表现为复发性急性肝衰竭的囊泡贩运障碍:NBAS、RINT1和SCYL1缺乏症。

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Bianca Peters, Tal Dattner, Lea D Schlieben, Tian Sun, Christian Staufner, Dominic Lenz
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引用次数: 0

摘要

在囊泡贩运遗传疾病中,有三种可导致复发性急性肝衰竭(RALF):NBAS、RINT1 和 SCYL1 相关疾病。这三种疾病的特点是发热感染引发肝危象,在 RALF 病因中占相当大的比例。NBAS和RINT1相关疾病的肝危象发生频率和严重程度会随着年龄的增长而降低,而SCYL1变异型患者则会出现进行性胆汁淤积病程。所有这三种疾病都有多系统、部分重叠的表型,表现各异,包括肝脏、骨骼和神经系统,所有器官系统都具有高分泌活性。这些疾病没有特异性的生物标志物,病因不明的 RALF 患者应进行全外显子组测序。NBAS、SCYL1和RINT1参与了前向和逆行的囊泡运输。病理机制仍未明确,但有证据表明,主要受各自基因缺陷及其相互作用伙伴影响的蛋白质浓度和稳定性降低,可能导致囊泡转运受损。前向转运功能受损会影响蛋白质的分泌,这为不同器官的表现提供了可能的解释,如骨骼因缺乏胶原蛋白而发生改变,或糖尿病患者的胰岛素分泌受到影响。逆行转运功能障碍会影响膜回收和自噬。囊泡转运功能障碍会导致内质网应激增加,在肝细胞中可发展为肝细胞溶解。虽然目前尚无根治性疗法,但尽早实施应急方案似乎对优化治疗管理至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Disorders of vesicular trafficking presenting with recurrent acute liver failure: NBAS, RINT1, and SCYL1 deficiency.

Among genetic disorders of vesicular trafficking, there are three causing recurrent acute liver failure (RALF): NBAS, RINT1, and SCYL1-associated disease. These three disorders are characterized by liver crises triggered by febrile infections and account for a relevant proportion of RALF causes. While the frequency and severity of liver crises in NBAS and RINT1-associated disease decrease with age, patients with SCYL1 variants present with a progressive, cholestatic course. In all three diseases, there is a multisystemic, partially overlapping phenotype with variable expression, including liver, skeletal, and nervous systems, all organ systems with high secretory activity. There are no specific biomarkers for these diseases, and whole exome sequencing should be performed in patients with RALF of unknown etiology. NBAS, SCYL1, and RINT1 are involved in antegrade and retrograde vesicular trafficking. Pathomechanisms remain unclarified, but there is evidence of a decrease in concentration and stability of the protein primarily affected by the respective gene defect and its interaction partners, potentially causing impairment of vesicular transport. The impairment of protein secretion by compromised antegrade transport provides a possible explanation for different organ manifestations such as bone alteration due to lack of collagens or diabetes mellitus when insulin secretion is affected. Dysfunction of retrograde transport impairs membrane recycling and autophagy. The impairment of vesicular trafficking results in increased endoplasmic reticulum stress, which, in hepatocytes, can progress to hepatocytolysis. While there is no curative therapy, an early and consequent implementation of an emergency protocol seems crucial for optimal therapeutic management.

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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
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