Adenosine deaminasedeficient severe combined immunodeficiency (ADA-SCID)

This page has been produced jointly between PID UK, Great Ormond Street Hospital (GOSH) and the Great North Children’s Hospital. It describes the adenosine deaminase (ADA)-deficient specific form of severe combined immunodeficiency (SCID) and should be read in conjunction with the general overview leaflet on SCID.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 the leaflet Genetic aspects of immunodeficiency, available on the PID UK website at www.piduk.org/whatarepids/geneticaspectsofpid

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 the separate CID information leaflet available on the PID UK website at www.piduk.org/static/media/up/cidinchildren.pdf

The signs and symptoms of the immunodeficiency in ADA-SCID are the same as in all other forms of SCID. However, patients with ADA-SCID can also have some or all of the following problems:

• Bones: unusual rib ends may be seen on a chest X-ray, and other changes of bone development sometimes occur but do not usually cause symptoms.
• Central nervous system: development may be slower than in healthy children and there may be behavioural and psychological problems, such as hyperactivity and poor social behaviour.
• Hearing: deafness is sometimes a problem.

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

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.

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 PID UK’s booklet Genetic aspects of PID for further information available online at www.piduk.org/static/media/up/geneticaspectsofpid.pdf

• adenosine a chemical that builds up when ADA is absent and is toxic to developing immune cells.
• adenosine deaminase (ADA) an enzyme found in lymphocytes (and other cells), responsible for removing certain toxins produced by their metabolism. In its absence, lymphocytes fail to develop and function, which is one of the causes of severe combined immunodeficiency (SCID).
• autosomal recessive a type of inheritance where the presence of one copy of a faulty gene does not affect the individual him or herself. However, when two carriers of the same faulty gene have children there is a 25 per cent (or 1 in 4) chance of a child inheriting two copies of the faulty gene (one from each parent) for each pregnancy. If this happens, the child is affected by the disorder.
• B cells (B lymphocytes) cells of the immune system derived from bone marrow and involved in the production of antibodies.
• enzyme a protein that acts as a catalyst (trigger) to a specific biochemical reaction. Enzymes make the chemistry of cells work. 
• enzyme replacement therapy treatment to replace a missing or poorly functioning enzyme.
• gene section of DNA on a chromosome that codes for a functional RNA molecule and thus a protein. Put another way, a word rather than a letter in the genetic code. Genes are the fundamental units of inheritance that carry the instructions for how the body grows and develops.
• gene therapy attempting to cure genetic diseases by placing a normal ‘healthy’ gene into cells that have a faulty version of that gene.
• genetic counselling advice from a specialist geneticist regarding the implications of carrying or being affected by a genetic disorder. 
• haematopoietic stem cell transplantation (HSCT) the transfer of stem cells from a donor – either related or unrelated – to a recipient. Stem cells may be obtained from bone marrow (by aspiration usually from the hip bones), peripheral blood (PBSCs) or stored umbilical cord blood. Haematopoietic means blood forming. The donor cells are given by intravenous infusion and make their way to the recipient bone marrow to provide a new immune system, thus curing the immunodeficiency.
• lymphocytes small white blood cells, normally present in the blood and in lymphoid tissue, that carry out the functions of the immune system. There are two major forms of lymphocytes, B cells and T cells, which have distinct but related functions in generating an immune response.
• mutation a change in the structure of a gene or group of genes. Such changes can be passed on to the next generation. Many mutations cause no harm but others can cause genetic disorders, such as primary immune deficiencies.
• natural killer (NK) cells a type of lymphocyte, particularly important in fighting virus infections and protecting against cancer.
• PEG-ADA a chemically modified form of ADA that can be given by injection to improve immune function while awaiting corrective treatment.
• pneumocystis jirovecii pneumonia a severe form of pneumonia caused by an organism called Pneumocystis jirovecii.
• T cells (T lymphocytes) lymphocytes that are processed in the thymus, an organ in the chest. They are responsible, in part, for carrying out the immune response.