Real-time quantitative PCR
Newborn screen for severe combined immunodeficiency uses quantitative PCR to measure the number of T-cell receptor excision circles (TREC) that are present in the blood. These are circular DNA fragments that are created as a by-product of normal T-cell development in the thymus

Immunophenotype:
Presence (T–B+ SCID) or absence (T–B– SCID) of B cells & NK cells in the peripheral blood:
- X-linked SCID: T- B+ NK-
- Adenosine deaminase (ADA) deficiency: T- B- NK-
- Mutations in recombination activating genes: T- B- NK+
- IL7Rα deficiency: T- B+ NK+

Management
Non-curative treatments:
Enzyme replacement therapy (for patients with ADA-SCID)
- Polyethyleneglycol-coupled adenosine deaminase (PEG-ADA)
- Metabolizes the toxic substrates of the ADA enzyme and prevents their accumulation
- Used to restore T-cell function in the short term, enough to clear any existing infections before proceeding with curative treatment such as a bone marrow transplant
Curative treatments:
- HSCT (Haematopoetic stem-cell transplantation)
- Gene therapy
Summary
