The genetic basis of mast cell activation disease - looking through a glass darkly

Mast Cell Activation Disease and Microbiotic Interactions

“…KIT D816V is consistently found in SM (490% of cases) 2 and likely drives prominent pathologic features, including MC proliferation, aggregation, spindling, tryptase overexpression, and CD25 coexpression. 2 However, repeated findings that patients with MCAS harbor multiple mutations in KIT, albeit in no yet-apparent recurrent patterns 9,10 (and almost never including KIT D816V ), together with similar mutational heterogeneity in KIT and other MC regulatory elements in patients with mastocytosis, 11 align with observations of marked clinical heterogeneity in patients with MCAS and mastocytosis. Although MCAS appears usually clonal in the research laboratory, most commercial laboratories today assess MC clonality only by KIT mutation analysis at codon 816 (via polymerase chain reaction) or by MC CD25 or CD2 expression (by flow cytometry).…”

“…The estimated incidence in western Europe is 5 to 10 per 1 million population per year 19,20 ; the prevalence is 0.3 to 13 to 100,000. 11 Only preliminary epidemiologic data on MCAS have been reported. In Germany, the prevalence of MCAD has been estimated at 5% to 10% of the general population, [11][12][13] which may be unsurprising because MCAS may underlie many common conditions in subsets of patients, such as those with fibromyalgia and irritable bowel syndrome (IBS).…”

“…Evidence for epigenetic pathogenicity in MCAD is emerging; patients with MCAD bear abnormal epigenomes. 11,12,14 However, lifestyle-influenced factors, such as diet; alcohol use; and, yes, microbiota, 15,16 may influence MCAD phenotype.…”

“…11,12 Yet, a familial predisposition for MC activation disease (MCAD) has been demonstrated. 11,13 Complexity multiplies on recognition that different affected members of an affected kindred usually bear disparate presentations and MC mutational profiles. Perhaps inheritable epigenetic mutations create genetic fragility states susceptible to specific stressors, inducing specific (and/or random?)…”

Cardiovascular symptoms in patients with systemic mast cell activation disease

“…9,[18][19][20] Mast cell chymase also participates in the activation of big endothelin to endothelin-1. 21 Other mediators such as cytokines and the growth factors in all domains of KIT but not affecting codon 816 (for review, see [55]) and the diagnosis can be made according to the current international provisional definition criteria (Supplementary Table 1). Due to both the widespread distribution of MCs and the great heterogeneity of aberrant mediator expression patterns, symptoms can occur in virtually all organs and tissues; hence, the clinical presentation of MCAD is very diverse, sometimes to the even-furtherconfounding point of presenting opposite abnormalities in different patients.…”