Precision medicine study identifies decades-old mysterious, rare and debilitating disease.


The innate immune system is hard-wired to protect people from infection. However, mutations in these protective genes can lead to uncontrolled inflammation, resulting in autoinflammatory disease.  Autoinflammatory diseases are characterized by recurrent episodes of fever with systemic and organ-specific inflammation, as well as uncontrolled activation of the innate immune response in the apparent absence of an infectious trigger.  Now, a mysterious, decades-old autoinflammatory disease has finally been identified by researchers led by Walter and Eliza Hall Institute, who discovered a genetic mutation directly associated with the condition, as well as potential for curing it.  The opensource study is published in the journal Science Translational Medicine.

Previous studies show that the mysterious rare, debilitating disease that has afflicted generations of European families, has long baffled their doctors.  In the affected families, it is passed on from generation to generation, with about half of the children developing the same symptoms as their parent. However, doctors were unable to find the origins of the problem, let alone to come up with a treatment.  The current study investigated families in France, Belgium and England who had been living with an unknown condition that caused severe skin lesions, fevers, pain and exhaustion.

The current study has now defined the disease as Pyrin Associated Autoinflammation with Neutrphilic Dermatosis (PAAND).  Results show that the cause of the disease, a genetic mutation, is found in gene called MEFV. The lab explain that this gene is also known to cause an inflammatory disease called Familial Mediterranean Fever (FMF) in patients who inherit mutated copies from both their mother and father.  Data findings show that in the mutation found in PAAND patients, however, only a single copy of the mutation is needed to cause the disease, so it affects half of the children of patients.

The group state that the PAAND mutation causes the body to respond as if there is an infection, which leads to the skin making an inflammatory protein which causes fevers, pain and skin lesions, and that by identifying the cause they had been able to effect a treatment.  They go on to add that early results show a rapid clearance of skin lesions and a complete recovery from fevers and pain due to using precision medicine.

The team surmise that they are looking at rare and poorly understood conditions that do not fit into categories of disease we are familiar with.  They go on to add that the genetic analysis that is available has allowed them to penetrate the cause of disease in a way that was out of reach before.  For the future, the researchers state that this precision medicine approach is now being trialled as part of the Melbourne Genomics Health Alliance.

Source: Walter and Eliza Hall Institute

Clinical and immunological features of PAAND.   Histologic presentation of inflammatory infiltrate in the subcutis, involving subcutaneous vessels and extending into the surrounding panniculus and deep dermis. Scale bar, 500 μm. Higher magnification shows predominantly polymorphonuclear vascular and perivascular infiltrate (representative from patient II.7). Scale bar, 50 μm.  Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation.  Liston et al 2016.

Clinical and immunological features of PAAND. Histologic presentation of inflammatory infiltrate in the subcutis, involving subcutaneous vessels and extending into the surrounding panniculus and deep dermis. Scale bar, 500 μm. Higher magnification shows predominantly polymorphonuclear vascular and perivascular infiltrate (representative from patient II.7). Scale bar, 50 μm. Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Liston et al 2016.

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