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)

项目总结

项目成果

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

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

A chloride channel blocker prevents the suppression by inorganic phosphate of the cytosolic calcium signals that control muscle contraction.

• DOI: 10.1113/jp279917
• 发表时间: 2021-01
• 期刊: The Journal of physiology
• 作者: Ferreira JJ;Pequera G;Launikonis BS;Ríos E;Brum G
• 通讯作者: Brum G

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