Profile of the RYR-1 Foundation

Mutations in the RYR-1 gene are known to cause multiple types of muscle cell abnormalities, one of which is centronuclear myopathy. In 2017 The Information Point recently spoke with Rachel Bronstein, Program Coordinator at the RYR-1 Foundation, herself diagnosed with centronuclear myopathy caused by a mutation in the RYR-1 gene, to learn more about their work.

Tell us about the RYR-1 Foundation

The RYR-1 Foundation is a public charity, designated as a 501(c)(3) organization by the IRS. The Foundation was started by members of the Goldberg Family, who have been affected by RYR-1 muscle disease (myopathy). Currently, there is no other organisation that exists solely to advocate for and serve the needs of individuals with RYR-1 myopathy. The goal of the organisation is to fill this void.

Can you tell us about your logo

The logo of the Foundation is a back to front ‘R’ – the founders thought it was eye catching and interesting. The colors and pattern in the ‘RYR-1’ logo are designed to look like muscle fibers.

What can you tell us about RYR-1 myopathy, its different muscle cell types and how they affect people

RYR-1 myopathy is caused by a mutation or mutations in the RYR-1 gene. The actual mutation will cause different types of abnormalities in the ryanodine receptor 1 (RYR-1), a calcium channel in skeletal muscle cells. Prior to genetic testing, muscle diseases were diagnosed based on muscle biopsy. RYR-1 myopathy affects different individuals in various ways. Mutations in the RYR-1 gene can lead to changes in the muscle cell that result in varying appearances based on muscle biopsy. These include Central Core Disease (CCD), Centronuclear Myopathy (CNM), Multiminicore Disease (MMD) and Congenital Fiber-Type Disproportion (CFTD). In addition, individuals with RYR-1 mutations can be at increased risk for malignant hyperthermia (MH), a potentially fatal reaction to anesthesia. In fact, some individuals with RYR-1 mutations will have little, if any, muscle weakness but will only have a susceptibility to MH (MHS).

Participants at RYR-1 family conference.

How rare is RYR-1 myopathy

RYR-1 myopathy is classified as an orphan disease. Its exact prevalence is not known.

Why should people join your patient registry

There are several reasons why the patient registry is extremely critical. All affected individuals with RYR-1 myopathy are encouraged to join the RYR-1 Foundation’s registry. This database will serve to:

a) Increase our understanding of RYR-1 muscle disease

RYR-1 myopathy is a rare disease, although likely not as rare as some believe. RYR-1 gene abnormalities have been associated not only with congenital myopathy but also with MHS, intolerance of certain cholesterol lowering drugs (‘statin myopathy’) and rhabdomyolysis. Building a patient database will allow physicians, researchers, and genetic counselors to better understand the different forms of RYR-1 myopathy, its natural history and its prevalence.

b) Conduct clinical trials

As a rare disease, RYR-1 myopathy can present a challenge to researchers, pharmaceutical companies and physicians who want to test potential therapies. Without easy access to patients who can serve as study subjects, clinical trials cannot be performed. And without clinical trials, hope for a cure is diminished. Thus, by developing a database of RYR–1 myopathy patients, we can collaborate with those who have found potentially promising therapies.

c) Find a cure

This is the ultimate goal of the RYR-1 Foundation. As mentioned above, without clinical trials to test potential therapies, finding a cure is highly unlikely.

Mike and Jackson

In 2015 you announced your first request for grant applications and this was followed by a second round of grant applications in 2016 – what can you tell us about this

The RYR-1 Foundation began accepting grant applications in July 2015 as a way to help facilitate research for RYR-1 myopathy. We ultimately awarded almost $300,000 in research grant funding. In addition, we recently have awarded over $500,000 in grants for 2017-2018. It is our hope that with the funding of research grants, we will come one step closer to finding an effective treatment or a cure for RYR-1 myopathy. Our research priorities are based on the input we receive from our Scientific Advisory Board and we look forward to supporting many worthy research projects.

You sponsored the Gordon Research Conferences in 2015 and 2017 – what can you tell us about this

These conferences focus on the main mechanisms related to the role of the RYR-1 receptor in muscle contraction. The Foundation wanted to support this as it directly relates to RYR-1 myopathy and dysfunction of the RYR-1 receptor. The meetings are led and attended by experts in RYR-1-related diseases.

Tell us about your first family conference

The first ever RYR-1 International Family Conference was held in Baltimore, Maryland in July 2016. It was an overwhelming success. Over 200 individuals from around the world came together to listen to world-renowned experts speak about RYR-1-related-myopathies. This conference was vital to our mission of supporting individuals and their families with this rare condition. A question and answer session allowed affected individuals and their family members to obtain answers from our panel of experts. The conference would not have been possible without the amazing organisational skills and tireless efforts of Jeni Ryan, a trustee of the RYR-1 Foundation. The RYR-1 Foundation hopes to host a Family Conference every two years. The next one is in the process of being planned for the summer of 2018. An announcement will be made soon with details including dates and location.


You participated in and co-hosted the 217th ENMC workshop on RYR1-related myopathies – what can you tell us about this

Due to the rarity of RYR-1 myopathy, there had been no regularly scheduled meetings devoted to this condition. In response, the RYR-1 Foundation co-hosted a three day RYR-1 workshop in the Netherlands, which included some of the world’s leading authorities in muscle disease. This was a unique opportunity for these clinicians and researchers to share their research, exchange ideas, and discuss future research projects.

