X-linked Lymphoproliferative Disease (Duncan's syndrome)

This is a very rare genetic disease and affects about a hundred families around the world (although many others are probably undetected). It is thought that the disease results from an inability to control Epstein-Barr virus (EBV) infections, leading to hyperactivation of the the immune system. Seventy percent of patients with this disease die by the age of ten. Bone marrow transplantation is the best treatment.

The symptoms include:

• Severe mononucleosis-like disease (glandular fever)
• Non-Hodgkins Lymphoma caused by EBV - resulting in swollen lymph glands, anemia and malaise
• Hypogammaglobulinaemia (low immunoglobulins levels) which leads to immunosuppression and opportunistic infections

The disease results from a mutation in the SH2D1A gene which makes a protein called SLAM-associated protein (SAP). SLAM stands for signaling lymphocyte-activation molecule and is also known as CDw150.

SH2D1A (i.e. the SAP gene) is on the X-chromosome and since males have only one X-chromosome, disease will result from a single mutation. Females have two X-chromosomes and thus a recessive single mutation (heterozygote) will not show disease. SLAM is found on both B and T cells and is a self-ligand, that is the SLAM on one cell can bind to the SLAM on another cell. It is involved in bidirectional signaling between B and T cells and results in proliferation. SAP is a T cell protein and is a natural inhibitor of SLAM, blocking the recruitment of proteins with SH2 domains to the SLAM during signaling, thereby suppressing proliferation. In X-linked Lymphoproliferative Disease, the patient cannot eliminate EBV-infected B cells because of defective EBV-specific helper-T-cell and cytotoxic-T-cell responses.