编码ryanodine受体(RyR)骨骼肌同工型(RyR1)的RYR1突变是遗传性神经肌肉疾病的常见原因。尽管它在广泛的组织中表达,与RYR1突变相关的非骨骼肌表现鲜有报道.这里,我们报告了三名诊断为中枢核心疾病(CCD)的患者,King-Denborough综合征(KDS)和恶性高热易感性(MHS),分别,除了他们的(推定的)RYR1相关疾病外,他们还出现了急性胰腺炎的症状和体征。在两个病人中,反复发作,严重的多系统受累和后遗症。RyR1介导的钙信号在正常胰腺功能中起重要作用,但也与急性胰腺炎的病理生理学密切相关。特别是在胆汁酸和乙醇诱导的形式中。来自相关动物模型的发现表明,这些病症中的胰腺损伤可以通过施用特异性RyR1拮抗剂丹曲林和改变胰腺代谢(包括钙信号传导)的其他化合物来改善。这些观察结果表明,RYR1功能获得变异的患者发生急性胰腺炎的风险可能会增加,因此,在对这些人进行健康监测时应考虑的情况。
Mutations in
RYR1 encoding the ryanodine receptor (RyR) skeletal muscle isoform (
RyR1) are a common cause of inherited neuromuscular disorders. Despite its expression in a wide range of tissues, non-skeletal muscle manifestations associated with
RYR1 mutations have only been rarely reported. Here, we report three patients with a diagnosis of Central Core Disease (CCD), King-Denborough Syndrome (KDS) and Malignant Hyperthermia Susceptibility (MHS), respectively, who in addition to their (putative)
RYR1-related disorder also developed symptoms and signs of acute pancreatitis. In two patients, episodes were recurrent, with severe multisystem involvement and sequelae.
RyR1-mediated calcium signalling plays an important role in normal pancreatic function but has also been critically implicated in the pathophysiology of acute pancreatitis, particularly in bile acid- and ethanol-induced forms. Findings from relevant animal models indicate that pancreatic damage in these conditions may be ameliorated through administration of the specific RyR1 antagonist dantrolene and other compounds modifying pancreatic metabolism including calcium signalling. These observations suggest that patients with
RYR1 gain-of-function variants may be at increased risk of developing acute pancreatitis, a condition which should therefore be considered in the health surveillance of such individuals.