What do you hope the RYR-1 Foundation will achieve in 2017

As mentioned above, we have committed a large sum of money to research grants related to RYR-1-related diseases; we look forward to reviewing the results of these ongoing research projects. In addition, we hope to increase the size of our patient registry. Other goals include improving our outreach to individuals, families, researchers and physicians. We also have begun planning for the 2018 RYR-1 International Family Conference.

Our motto, ‘Strength in Numbers’, reminds us that any success we achieve will be dependent on not only the leadership and staff of the RYR-1 Foundation but also our many generous donors, volunteers, affected individuals, physicians, and researchers. As a non-profit public charity, we immensely appreciate your support.

Titin mutations cause centronuclear myopathy

This story first appeared in the Information Point newsletter Our World in 2013, when Sarah Foye, Lindsay Swanson, MS, CGC and Elizabeth Torosian told the The Information Point about the discovery that mutations in the Titin (TTN) gene can cause centronuclear myopathy.

As you may know, the congenital myopathies are a group of inherited disorders (passed down from parent to child) that affect the structure of muscles. The class of myopathies known as centronuclear myopathy (CNM) have historically been named due to the muscle cells appearance under the microscope. The nuclei of muscle cells affected by CNM tend to be found in the center of the cell, unlike in healthy muscles where the nucleus is found on the edge of the cell. These internalized nuclei are what give CNM it’s name, but there are several genes known to cause various forms of CNM. These genes are MTM1, DNM2, RYR1, BIN1 and TTN however some genes still remain unknown.

New gene discoveries are taking place as muscle disorder researchers learn more about CNM and more technologies become available. One new technology being utilized in the research lab of Dr Alan Beggs includes whole exome sequencing (WES) and whole genome sequencing (WGS). These new technologies, which can be less expensive than traditional genetic sequencing, allow researchers to look at larger chunks of the human genetic code.

Using this technology, the Beggs Lab, along with a group of collaborators, discovered that mutations in the Titin (TTN) gene can cause CNM. Titin, the largest known protein in the human body, is coded by the TTN gene. It is a structural protein that acts as a molecular spring within the muscle cell, as seen in the drawing to the right. Although Titin has long been known to be a structural protein within the muscle cell, examination of the gene TTN has been limited due to it’s gigantic size. However, the use of new genetic testing methods like WES and WGS have allowed researchers to understand more about Titin and the TTN gene. You can read more about this in the article below.

Beggs et al, used the new genetic testing methods to screen a group of subjects who were diagnosed with CNM by muscle biopsy but tested negative for mutations in all genes known to cause CNM. Through this process, they identified that TTN mutations were likely the genetic cause in five individuals with CNM. You can read more about this in the article below:

However, there still remains a large category of people diagnosed with CNM whose genetic cause remains unknown. With new gene discoveries and new technologies, it can be expected that people can jump from the ‘unknown’ category into a category with a known gene. New clinical testing can help ease the diagnosis by testing for many genes simultaneously. The University of Chicago Genetic Services Laboratories is now offering a state of the art test in which multiple congenital myopathy genes can all be tested at once. Known as next generation sequence genetic testing. This type of testing is faster and cheaper than prior testing methods. This panel includes the TTN gene. If you or a family member have been diagnosed with MTM or CNM but never had a genetic mutation identified or confirmed through a clinical lab, please consider discussing this with your doctor or a genetic counselor.

One final point to note is that TTN mutations are known to cause a heart problem known as adult onset dilated cardiomyopathy. This can have important clinical implications for people who may have CNM caused by a TTN mutation and may be another important reason to have the genetic testing done. Additionally, any person with heart problems and a congenital myopathy may strongly consider TTN as a possibly cause.

International collaboration

Since 2011 the Myotubular Trust has been funding a grant to Dr Jocelyn Laporte at IGBMC in France to use next generation gene sequencing technology to find some of the other genes that cause myotubular and centronuclear myopathy. Jocelyn Laporte says ‘The team in Strasbourg is supported by Myotubular Trust to identify genes linked to myotubular and centronuclear myopathies using the novel genome sequencing approach. Due to this support the lab were able to participate to an international collaborative study that culminated in the identification of mutations in Titin in patients presenting with centronuclear myopathy. Titin is the largest protein of the human body and acts as a molecular spring during muscle contraction and relaxation. Other families with centronuclear myopathy that have previously eluded genetic diagnosis may turn out to be linked to this same gene. Researchers can now use this finding to better establish diagnosis and understand how these myopathies occur’.

The discovery of the Titin protein’s role in this condition is a great example of the power of international collaboration between leading neuromuscular research teams. This is really good news for our community

Genetic testing

If you have been diagnosed with myotubular myopathy but have never had your MTM1 mutation identified of confirmed in a clinical laboratory, you may want to consider enrolling in the MTM Genetic Testing study.

For European patients, where the culprit gene has not been identified via genetic testing, retesting can be requested via a clinician, as most diagnostic laboratories in Europe are currently validating these novel sequencing technologies. In Europe, such a request for re-testing must be made via a clinician, rather than directly to a laboratory and testing is free in some countries.