Hereditary Alpha Tryptasemia (HaT)

Hereditary alpha tryptasemia (HαT) is an autosomal-dominant genetic trait present from birth. It is relatively common, estimated to be present in approximately 7 per cent of the global population.^{1, 2}

HαT is caused by having extra copies of the TPSAB1 alpha-tryptase gene, which leads to an increased tryptase production, a protein normally stored in mast cells. As a result, people with HαT often have higher baseline serum tryptase (bST) levels than the general population, even in the absence of an allergic trigger.¹

Many people with HαT remain entirely healthy and symptom free (asymptomatic), never require treatment, and may only discover they have the trait after tryptase testing is performed for another reason, such as an episode of anaphylaxis.*

In well established research HαT is seen to be conservatively associated with an increased prevalence of symptoms including insect venom (hymenoptera) allergy and associated anaphylaxis, retaining baby/milk (primary) teeth, recurrent skin (cutaneous) flushing and itchy skin (pruritus). Other literature also suggests it may also relate to broader symptoms such as abdominal pain, loose stools, irritable bowel syndrome, brain fog. However, in review the studies producing this data were found to have issues of referral bias, or rely on self-reporting of impacted people which was not validated through clinical means. Consequently ongoing research is needed to determine if a broader common symptom profile in people with HαT exists. ¹

*Note: This can sometimes be referred to as an ‘incidental finding’ by clinicians.

Testing

Asymptomatic people do not require hereditary alpha tryptasemia (HαT) testing for diagnosis or monitoring.

In people presenting with mast cell-driven symptoms who are being investigated for MCADs, particularly where a genetic (clonal) mast cell activation disorder is suspected, it is considered that establishing HαT status may be a useful part of the diagnostic evaluation.^3,6

If your clinician has indicated that this testing is appropriate for you and requires information about Australian or international laboratories that offer HαT testing, you or your practitioner are welcome to contact TAMS.

Treatment

HαT itself does not require treatment.

People with HαT may only require treatment where symptoms of mast cell activation, such as flushing, rashes,  gastrointestinal symptoms, or unprovoked anaphylaxis.⁸ In the case of people who experience these symptoms management generally follows the same principles used for MCADs.

If you have recently been identified as positive for the genetic trait HαT, and believe you are experiencing associated symptoms, speak with your clinician about whether any preliminary investigations or treatments are appropriate for your individual circumstances.

Learn more about common MCAD treatments on our Mastocytosis and MCAS pages.

HαT FAQ

How does HαT relate to having an MCAD? Did it cause it?
Current evidence does not support HαT as a considered cause or trigger of mast cell activation disorders (MCADs).

While some literature reflects an over-representation of people with HαT and an MCAD it is considered that this may because people who present with symptoms are more likely to be investigated for MCADs or conversely more likely to be investigated for HαT. particularly in cases of clonal MCADs. ^{3, 9}

Broadly it remains unclear whether HαT plays a role in the development of MCADs or whether it acts as a modifier in some individuals, influencing laboratory findings or symptom patterns.

If I have HaT do I also automatically have a venom allergy? 
Some data suggests people with HαT have a higher frequency of venom allergy when compared to the broader population, however these findings were based on limited data, and when further analysed they did not achieve statistical relevance.¹

If you have a confirmed HaT diagnosis and are concerned about having venom allergy please discuss this with your treating general practitioner.

What is the inheritance rate/pattern of HaT
Hereditary alpha tryptasemia is an autosomal-dominant genetic trait inherited from parent to child. This means the gene involved is located on one of the non-sex chromosomes, and inheriting a single altered copy from either parent will result in HαT being present. ^{1,4, 7}
When one parent carries the trait, each child has a 50 per cent chance of inheriting it, regardless of sex.² In rarer circumstances, where both parents carry the trait, additional copies may be inherited. While a higher number of copies is generally associated with higher baseline blood tryptase levels, the number of copies does not predict symptoms or guarantee any health issues, and most people with HαT remain asymptomatic.⁴

Because HαT is not associated with an automatic risk of symptoms and has not been confirmed as a cause of secondary conditions, including mast cell activation disorders, family planning interventions are not generally indicated for this community group.

