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.
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.
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.
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
Case-only
Retrospective
Not listed
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.
Determine frequency of subgroups of RYR1-related disorders
Based on the data obtained for the primary aim, we will also calculate the frequency of specific subgroups of RYR1-related disorders, including the various congenital myopathies (CCD, MmD, CNM, CFTD, CMNS) and Malignant Hyperthermia (MH). For each patient, the clinical and histopathological diagnosis will be verified by review of the clinical notes and the original muscle biopsy wherever possible.
To establish genotype-phenotype correlations in RYR1-related disorders
We will validate the apparent association between RYR1-related KDS and a RYR1 central domain MH mutational hotspot. The RYR1 p.Thr4288\_Ala4290dup has been previously reported in association with MH reactions, often in individuals carrying at least one additional RYR1 variant \[Levano et al., 2008; Sambuughin et al., 2009\]. We have also found RYR1 p.Thr4288\_Ala4290dup in a cohort of patients presenting with RYR1-associated exertional myalgia/rhabdomyolysis, often associated with an apparent enhanced athletic ability \[Dlamini et al. 2013\]; these associations will be validated in this larger dataset.
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King's College London
Lead sponsor
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
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