The Prevalence of RYR1-related Disease

ABSTRACT

The skeletal muscle ryanodine receptor (RYR1) gene encodes an important calcium channel in skeletal muscle, with a crucial role in muscle contraction. Mutations (i.e. disease-causing changes) in RYR1 are associated with a very 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.

The lack of reliable epidemiological 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, focussing 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 approaches well-established in the epidemiological assessment of human disease and other mammalian populations.

This study will provide important information regarding the actual disease burden of RYR1-related disorders on a worldwide scale, inform appropriate research resource allocation, and preparation for trial readiness.

I. RYR1 RESEARCH PRIORITY AREA

A. Prevalence of RYR1-related Diseases

II. IMPACT ON RYR1-RELATED DISEASE

There are several reasons why this research is important and will make a significant difference in the RYR-1 Foundation's mission of finding treatments and cures for RYR1-related diseases:

For the first time, this study will provide reliable and up-to-data epidemiological data concerning the prevalence of RYR1-related disorders as a group, and with regards to specific subgroups within this wider group. Currently available epidemiological data are outdated and do not reflect the changes in diagnostic practices and the related increase in diagnostic yield over the last decade. Moreover, in contrast to the few currently available, regionally limited studies, this is the first epidemiological study concerning RYR1-related disorders taking a nationwide approach involving two large European countries with ethnically mixed populations, thus limiting the potential impact of regional differences in expertise and diagnostic rigour. Moreover, unlike previous studies this study will not only focus on RYR1-related myopathies but on RYR1-related disorders in their entirety, including congenital myopathies and malignant hyperthermia susceptibility.

Reliable epidemiological data concerning a group of disorders and/or specific subgroups within are an essential part of the preparation for clinical trial readiness, and will enable clinical translation of novel therapeutic developments concerning RYR1-related disorders into clinical practice. A number of novel therapeutic approaches are currently at the pre-clinical or clinical trial stage, with some of these approaches expected to be introduced into clinical practice over the next few years.

This study will highlight the true societal and individual disease burden of RYR1-related disorders and provide a stimulus for the appropriate allocation of health and research resources dedicated to this important group of neuromuscular disorders. Moreover, highlighting the relative frequency of specific subgroups (i.e. congenital myopathies, MH) within the wider group of RYR1-related disorders will help to focus and tailor future research efforts, as the underlying pathogenic mechanisms and individual disease manifestations in different subgroups are widely different. More importantly, therapeutic strategies aimed at patients suffering from congenital myopathies will not necessarily benefit those suffering from MH, and different treatment approaches based on reliable epidemiological data may be required.

Finally, obtaining more detailed genotype-phenotype data is likely to provide important insights in the currently not fully explored links between congenital myopathy and malignant hyperthermia phenotypes, and the intriguing continuum between malignant hyperthermia susceptibility, exertional myalgia/rhabdomyolysis and enhanced athletic performance, respectively.

III. SPECIFIC AIMS AND RATIONALE

The specific primary aims of this project are i) to investigate the prevalence of RYR1-related disorders in two different countries, the United Kingdom and the Netherlands; ii) to delineate the relative frequency of specific subgroups (in particular congenital myopathies vs Malignant Hyperthermia) within the overall group of RYR1-related disorders; and iii) to establish genotype-phenotype correlations for specific subgroups of RYR1-related myopathies and related disorders.

Although not a primary aim of this study, the designated Post-doctoral researcher will also be invited to contribute to other ongoing work on RYR1-related disorders from the department.

i) Prevalence of RYR1-related disorders: It is assumed that mutations in RYR1 are one of the most common genetic causes of non-dystrophic neuromuscular disorders, however, there are currently only few studies reporting the prevalence of these common conditions. Moreover, these studies are regionally limited and more than 10 years old, not reflecting recent changes and regional differences in diagnostic practice. An international collaborative study focussing on the prevalence of RYR1-related disorders is therefore much needed and timely.

ii) Frequency of specific subgroups of RYR1-related disease: Over the last two decades, the spectrum of RYR1-related disorders has continuously evolved, encompassing a very wide range of conditions, including several congenital myopathies (in particular, Central Core Disease, CCD; Multi-minicore Myopathy, MmD; Centronuclear Myopathy, CNM; Congenital Fibre Type Disproportion, CFTD), Malignant Hyperthermia Susceptibility (MHS), and related permanent (King-Denborough Syndrome, KDS) and episodic (exertional rhabdomyolysis, ERM; atypical periodic paralysis) myopathies. There are currently no data regarding the frequency of these specific subgroups, and a specific study addressing this shortcoming is urgently needed.

