The HH: A Large Cohort of Patients with Congenital Myopathies of Uncertain Etiology

HH：一大群患有病因不明的先天性肌病的患者

• 批准号: 10214533
• 负责人: Michael Fill
• 金额: $ 48.32万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214533
• 关键词: Adult; Affect; Affinity; Agonist; Anesthetics; Biopsy; Buffers; CAV1 gene; Caffeine; Canada; Cell Culture Techniques; Cell physiology; Cells; Central Core Myopathy; Chemical Stimulation; Chronic; Chronically Ill; Clinic; Clinical; Clinical Trials; Collaborations; Complement; Contracture; Coupled; Coupling; Creatine Kinase; Cultured Cells; Cysteine; Cytosol; Dantrolene; Data; Defect; Deformity; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Management; Dose; Electric Stimulation; Etiology; Event; Exposure to; Fiber; Fingerprint; Frequencies; Future; Genetic; Genotype; Gold; Grant; Halothane; Heritability; Histopathology; Human; Hypersensitivity; Image; Individual; Inherited; Intervention; Investigation; Ions; Knowledge; Laboratories; Link; Malignant hyperpyrexia due to anesthesia; Measurement; Measures; Mechanics; Medical Genetics; Medical History; Membrane; Molecular; Muscle; Muscle Cramp; Muscle Fibers; Muscle function; Muscle relaxants; Mutation; Myalgia; Myopathy; Names; Normalcy; Operative Surgical Procedures; Outcome; Parents; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Phenotype; Physiology; Play; Population; Predisposition; Prevalence; Process; Property; Protein Isoforms; Proteins; Protocols documentation; Research; Resources; Rest; Rhabdomyolysis; RyR1; Ryanodine Receptors; Sampling; Sarcoplasmic Reticulum; Serum; Ships; Signal Transduction; Skeletal Muscle; Specificity; Stress; Striated Muscles; Structure; Symptoms; System; Testing; Therapeutic; Therapeutic Intervention; Time; Underserved Population; Variant; Work; base; bone; carvedilol; clinical phenotype; cohort; congenital myopathy; design; disease phenotype; exome; experience; extracellular; indexing; individual patient; novel; novel therapeutics; prospective; public health relevance; receptor expression; research clinical testing; sensor; tool; triadin; voltage

Project Summary Intracellular Ca signals reach great intensity in muscle, where they are key to the “Excitation- Contraction Coupling” (ECC) process. In striated muscles they are produced by a supramolecular assembly that we named the couplon, which crucially includes ryanodine receptors (RyRs), channels of the sarcoplasmic reticulum (SR). Multiple diseases arise from abnormal ECC; among them, the paradigmatic Malignant Hyperthermia is diagnosed by the “CHCT”, a conventional challenge with caffeine and halothane. In a 72- patient sample, we have found that roughly 20% tested positive, 40% were negative and 40% tested equivocally, meaning that they Hyper-reacted to Halothane, but not to caffeine. Clinical work found that these patients, which we call the “HH”, are sick, suffering from muscle pain, weakness, high sensitivity to stress, or heat, or statins, and experience rhabdomyolysis and other setbacks. This is in stark contrast with most MH- positive patients, who have a susceptibility to well-known triggers, but otherwise no active disease phenotype. Here, two physiology labs have teamed with the clinic that studies the greatest number of congenital non- dystrophic myopathies in the hemisphere (the MHIU) to propose a comprehensive study of approximately 300 patients. A detailed clinical and genetic picture of each tested patient will be matched by: (1) a cell-level quantification of Ca handling (from measurements of steady and stimulated Ca ion concentration in cytosol and SR, as well as steady and stimulated fluxes between these compartments in adult and cultured cells derived from patients’ biopsies), and (2) a matching molecular description, from measurements of function of single SR Ca release RyR1 channels derived from the patients. Many of these measurements will be the first done in human cells. The results will be interpreted in terms of “pathogenic pathways”, which track the causal chain, starting from a primary defect (e.g. an excessive tendency for RyR to open) to account for and predict the multiple changes that occur downstream. This mechanistic knowledge will then be used to devise therapeutic interventions, tailored rationally to offset the primary defect or the main drivers of the established pathogenic pathways. These may include steady changes in ion composition of the extracellular medium, the classic drug dantrolene and/or application of a large set of newly synthesized RyR-inhibiting drugs, carvedilol derivatives modified from the parent drug to eliminate its beta-blocking action. Among the novel derivatives, 34 were prescreened favorably in a RyR expression system. The best of these, identified based on affinity, efficacy and RyR-isoform specificity, will be applied to single human RyR1 channels, myotubes and myofibers; their outcomes will be compared to those of dantrolene and interpreted within the mechanistic context established in this project. The close bench-clinical correlation of our study makes it possible to tailor the design of potential therapeutic interventions (initially informed by the collective properties of the HH and MH cohorts) to the phenotype (molecular, cellular, or organismal) of individual patients. In future iterations, the top therapeutic paradigms will join clinical testing already going on at the MHIU. (Rev. 11/02/16)

