ADA-associated severe combined immunodeficiency

ADA-associated severe combined immunodeficiency (SCID) is a rare autosomal recessive genetic condition that affects the immune system as a result of a deficiency in the adenosine deaminase enzyme. The resulting accumulation of toxic purine metabolism by-products results in severe lymphopenia, affecting B, T and NK cells. Affected patients have severe, recurrent infections from birth and the condition is typically fatal in the first 12 months without treatment.

ADA-associated SCID is primarily characterised by profound lymphopaenia. This leads to susceptibility to severe, life-threatening infections, including bacterial, viral, fungal and parasitic pathogens.

Typical infections include severe pneumonia or sepsis due to opportunistic pathogens such as Pneumocystis jiroveci, Pseudomonas sp, Candida sp and cytomegalovirus. Infections tend to be persistent, invasive and life-threatening despite conventional treatment. Vaccine-strain infection following administration of live vaccinations, such as BCG or rotavirus, may also occur. Patients are also found to have absent thymus gland and lymph nodes.

Other features may include:

• failure to thrive;
• chronic diarrhoea;
• sensorineural hearing loss;
• neurodevelopmental delay;
• pulmonary inflammation; and
• characteristic skeletal anomalies, including scapular spurring.

As transplacental immunity wanes, infants develop recurrent infections by six months of age. Persistence of symptomatic infection following administration of live vaccinations in the first few months of life may occur. Some infants develop an erythematous rash associated with spontaneous graft-versus-host disease from birth.

Hypomorphic variants in ADA are seen in up to 20% of patients. These individuals retain partial enzyme activity, resulting in a milder presentation of SCID with later onset and additional features, including autoimmune manifestations and chronic viral infections. In rare cases, some patients have presented in adulthood with near normal immune function despite low ADA activity.

ADA-associated SCID is caused by biallelic pathogenic genetic variants in the ADA gene.

Most ADA pathogenic variants cause reduction of the ADA enzyme, with <5% activity detectable. There is an inverse relationship between the level of enzyme activity and the severity of clinical disease.

There is a recognised genotype-phenotype correlation in ADA-associated SCID, as outlined below.

• Typical ADA-associated SCID with profound immunodeficiency typically results from complete loss-of-function (null) variants, such as nonsense, frameshift and large deletions.
• Hypomorphic ADA-associated SCID, in which there is some residual ADA activity and a milder phenotype, can be seen with some missense variants, small in-frame deletions and splice site variants.

Founder variants are also recognised in some populations, including c.7C>T; p.Gln3Ter in those with Somali ancestry, c.424C>T; p.Arg142Ter in those with Canadian Mennonite ancestry; and c.646G>A; p.Gly216Arg in those with Amish ancestry.

ADA-associated SCID can be diagnosed following clinical evaluation or through the newborn blood spot screening programme using the T-cell receptor excision circles assay. Where either is suggestive of SCID, laboratory evaluation is required. Patients may have a family history of immunodeficiency.

ADA-associated SCID causes a T-B-NK- SCID immunophenotype. In addition, the following features may be noted:

• full blood count may show reduced lymphocyte count;
• lymphocyte subset testing shows absent or very low levels of T, B and NK cells;
• immunoglobulin levels are reduced and have impaired antibody responses (IgG levels may be reflective of maternal levels in infants less than six months old);
• absent thymus gland with characteristic scapular spurring may be noted on chest radiography; and
• ADA levels are very low using ADA enzyme assay.

Genomic testing confirms the diagnosis and differentiates ADA SCID from other types of T-B-NK- SCID.

The European Society for Immunodeficiencies diagnostic criteria for SCID is outlined below.

• At least one of the following:
  • invasive bacterial, viral or fungal/opportunistic infection;
  • persistent diarrhoea and failure to thrive; and/or
  • affected family member; and
• manifestation in the first year of life; and
• HIV excluded; and
• two of the following four T cell criteria fulfilled:
  • low or absent CD3, CD4 or CD8 T cells;
  • reduced naive CD4 and/or CD8 T cells;
  • elevated gamma delta (γδ) T cells; and/or
  • reduced or absent proliferation to mitogen or T-cell receptor stimulation.

For information about testing, see ‘Infant with severe combined immunodeficiency with adenosine deaminase deficiency‘.

ADA-associated SCID may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to clinical immunology services. Please refer to the local pathway for your region for this condition.

ADA-associated SCID is caused by biallelic pathogenic genetic variants in the ADA gene. It is inherited in an autosomal recessive pattern and accounts for about 30% of SCID cases. SCID has an estimated incidence of about 1 per 100,000 live births worldwide.

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate. De novo variants may also arise. Heterozygous carriers do not appear to be affected by the disease.

• If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
• • 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
  • 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
  • 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

SCID is a fatal condition unless definitive treatment to reconstitute the immune system is undertaken.

Immediate management principles involve treating infection and prevention of opportunistic infections. This includes:

• no live vaccinations;
• aggressive treatment of infections, including with anti-fungal and anti-viral agents;
• isolation from exposure to pathogens;
• immunoglobulin replacement;
• parenteral nutrition; and
• irradiated, cytomegalovirus negative blood products, if required.

The primary curative treatment is haematopoietic stem cell transplantation (HSCT). This involves replacing stem cells from the patient’s bone marrow with that of a compatible donor. Patients who receive allogeneic HSCT soon after birth tend to have the best outcomes with fewer complications. Five-year survival rates are >90% with HSCT when the patient is under three months old. However, this survival rate declines with increasing age of transplantation and presence of active infections at the time of transplant. Patients require long-term monitoring following HSCT to assess immune reconstitution, as well as monitoring for potential complications.

ADA enzyme replacement therapy is a treatment option involving weekly injections of PEG-ADA. This restores ADA activity to allow recovery of lymphocyte production and helps to clear toxic metabolites. It is often used as a bridge therapy prior to HSCT or an alternative in patients in whom HSCT is not suitable or available.

Another safe, effective treatment for ADA-associated SCID is gene therapy, which involves patient stem cells being corrected in vitro using retroviral gene transfer and then re-infused back into the patient.

ADA-associated SCID may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

For clinicians

• European Society for Immunodeficiencies: Diagnosis criteria
• Jeffrey Modell Foundation: 10 warning signs of primary immunodeficiency
• OMIM: 102700 Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

References:

• Flinn AM and Gennery AR. ‘Adenosine deaminase deficiency: a review‘. Orphanet Journal of Rare Diseases 2018: volume 13, issue 65. DOI: 10.1186/s13023-018-0807-5
• Ivarola P, Urdinez L, Oleastro M and others. ‘A clinical neurological approach to the child With adenosine deaminase deficiency‘. Pediatric Neurology 2024: volume 158, pages 49–56. DOI: 10.1016/j.pediatrneurol.2024.05.022

For patients

• Great Ormond Hospital for Children NHS Foundation Trust: Severe combined immunodeficiency (SCID)
• Immunodeficiency UK: ADA-SCID