The Prevalence of RYR1-related Disease - an International, Collaborative Multicentre Study
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 2,000
- 试验地点
- 1
- 主要终点
- The prevalence of RYR1-related disorders
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Observational
- 观察模型
- Case Only
- 时间视角
- Retrospective
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •Criteria for the diagnosis of a congenital myopathy are the presence of suggestive clinical features and supportive muscle biopsy findings, or the presence of supportive histopathological findings in a first degree relative with similar clinical features and the same RYR1 genotype. Criteria for the diagnosis of MH susceptibility are clinical features suggestive of malignant hyperthermia (as defined by a diagnostic Larach score) and/or a positive IVCT/CHCT test, or a relative with a history of MH and the same RYR1 genotype. Exclusion criteria will be a clinical diagnosis of a congenital myopathy or malignant hyperthermia without any of the supportive evidence as outlined above, or not being resident in one of the participating countries.
排除标准
- •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.
结局指标
主要结局
The prevalence of RYR1-related disorders
时间窗: Jan 2011 - Dec 2020
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.
次要结局
- 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)