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

> **NIH NIH R01** · RUSH UNIVERSITY MEDICAL CENTER · 2021 · $483,172

## Abstract

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 tai...

## Key facts

- **NIH application ID:** 10214533
- **Project number:** 5R01AR071381-05
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Michael Fill
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $483,172
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214533

## Citation

> US National Institutes of Health, RePORTER application 10214533, The HH: A Large Cohort of Patients with Congenital Myopathies of Uncertain Etiology (5R01AR071381-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10214533. Licensed CC0.

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