Understanding “unspecific vague complaints” through genetics. With the example of “Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number”

Practicing physicians are well aware of “the patient with vague complaints –– who keeps insisting there must be something wrong and it’s not just in their head.”


Attached are two combined filesThe first is a News’N’Views editorial, and it starts with a long “list of medical terms” formulated (17th century) in Molière’s pseudo-Latin ––which concludes one of his most famous plays, Le Malade Imaginaire.  Argan, the main character of the play, typifies a common, yet most com­plex and clinically challenging, kind of patient –– presenting with numerous apparently unre­lated and ever-shifting symptoms and signs.  Over the years, many of these unexplained complaints have been given descriptive names that often suggest non-organic causes and sig­nal to physicians the uselessness of extensive investigations. Among these conditions –– irri­table bowel syndrome, and generalized itch, are well known to clinicians, along with heartburn, flushing and non-focal body pain. “Sick Building Sydrome”, “Idiopathic Environmental Intolerance” and “Multiple Chemical Sensitivity” also come to mind.


More recently, it has become clear that many of these disorders are, in fact, sometimes co-inherited in families in a dominant fash­ion, suggesting the possibility that they may have a common genetic basis. Mast cells have often been implicated in the pathogenesis of these conditions, because many patients with complex symptoms display elevated basal serum levels of tryptase, a mast cell–derived mediator of response to “stress signals”.


The second is an article about elevated basal serum tryptase levels, intended to be related to the editorial. These elevated serum levels are present in 4–6% of the general population –– but the cause and relevance of such increases are unknown.  These authors previously had described patients with dominantly-inherited elevated basal serum tryptase levels associated with multi-system complaints –– including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities (including joint hypermobility).  In the present report, authors have identified germline duplications and triplications in the TPSAB1 gene –– which encodes a-tryptase –– and these copy-number increases segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multi-system complaints.


Individuals harboring alleles encoding three copies of a-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect.  Moreover, authors found in two additional cohorts (N = 172 individuals) having elevated basal serum tryptase levels which were exclusively associated with duplication of a-tryptase–encoding sequence in TPSAB1; affected individuals reported symptom complexes seen in the authors’ initial familial cohort.  These intriguing findings link duplications in TPSAB1 copy-number with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.  “Yes, Virginia, there is sometimes an explanation to ‘imaginary things’.”

 Nat Genet Dec 2o16; 48: 1564–1569 [article] and pp 1450-51 [News’N’Views]

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