Objective

To describe our current understanding of hereditary α-tryptasemia (HαT), how HαT fits into the evolutionary context of tryptases and contemporary framework of mast cell–associated disorders, and to discuss the future clinical and therapeutic landscape for symptomatic individuals with HαT.

Data Sources

Primary peer-reviewed literature.

Study Selections

Basic, clinical, and translational studies describing tryptase gene composition, generation, secretion, and elevation and the associated clinical impacts of HαT and treatment of such individuals were reviewed.

Results

HαT is a common autosomal dominant genetic trait caused by increased TPSAB1 copy number encoding α-tryptase. Approximately 1 in 20 White individuals have HαT, making it by far the most common cause for elevated basal serum tryptase levels. Although many individuals with HαT may not manifest associated symptoms, the prevalence of HαT is increased in patients with clonal and nonclonal mast cell–associated disorders wherein it is linked to more prevalent and/or severe anaphylaxis and increased mast cell mediator-associated symptoms. Increased generation of mature α/β-tryptase heterotetramers, and their unique physiochemical properties, may be responsible for some of these clinical findings.

Conclusion

HαT is a common modifier of mast cell–associated disorders and reactions. Nevertheless, whether HαT may be an independent cause of clinical phenotypes with which it has been associated remains unproven. Correct identification of HαT is critical to accurate interpretation of serum tryptase levels in the clinical evaluation of patients. Beyond HαT, we foresee tryptase genotyping as an important parameter in the standard workup of patients with mast cell–associated disorders and development of therapeutic modalities targeting these patients and associated clinical phenotypes.

中文翻译：

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人类类胰蛋白酶遗传差异的临床相关性

客观的

描述我们目前对遗传性 α-类胰蛋白酶血症 (HαT) 的理解，HαT 如何适应类胰蛋白酶的进化背景和肥大细胞相关疾病的当代框架，并讨论有症状的 HαT 个体未来的临床和治疗前景。

数据源

主要的同行评审文献。

研究选择

回顾了描述类胰蛋白酶基因组成、产生、分泌和升高的基础、临床和转化研究，以及 HαT 的相关临床影响和此类个体的治疗。

结果

HαT 是一种常见的常染色体显性遗传性状，由编码 α-类胰蛋白酶的 TPSAB1 拷贝数增加引起。大约每 20 个白人中就有 1 个患有 HαT，这使其成为迄今为止基础血清类胰蛋白酶水平升高的最常见原因。尽管许多 HαT 患者可能不会表现出相关症状，但在患有克隆性和非克隆性肥大细胞相关疾病的患者中，HαT 的患病率增加，其中它与更普遍和/或严重的过敏反应以及肥大细胞介质相关症状增加有关。成熟 α/β-类胰蛋白酶异四聚体的生成增加及其独特的理化特性可能是其中一些临床发现的原因。

结论

HαT 是肥大细胞相关疾病和反应的常见调节剂。然而，HαT 是否可能是与其相关的临床表型的独立原因仍未得到证实。正确识别 HαT 对于在患者临床评估中准确解释血清类胰蛋白酶水平至关重要。除了 HαT，我们预见类胰蛋白酶基因分型是肥大细胞相关疾病患者标准检查和针对这些患者及相关临床表型的治疗方式开发的重要参数。