Learn about APDS

An overview of APDS for clinicians who would like to learn more about the disease

Learn about APDS

Overview

Activated PI3 Kinase Delta Syndrome (APDS) is a newly discovered cause of Primary Immunodeficiency (PID) and Hyper-IgM Syndrome. Clinicians and scientists working on exome sequencing patients with primary immunodeficiency in Cambridge, United Kingdom, observed the same missense mutation in a critical signalling kinase that is particularly highly expressed in immune cells termed PI3 kinase delta. On further testing, this mutation has been shown to be absent from over 4,000 healthy control subjects’ genomes as well as unaffected first degree relatives of affected patients, indicating that this mutation is causative of these subjects’ immunodeficiency. One subject has been identified with an apparent spontaneous mutation causing APDS, indicating that a history of inherited immunodeficiency is not absolutely required for a patient to have APDS.

To date, 17 subjects have been identified as carrying the APDS mutation out of a total of ~240 screened genomes from PID patients. Thus, although rare in the general population APDS is reasonably common among patients with PID.

Clinical features

APDS is a clinically heterogenous condition with variable penetrance among affected individuals. The most common manifestation is susceptibility to recurrent infections with Streptococcus pneumoniae and Haemophilus influenzae, particularly of the ear, sinuses and lungs. Other common features include a rise in circulating IgM, a reduction in IgG2, and lymphopaenia. Many patients also have splenomegaly. A more detailed description of the symptoms and signs seen in APDS is described here.

Diagnosing APDS

At present, and for the foreseeable future, the only way to definitively diagnose APDS is with genetic testing. APDS is never a clinical diagnosis; genotyping the PIK3CD gene is mandatory to prove or exclude the diagnosis. Patients who should be considered for screening include:

  1. Any patient with Primary Immunodeficiency;
  2. Any patient with Hyper-IgM syndrome;
  3. First degree relatives of patients with proven APDS.

Contact details to arrange genetic testing of patients who fulfil one of these criteria can be found here.

Management of APDS

Until now, patients with APDS have been treated with standard regimes used in PID. Many patients (but not all) have received treatment with regular IVIG. Prompt and aggressive management of intercurrent infection with anti-microbials is mandatory. One subject with particularly penetrant and severe disease received a bone marrow transplant at the age of eight, following which his condition markedly improved – however, APDS comprises a spectrum of clinical severity, and not all patients have disease severe enough to justify bone marrow transplantation. More details about the treatment of APDS can be found here.

Future developments

Now that the underlying mutation in APDS has been described and cheap and rapid genotyping is available for other subjects, it may be possible to conduct clinical trials of treatments that interfere in a targetted fashion with the overactive kinase in these patients. Although certain small molecule inhibitors of PI3K-delta would not be an appropriate treatment for patients with PID in general, patients with APDS may represent a subset in whom these treatments may have particular efficacy.

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