If you or your partner carry the HαT gene and have concerns about inheritance or broader genetic family planning considerations please discuss these with your general practitioner for guidance on a suitable referral.

Why isn’t HαT considered a mast cell activation disorder?
Hereditary alpha tryptasemia (HαT) is not classified as a mast cell activation disorder (MCADs), as it has not been proven to inherently involve abnormal mast cell activation.¹ HαT is relatively common, identified in approximately 7 per cent of the general population, so it is expected that millions of people will have HαT, and may also have other health conditions that are unrelated to HαT, making it difficult to reliably determine which symptoms, if any, are directly caused by HαT alone.^1,4

Some studies suggest HαT is more common among those diagnosed with mast cell activation disorders, but this is widely attributed to testing and referral bias.This means symptomatic people are also more likely to be evaluated for MCADs, and those with elevated baseline tryptase are more likely to be tested for HαT.^1,3 Overall, HαT alone has not been shown to cause increased mast cell proliferation or inappropriate activation.⁵

Some individuals with HαT may experience symptoms such as flushing, gastrointestinal issues, or severe anaphylaxis. When these patients do not meet the criteria for mast cell activation disorder (MCAD) but have similar symptoms and respond to MCAD treatment, the condition is sometimes referred to as ‘symptomatic HαT’.

However, as knowledge of MCAD has advanced, particularly regarding mast cell activation syndrome (MCAS) and its subtypes, individuals with HαT who have symptoms consistent with an MCAD, respond to mast cell–directed treatment, and meet diagnostic criteria may receive an MCAD diagnosis (e.g., indolent systemic mastocytosis or monoclonal MCAS) and a further classification of having ‘HαT-associated MCAD’. While this is relatively newly proposed terminology, and does not take the place of your primary diagnosis (e.g., idiopathic MCAS) it may help specialists interpret test results, anticipate management needs and plan for any potential anaphylaxis risk.

I have hereditary alpha tryptasemia (HαT) but no symptoms. Should I take medication?
If you do not have symptoms, daily treatment is not recommended or required.

In people without symptoms, elevated tryptase levels reflect the underlying genetic variation associated with HαT rather than active disease. There is currently no evidence that treating asymptomatic people with HαT provides any health benefit. Additionally, no targeted medication exists to treat HαT in isolation.⁴

While some more intensive treatments can reduce tryptase levels in people with clonal mast activation cell disorders, such as systemic mastocytosis, these therapies are not indicated for HαT and have not been studied or recommended for asymptomatic or symptomatic HαT in isolation.

HaT with anaphylaxis
An important exception is for individuals with a history of unexplained anaphylaxis, or anaphylaxis triggered by foods or insect venom. In these situations, it is important to speak with your treating physician about whether carrying an adrenaline (epinephrine) autoinjector is appropriate, regardless of whether you are otherwise asymptomatic.⁸

Is hereditary alpha tryptasemia fatal?

Based on the limited data currently available, hereditary alpha tryptasemia, on its own, is not associated with reduced life expectancy.

Although published data on long-term outcomes in people with hereditary alpha tryptasemia (HαT) are currently limited, available evidence from affected individuals and associated reports on extended families indicates that HαT alone does not reduce life expectancy compared to the general population.⁴ Furthermore, many individuals with HαT remain asymptomatic throughout their lives.¹

However, some data shows that people with HαT who have allergies to certain foods or insect venom may have more severe allergic reactions, including anaphylaxis.⁵

Individuals with a history of severe allergic reactions should consult their treating clinician to understand their individual risk profile and to receive guidance on appropriate management. Recommendations may include avoidance strategies, establishing an emergency action plan, and carrying an adrenaline (epinephrine) autoinjector if indicated.

More information

For more information about HaT please see this free webinar published by The Mast Cell Disease Society (U.S).