Hereditary alpha-tryptasemia in patients with postural orthostatic tachycardia syndrome

Autonomic disorders such as postural orthostatic tachycardia syndrome (POTS) have been reported at higher rates in patients with extra copies of the TPSAB1 gene encoding alpha-tryptase, a genetic trait known as hereditary alpha-tryptasemia (HαT). Patients with HαT have an elevated basal serum tryptase level (bST), with normal being defined as less than 11.4 ng/mL. It has been suggested that 8 ng/mL may be a more sensitive lower limit for the detection of HαT (1). However, some healthy individuals without HαT also have bST levels between 8–11.4 ng/mL (2, 3). It has been reported that up to 34–46% of patients with HαT have autonomic symptoms and positive tilt table testing (1) but this may be a reflection of a modifiable effect that HαT has on POTS, making autonomic disorders more readily detected, similar to the effect that HαT has on hypermobility disorders (4). Referral or recruitment biases also likely contributed to previously reported associations. Additional clinical features associated with HαT may include skeletal abnormalities, gastroesophageal reflux symptoms, arthralgias, headaches, body aches, irritable bowel syndrome, sleep issues, immediate systemic hypersensitivity reactions, and systemic venom reactions (5). Some of these findings may be a reflection of referral biases and findings have not been consistently reported (6). However, through genotyping of well-defined cohorts of patients, greater clarity may be gained into which of these phenotypes may truly be associated with HαT (4). HαT is rare in patients with bST less than 8 ng/mL, but individuals with bST as low as 6.2 ng/mL have been reported (7). The prevalence of HαT is estimated at 5.7% in Caucasian individuals (8) with studies reporting a range between 4–7.5% (5, 6). Given the reported association of autonomic disorders among patients with HαT, we sought to determine whether either elevated bST suggestive of HαT or genetically diagnosed individuals with HαT were more common within an unbiased, well-phenotyped POTS cohort.

In order to investigate the prevalence of HαT in patients with POTS, the results of tilt-table testing from May 2015 – July 2020 at Scripps Clinic were reviewed. In adults, POTS was diagnosed based on an increase of 30 beats per minute or more during the tilt up with symptoms of orthostatic intolerance (9). In children, an increase of 40 beats per minute or more was needed to diagnose POTS. This orthostatic increase in heart rate was in the absence of orthostatic hypotension. The electronic medical records of patients meeting criteria for POTS were then reviewed for serum tryptase levels and previous genetic testing for HαT. Based on recommendations for evaluating symptomatic patients for mast cell-related disorders (8) and recommendations for tryptase genotyping in patients with elevated basal serum tryptase (3), patients with a basal serum tryptase level greater than 6.5 ng/mL and no previous genetic testing for HαT were contacted and offered genetic testing through the National Institutes of Health.

Patient characteristics are summarized in Table 1. During the study period, 493 patients met criteria for POTS with the majority, 426, of these patients being female. 404 out of the 493 patients were white. The average age at testing was 30.14 years with a range of 11–71 years of age. For the 493 patients diagnosed with POTS, 256 patients had a bST drawn, with 250 of these values available for review. The bST values and genetic testing are summarized in Table 2. 232 patients had a bST less than 8 ng/mL. Nine patients had a bST level between 8.0 – 11.4 ng/mL, which is within normal limits for most clinical laboratories, but can be seen among individuals with HαT. Nine patients had a bST greater than 11.4 ng/mL. Upon review of records for genetic testing, only 4 patients had previous genetic testing for HαT, all of whom were positive and had tryptase values > 11.4 ng/mL.

Table 1:

Patient Characteristics

Total number of patients diagnosed with POTS	493
Gender	Female: 426
	Male: 67
Race	White: 404
	Unknown or other: 53
	Hispanic: 23
	Black: 8
	Asian: 3
	American Indian or Alaskan native: 2
Average age at testing (range in years)	30.14 (11–71)
Number of patients who have serum tryptase drawn	256
Number of serum tryptase values available	250

Table 2:

Basal serum tryptase levels

Serum tryptase value in ng/mL	Number of patients	Number of patients with genetic testing for HαT	Number of patients with positive genetic testing for HαT
< 2 ng/mL	16	0	0
2–6.4 ng/mL	207	0	0
6.5–8 ng/mL	9	4	0
8–11.4 ng/mL	9	1	1
> 11.4 ng/mL	9	4	4

Basal serum tryptase levels were available for 250 patients diagnosed with POTS via tilt table testing. The majority (232) were less than 8 ng/mL. 18 patients had levels greater than 8 ng/mL, corresponding with increased likelihood of hereditary alpha-tryptasemia. HαT: hereditary alpha-tryptasemia.

Patients with a bST level greater than 6.5 ng/mL (n = 27) and no previous genetic testing were contacted and offered tryptase genotyping, 5 of which agreed to proceed. Only one of the 5 patients had positive genetic testing for HαT; this patient had a tryptase of 11.3 ng/mL. Four patients with tryptase levels between 6.5–8 ng/mL had negative genetic testing, consistent with the very low prevalence of HαT among individuals with bST levels below 8 ng/mL (8). Details on the cohort and results of genetic testing are further illustrated in Online Repository Table 1.

Since genetic testing was unable to be obtained on all of the patients with a moderate to significant tryptase elevation, calculations were done using Poisson distribution and theory (10) to compare the incidence of tryptase elevation and HαT between our POTS cohort and the general population. Inferring the extreme possibility that all patients with a basal serum tryptase greater than 8 ng/mL have HαT, the prevalence in our cohort with POTS is 7.2%. Given a prevalence of 6% (or 15 out of 250 individuals) of HαT in the general population (8), the maximum possible rate of 7.2% (or 18 out of 250 individuals) in our cohort with POTS does not differ significantly from the general population (incidence rate difference −0.012, 95% CI 0.05704 to 0.03304, P-value 0.6015; incidence rate ratio 0.8333, 95% CI 0.3909 to 1.7510, P-value 0.6075). Using 2% as the minimum possible rate of HαT in patients with POTS (5 out of 250 patients with positive tryptase genotyping), there is a statistically significant difference between our cohort and the general population (incidence rate difference 0.04, 95% CI 0.00494 to 0.07506, P-value 0.0253; incidence rate ratio 3.0000, 95% CI 1.0365 to 10.551, P-value 0.0266). HαT is not increased in patients with POTS and may be decreased.

The maximum inferred prevalence of HαT in patients with POTS is not significantly higher than the general population. Indeed, the confirmed prevalence is likely to be lower than 7.2%. It is unknown whether HαT has a modifiable effect on symptoms in patients with POTS. Given that the order for tryptase was placed for clinical purposes, it is not clear exactly what criteria were used and why only 50% of the entire cohort had a tryptase ordered, although it may be deduced that clinical suspicion for a mast cell disorder was higher in these patients, prompting investigation with bST. Even in this selected cohort, the estimated maximal prevalence of HαT in patients with POTS is not different from the general population. It is important to note that autonomic symptoms reported with HαT may not conform to a specific disorder such as POTS, similar to how gastrointestinal symptoms with HαT do not adhere to a defined diagnosis (11). Although dysautonomia distinct from POTS has been reported in patients with mast cell disorders (12), our data suggest that POTS is not associated with a higher than expected rate of HαT.

Clinical Implications:

Autonomic disorders have been reported at higher rates in patients with hereditary alpha-tryptasemia (HαT), but the reverse does not appear to be true. The estimated prevalence of HαT in patients with postural orthostatic tachycardia syndrome (POTS) is not significantly higher than that of the general population.