This information describes the causes, treatment and diagnosis of the adenosine deaminase (ADA)-deficient specific form of severe combined immunodeficiency (SCID). The contents should be read in conjunction with overview of SCID available here.

The information has been produced jointly between Immunodeficiency UK, Great Ormond Street Hospital (GOSH) and the Great North Children’s Hospital.

ADA-SCID is a specific form of severe combined immunodeficiency(SCID). It is inherited as an autosomal recessive condition. This means that a child has to inherit the faulty gene from both parents to have the condition. There may be a family history of previously affected children, particularly if there are first or second-cousin marriages or partnerships in the family. More information about autosomal recessive inheritance can be found in our leaflet  Genetic aspects of primary immunodeficiency.

What causes it?

ADA-SCID is caused by mistakes (mutations) in the ADA gene, which result in absent or very low levels of the enzyme ADA. Enzymes are protein substances that help speed up chemical reactions in the body. Lack of the ADA enzyme causes a build-up of a toxic substance called deoxyadenosine. This prevents cells from dividing effectively.

White blood cells (especially lymphocytes, and more specifically T cells, B cells and natural killer (NK) cells) that are important for a healthy immune system are very sensitive to these toxic effects and fail to develop normally, leading to SCID.

However, the ADA gene is important in all cells of the body, and therefore patients with ADA-SCID often also have symptoms and signs outside the immune system. In some cases there may be a low level of working ADA enzyme, leading to a less severe ‘delayed’ onset of combined immune deficiency (CID) – please refer to our separate information on CID.

There may also be problems with other body systems, including the kidneys, liver and lungs.

How is it diagnosed?

Infants with typical early onset ADA-SCID have poor growth and frequent, severe and unusual infections, such as pneumonia with an organism called Pneumocystis jirovecii (a yeast-like fungus) that does not usually cause illness in healthy individuals. Breathing difficulties can also occur in infants with ADA-SCID without any detectable infection.

Blood count testing shows a very low lymphocyte count, and basic immunology tests show very low or absent levels of T, B and NK lymphocytes. Doctors refer to this pattern of SCID as ‘T -, B -, NK – SCID’, and this is highly suggestive of a diagnosis of ADA-SCID. The level of ADA enzyme activity in the blood can be measured and is usually less than one per cent of the normal levels seen in healthy children. Additionally, the levels of adenosine can be measured and will be much higher than normal.

Other (non-immunology) investigations

If ADA deficiency is confirmed, it is important to assess hearing as early as possible because of the high risk of deafness. A psychologist will also carry out a developmental assessment. The need for other investigations will depend on whether other systems of the body are involved.

The first stages of treatment and precautions are the same as in all forms of SCID.

However, in contrast to other forms of SCID, it is possible to replace the missing enzyme using a medication known as PEG-ADA. This is often referred to as enzyme replacement therapy. It is given as a weekly injection into a muscle, for instance, the thigh muscle.

PEG-ADA treatment corrects the ADA and adenosine levels in the blood, and usually leads to gradual improvement and partial correction of immune function. It can be used until a more definitive therapy is available, such as haematopoietic stem cell transplant (HSCT) or gene therapy.

Clinical trials of gene therapy for ADA deficiency are ongoing in Europe and the USA, with Great Ormond Street Hospital being one of the centres where this treatment is available.

A related, commercial gene therapy treatment called Strimvelis has been recently approved by NICE and is available to families as an alternative treatment in Milan. The differences between these different gene therapy options will be discussed with the families in detail. The choice between HSCT or gene therapy will depend on whether there are well-matched donors available for transplant and will be discussed at length between the parents and the transplant and gene therapy teams.

Long-term follow-up will be important even after successful treatment of ADA-SCID. The non-immune signs and symptoms of ADA-SCID, particularly developmental, behavioural and psychological effects, will need to be carefully monitored and managed.

Genetic counselling is important for future family planning as both parents will usually carry a copy of the faulty gene and any subsequent children born will have a 1 in 4 chance of being affected. This risk is the same with every pregnancy.

Carrier testing for at-risk family members and prenatal testing for future pregnancies are available once the genetic mutation has been identified in the family. Please refer to our booklet  ‘Genetic aspects of primary immunodeficiency’

You can download our information booklet here