The Prevalence of RYR1-related Disease

NCT06791369 | Not Yet Recruiting

• 1 other identifier: IRAS ID 335736
• Study Type: observational
• Target: 2,000
• Locations: 1 country
• Sites: 1

Brief Summary

The skeletal muscle ryanodine receptor (RYR1) gene encodes an important calcium channel in skeletal muscle, with an important role in muscle contraction. Mutations (i.e. disease-causing changes) in RYR1 are associated with an immensely wide range of clinical problems, ranging from inborn muscle conditions with profound weakness at birth ("congenital myopathies"), to a potentially fatal anaesthesia complication ("Malignant Hyperthermia, MH") in otherwise healthy individuals. Although RYR1-related conditions are believed to be amongst the most common neuromuscular disorders, their precise prevalence (i.e. the number of cases in a particular population at a given time) is currently unknown. Moreover, there is no information regarding the relative frequency of specific congenital myopathies, MH and related manifestations, such as the associated bleeding abnormality recently described by our team. The lack of reliable prevalence data represents a major obstacle to addressing the needs of individuals affected by RYR1-related conditions, to appropriate resource allocation, and to preparation for clinical studies ("trial-readiness") essential for therapy development. To address this shortcoming, we will conduct an international collaborative study involving neuromuscular and MH centres from the UK and the Netherlands, focusing on the prevalence of RYR1-related conditions, as a group and per subtype. The countries participating in this study were included because of 1) centralized RYR1 testing, 2) the presence of at least one database/registry with population-wide coverage capturing RYR1-related disorders and 3) of national myopathy and MH expertise centres. Information regarding RYR1-mutated individuals and their specific diagnosis will be obtained from national databases/registries, and analysed utilizing statistical methods that are well-established in the field of epidemiology. This study will provide important information regarding the actual disease burden of RYR1-related disorders on a wider scale, inform appropriate research resource allocation, and preparation for trial readiness. This study will be funded by the RYR1-Foundation.

Conditions

Neuromuscular Disease; Malignant Hyperthermia; Congenital Myopathy; Multiminicore Disease; Nemaline Myopathy; Centronuclear Myopathy; Central Core Disease; Congenital Fiber Type Disproportion

Keywords

RYR1; Ryanodine Receptor Type 1; Malignant Hyperthermia; Congenital Myopathy

Outcome Measures

Primary Outcomes (1)

• The prevalence of RYR1-related disorders

  To determine the prevalence of RYR1-related disorders, we will collect demographic, genetic, clinical and pathological data from patients diagnosed and reviewed in two different countries, the United Kingdom and the Netherlands, with populations of 67 and 17 million, respectively. Point prevalences for each country will be calculated based on the number of patients alive on the 31.12.2020, in comparison to national population numbers.

  Jan 2011 - Dec 2020

Secondary Outcomes (2)

• Determine frequency of subgroups of RYR1-related disorders

  Jan 2011 - Dec 2020

• To establish genotype-phenotype correlations in RYR1-related disorders

  Jan 2011 - Dec 2020

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

We will collect the data from local databases/registries already existing at the participating centres: * Malignant Hyperthermia Investigation Unit, St James's University Hospital, Leeds * Great Ormond Street Hospital, London * Evelina London Children's Hospital, London * Radboud University Medical Centre, Nijmegen

You may qualify if:

• the presence of (an) unequivocally pathogenic RYR1 mutation(s)
• clinical features of a recognized RYR1-related disorder (i.e. a congenital myopathy, MH or related phenotypes)
• at least one specialist review at one of the national expertise centres
• being resident in one of the participating countries.

You may not qualify if:

• a clinical diagnosis of a congenital myopathy or malignant hyperthermia without any of the supportive evidence as outlined above
• not being resident in one of the participating countries.

Sponsors & Collaborators

• King's College London: lead
• Great Ormond Street Hospital for Children NHS Foundation Trust: collaborator
• Radboud University Medical Center: collaborator
• University of Leeds: collaborator
• Guy's and St Thomas' NHS Foundation Trust: collaborator

Study Sites (1)

King's College London

London, United Kingdom

Location

Related Publications (10)

• Zhou H, Lillis S, Loy RE, Ghassemi F, Rose MR, Norwood F, Mills K, Al-Sarraj S, Lane RJ, Feng L, Matthews E, Sewry CA, Abbs S, Buk S, Hanna M, Treves S, Dirksen RT, Meissner G, Muntoni F, Jungbluth H. Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord. 2010 Mar;20(3):166-73. doi: 10.1016/j.nmd.2009.12.005. Epub 2010 Jan 18.

  PMID: 20080402 BACKGROUND

• Wilmshurst JM, Lillis S, Zhou H, Pillay K, Henderson H, Kress W, Muller CR, Ndondo A, Cloke V, Cullup T, Bertini E, Boennemann C, Straub V, Quinlivan R, Dowling JJ, Al-Sarraj S, Treves S, Abbs S, Manzur AY, Sewry CA, Muntoni F, Jungbluth H. RYR1 mutations are a common cause of congenital myopathies with central nuclei. Ann Neurol. 2010 Nov;68(5):717-26. doi: 10.1002/ana.22119.