项目摘要 细胞内CA信号在肌肉中达到强度很高，在肌肉中，它们是“激发”的关键。 收缩耦合”（ECC）过程。在条纹的肌肉中，它们由超分子组件产生 我们命名了这对夫妇，该夫妇完全包括ryanodine受体（RYRS），肌质的通道 网状（SR）。多种疾病来自异常的ECC；其中，范式恶性 高温诊断为“ CHCT”，这是Cafeine和Halothane的常规挑战。在72- 患者样本，我们发现大约20％的测试阳性，40％为阴性，40％测试 等准地，这意味着它们与氟烷相反，而不是咖啡因。临床工作发现这些 我们称之为“ HH”的患者患病，患有肌肉疼痛，无力，对压力或高度敏感或 热或他汀类药物，体验横纹肌溶解和其他挫折。这与大多数MH-形成鲜明对比 积极的患者，他们对众所周知的触发因素有敏感性，但没有活跃的疾病表型。 在这里，两个生理学实验室与诊所合作，研究了最多的先天性非 - 半球（MHIU）的营养不良肌病，提出了大约300的全面研究 患者。每位经过测试患者的详细临床和遗传图片将与：（1）细胞级 CA处理的数量（来自细胞质中稳定和刺激的CA离子浓度的测量 SR，以及成人和培养细胞中这些隔室之间的稳定和刺激的通量 从患者的活检中）和（2）匹配的分子描述，从单个SR的功能测量 CA释放从患者中得出的RYR1通道。这些测量中的许多将是第一个完成的 人类细胞。结果将以“致病途径”来解释，该途径跟踪因果链， 从主要缺陷开始（例如，RYR开放的过多趋势）来解释并预测 下游发生多个变化。然后，这种机械知识将用于设计治疗。 干预措施，以合理的方式量身定制，以抵消主要缺陷或已建立病原体的主要驱动因素 途径。这些可能包括经典药物的细胞外培养基的离子组成的稳定变化 Dantrolene和/或应用大量新合成的RYR抑制药物，Carvedilol衍生物 从母体药物修改以消除其β受体阻滞作用。在新颖的衍生物中，有34个是 在RYR表达系统中预先筛查。其中最好的，基于亲和力，效率和 RYR-异型特异性将应用于单个人类RYR1通道，肌管和肌纤维；他们的 结果将与丹特罗伦（Dantrolene）的结果进行比较，并在机械背景下进行解释 这个项目。我们研究的紧密台式临床相关性使您可以量身定制潜力的设计 治疗干预措施（最初由HH和MH队列的集体特性告知） 单个患者的表型（分子，细胞或有机物）。在将来的迭代中，顶级治疗 范例将加入MHIU已经进行的临床测试。 （Rev. 11/02/16）

项目成果

A multi-dimensional analysis of genotype-phenotype discordance in malignant hyperthermia susceptibility.

恶性高热易感性基因型-表型不一致的多维分析。

• DOI: 10.1016/j.bja.2020.07.042
• 发表时间: 2020
• 期刊: British journal of anaesthesia
• 影响因子: 9.8
• 作者: IbarraMoreno,CarlosA;Kraeva,Natalia;Zvaritch,Elena;Figueroa,Lourdes;Rios,Eduardo;Biesecker,Leslie;VanPetegem,Filip;Hopkins,PhilipM;Riazi,Sheila
• 通讯作者: Riazi,Sheila

Anaesthesia and neuromuscular disorders: what a neurologist needs to know.

麻醉和神经肌肉疾病：神经科医生需要了解什么。

• DOI: 10.1136/practneurol-2020-002633
• 发表时间: 2020
• 期刊: Practical neurology
• 影响因子: 2.8
• 作者: vandenBersselaar,LuukR;Snoeck,MarcMJ;Gubbels,Madelief;Riazi,Sheila;Kamsteeg,Erik-Jan;Jungbluth,Heinz;Voermans,NicolC
• 通讯作者: Voermans,NicolC

Episodic RYR1-Related Crisis: Part of the Evolving Spectrum of RYR1-Related Myopathies and Malignant Hyperthermia-Like Illnesses.

• DOI: 10.1213/xaa.0000000000001377
• 发表时间: 2021-01-19
• 期刊: A&A practice
• 作者: Dowling JJ;Riazi S;Litman RS
• 通讯作者: Litman RS

Skeletal Muscle Metabolic Dysfunction in Patients With Malignant Hyperthermia Susceptibility.

恶性高热易感性患者的骨骼肌代谢功能障碍。

• DOI: 10.1213/ane.0000000000002232
• 发表时间: 2017
• 期刊: Anesthesia and analgesia
• 影响因子: 5.7
• 作者: Thompson,SaraJ;Riazi,Sheila;Kraeva,Natalia;Noseworthy,MichaelD;Rayner,TammyE;Schneiderman,JaneE;Cifra,Barbara;Wells,GregD
• 通讯作者: Wells,GregD

Untargeted metabolomics profiling of skeletal muscle samples from malignant hyperthermia susceptible patients.

• DOI: 10.1007/s12630-020-01895-y
• 发表时间: 2021-06
• 期刊: Canadian journal of anaesthesia = Journal canadien d'anesthesie
• 作者: Bojko B;Vasiljevic T;Boyaci E;Roszkowska A;Kraeva N;Ibarra Moreno CA;Koivu A;Wąsowicz M;Hanna A;Hamilton S;Riazi S;Pawliszyn J
• 通讯作者: Pawliszyn J