MCAS and CKIT mutations

MCAS was first recognized in 1991 but wasn’t named as a condition until 2007.  This term encompasses a large, probably prevalent series of illnesses associated with mast cells that are activated but not proliferating.  While the 2008 WHO classification does not recognize MCAS, it is being recognized more frequently and there have been several calls for standard diagnostic criteria. 

Most MCAS patients have been sick for decades.  Some may live their whole lives without knowing the reason for their illness.  They are generally inexplicably, chronically ill.  Their disease often fits no pattern, and usually laboratory testing for various conditions yields borderline or negative results.  When the results are positive, they are often not diagnostically significant.  Some patients have severe complications in one system (renal failure, for example) that cannot be explained.  Sometimes, another known disease is present and is blamed for all symptoms, even when this makes little sense.

Most patients can identify a specific point at which their health changed dramatically for the worse.  In hindsight, it usually followed a period of significant physical or emotional stress.  Many patients believe that this trigger caused the illness.  It is only after a thorough history with review of all systems that many people realize that their symptoms preceded the event, often going back to childhood. 

In MCAS, mast cell burden is generally normal, and symptoms are due exclusively to inappropriate activation and subsequent mediator release.  It is impossible to match therapy with symptoms and combinations must be tried until a successful one is found.  Most patients are able to eventually identify a successful regimen in which they feel much better most of the time, though periods of flares still persist. 

A source of frustration for MCAS patients is the fact that due to their generally low tryptase values and usually being CKIT-, they are often dismissed as being negative for mast cell disease.  There has been a suggestion in recent years to consider mast cell activation due an episode as being an elevation in tryptase of 20% over baseline + 2ng/ml.  Some providers use this formula, but it is unvalidated. 

The “CKIT mutation” tested for, and generally considered to be confirmatory for mast cell disease, is the D816V mutation.  However, despite often being negative for this specific mutation, multiple studies have shown that MCAS patients almost always have multiple mutations at other locations in the CKIT gene.  These mutations are likely responsible both for the individual constellation of symptoms, including sensitivities, as well as unique responses to various treatments.  It has been suggested that in the future, multiple mutations within the CKIT gene will be confirmatory for mast cell disease, instead of exclusively the D816V mutation.

Though the general school of thought for decades has been that mast cell disease is both rare and proliferative, in the last few years we have learned that this is often untrue.  Due to current, ongoing research by several prominent opinion leaders, we are learning new things about this condition regularly.