iii) Genotype-phenotype correlations in RYR1-related disorders: Defining genotype-phenotype correlations will help to further elucidate the complex relationship between RYR1-related MHS and CM phenotypes, and provide the basis for future research, including functional studies. Specific analyses to be undertaken will, for example, focus on RYR1 variants implicated in King-Denborough syndrome (KDS), a rare myopathy associated with dysmorphic features and profound malignant hyperthermia susceptibility (MHS), and on the p.Thr4288\_Ala4290dup, a RYR1 variant found at detectable frequency in individuals of African ancestry on databases of genomic variation, often associated with increased athletic ability. RYR1 p.Thr4288\_Ala4290dup has also been found in individuals with exertional myalgia/rhabdomyolysis (ERM) and malignant hyperthermia (MH), but it is currently unclear if this observation reflects a causal association or just the relatively high frequency of this variant in certain populations. To resolve this question, we will compare the frequency of p.Thr4288\_Ala4290dup in the datasets obtained in i) and ii) with its population frequency.

IV. PRELIMINARY/SUPPORTING DATA

i) Prevalence of RYR1-related disorders: There is currently only one study from the United States, indicating the prevalence of RYR1-related congenital myopathies as 1 in 90000 in a representative Paediatric population (Amburgey et al., Ann Neurol 2011;70:662-665); this is likely to be an underestimate, considering that this more than 10-year-old study precedes the widespread introduction of next generation sequencing into clinical diagnostics, and does not take into account presentations such as MH, or MH-related manifestations (such as exertional myalgia/rhabdomyolysis and late-onset axial myopathy) that have only been recognized over the last decade. A more recent UK-based study indicates mutations in RYR1 as the most common identifiable genetic cause of congenital myopathies \[Maggi et al., Neurology 2015;84:28-35\], but does not comment on their overall prevalence.

ii) Frequency of specific subgroups of RYR1-related disease: There is currently only one study from the UK concerning the frequency of specific RYR1-related congenital myopathies (CMs), suggesting that Central Core Disease (CCD) and Multi-minicore Disease (MmD) (the "core myopathies") are most common, whilst others such as Centronuclear Myopathy (CNM) and Congenital Fibre Type Disproportion (CFTD) are less frequent \[Maggi et al., Neurology 2015;84:28-35\]. There is currently no information regarding the relative frequency of CM versus malignant hyperthermia phenotypes, and of more recently emerged MH-associated manifestations such as exertional myalgia/rhabdomyolysis and late-onset axial myopathy.

iii) Genotype-phenotype correlations in RYR1-related disorders: Defining genotype-phenotype correlations will help to further elucidate the complex relationship between RYR1-related MHS and CM phenotypes, and provide the basis for future research, including functional studies. Specific analyses to be undertaken will, for example, focus on RYR1 variants implicated in King-Denborough syndrome (KDS), a rare myopathy associated with dysmorphic features and profound malignant hyperthermia susceptibility (MHS), and on the p.Thr4288\_Ala4290dup, a RYR1 variant found at detectable frequency in individuals of African ancestry on databases of genomic variation, often associated with increased athletic ability. RYR1 has also been found in individuals with exertional myalgia/rhabdomyolysis (ERM) and malignant hyperthermia (MH), but it is currently unclear if this observation reflects a causal association or just the relatively high frequency of this variant in certain populations. To resolve this question, we will compare the frequency of p.Thr4288\_Ala4290dup in the datasets obtained in i) and ii) with its population frequency.

V. DETAILED PROJECT DESCRIPTION

1\) EXPERIMENTAL PLAN AND METHODS:

A) Study description:

i) 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. Above countries will be included based on the availability of a) centralized RYR1 testing with population-wide coverage, and/or the presence of national expertise centres for b) congenital myopathies and malignant hyperthermia (MH) with patient databases/registries with population-wide coverage.

Inclusion criteria for patients are a) the presence of (an) unequivocally pathogenic RYR1 mutation(s), b) clinical features of a recognized RYR1-related disorder (i.e. a congenital myopathy, MH or related phenotypes), c) at least one specialist review at one of the national expertise centres and d) being resident in one of the participating countr

• Determine frequency of subgroups of RYR1-related disorders [Срок оценки: Jan 2011 - Dec 2020]
• To establish genotype-phenotype correlations in RYR1-related disorders [Срок оценки: Jan 2011 - Dec 2020]