  PMID: 20839240 BACKGROUND

• Maggi L, Scoto M, Cirak S, Robb SA, Klein A, Lillis S, Cullup T, Feng L, Manzur AY, Sewry CA, Abbs S, Jungbluth H, Muntoni F. Congenital myopathies--clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom. Neuromuscul Disord. 2013 Mar;23(3):195-205. doi: 10.1016/j.nmd.2013.01.004. Epub 2013 Feb 8.

  PMID: 23394784 BACKGROUND

• Loseth S, Voermans NC, Torbergsen T, Lillis S, Jonsrud C, Lindal S, Kamsteeg EJ, Lammens M, Broman M, Dekomien G, Maddison P, Muntoni F, Sewry C, Radunovic A, de Visser M, Straub V, van Engelen B, Jungbluth H. A novel late-onset axial myopathy associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene. J Neurol. 2013 Jun;260(6):1504-10. doi: 10.1007/s00415-012-6817-7. Epub 2013 Jan 18.

  PMID: 23329375 BACKGROUND

• Lopez RJ, Byrne S, Vukcevic M, Sekulic-Jablanovic M, Xu L, Brink M, Alamelu J, Voermans N, Snoeck M, Clement E, Muntoni F, Zhou H, Radunovic A, Mohammed S, Wraige E, Zorzato F, Treves S, Jungbluth H. An RYR1 mutation associated with malignant hyperthermia is also associated with bleeding abnormalities. Sci Signal. 2016 Jul 5;9(435):ra68. doi: 10.1126/scisignal.aad9813.

  PMID: 27382027 BACKGROUND

• Levano S, Vukcevic M, Singer M, Matter A, Treves S, Urwyler A, Girard T. Increasing the number of diagnostic mutations in malignant hyperthermia. Hum Mutat. 2009 Apr;30(4):590-8. doi: 10.1002/humu.20878.

  PMID: 19191329 BACKGROUND

• Jungbluth H, Zhou H, Hartley L, Halliger-Keller B, Messina S, Longman C, Brockington M, Robb SA, Straub V, Voit T, Swash M, Ferreiro A, Bydder G, Sewry CA, Muller C, Muntoni F. Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene. Neurology. 2005 Dec 27;65(12):1930-5. doi: 10.1212/01.wnl.0000188870.37076.f2.

  PMID: 16380615 BACKGROUND

• Dowling JJ, Lillis S, Amburgey K, Zhou H, Al-Sarraj S, Buk SJ, Wraige E, Chow G, Abbs S, Leber S, Lachlan K, Baralle D, Taylor A, Sewry C, Muntoni F, Jungbluth H. King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord. 2011 Jun;21(6):420-7. doi: 10.1016/j.nmd.2011.03.006. Epub 2011 Apr 22.

  PMID: 21514828 BACKGROUND

• Dlamini N, Voermans NC, Lillis S, Stewart K, Kamsteeg EJ, Drost G, Quinlivan R, Snoeck M, Norwood F, Radunovic A, Straub V, Roberts M, Vrancken AF, van der Pol WL, de Coo RI, Manzur AY, Yau S, Abbs S, King A, Lammens M, Hopkins PM, Mohammed S, Treves S, Muntoni F, Wraige E, Davis MR, van Engelen B, Jungbluth H. Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis. Neuromuscul Disord. 2013 Jul;23(7):540-8. doi: 10.1016/j.nmd.2013.03.008. Epub 2013 Apr 28.

  PMID: 23628358 BACKGROUND

• Amburgey K, McNamara N, Bennett LR, McCormick ME, Acsadi G, Dowling JJ. Prevalence of congenital myopathies in a representative pediatric united states population. Ann Neurol. 2011 Oct;70(4):662-5. doi: 10.1002/ana.22510.

  PMID: 22028225 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Biospecimens will not be collected. Pre-existing diagnostic data will be transferred by the direct clinical care team.

MeSH Terms

Conditions

Neuromuscular Diseases; Malignant Hyperthermia; Myotonia Congenita; Minicore Myopathy with External Ophthalmoplegia; Myopathies, Nemaline; Myopathies, Structural, Congenital; Myopathy, Central Core

Condition Hierarchy (Ancestors)

Nervous System Diseases; Intraoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Postoperative Complications; Hyperthermia; Body Temperature Changes; Signs and Symptoms; Myotonic Disorders; Muscular Diseases; Musculoskeletal Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Central Study Contacts

Heinz Jungbluth, MD PhD MRCP MRCPCH

CONTACT

+44 20 71883998; heinz.jungbluth@gstt.nhs.uk

Arti M Mistry, PhD MSci

CONTACT

arti.mistry@gstt.nhs.uk

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 17, 2024
• First Posted: January 24, 2025
• Study Start: February 1, 2025
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2026
• Last Updated: January 24, 2025

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)