The primary objective is to investigate the effect of a variant in RYR1 on the thermal stability of RyR-1. The secondary objective of the study is to investigate whether there is difference in clinical characteristics between patients with a…
ID
Source
Brief title
Condition
- Musculoskeletal and connective tissue disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of the study is the number of positive IVCT*s in the
extended protocol in the RYR1 group compared to the healthy control group.
Secondary outcome
Secondary endpoints of the study are the concentration of caffeine and
halothane leading to a pathological contracture in the extended IVCT in the
RYR1 group compared to the healthy controls. Other secondary endpoints are the
results of a questionnaires study focused on neuromuscular and heat intolerance
complains during exercise and a family history of EHS.
Background summary
Exertional heat stroke (EHS) is a life threatening medical condition defined as
hyperthermia (core temperature >40*C), central nerve system (CNS) dysfunction
occurring during or directly after exercise. Recent studies report several EHS
victims with a variant in RYR1, the gene coding for the ryanodine receptor
type-1 (RyR-1) in the sarcoplasmic reticulum of skeletal muscle cells. In vitro
thermal melt analysis studies reported a lower melting point of receptors with
a RYR1 variant. This might lead to thermal instability and increased risk for
EHS and exertional rhabdomyolysis (ER) but this was never studied before.
Malignant hyperthermia (MH) is a pharmacogenetic disorder triggered by volatile
anaesthetics and depolarizing muscle relaxants. MH susceptible individuals are
identified using RYR1 sequencing and the In Vitro Contracture Test (IVCT). An
extended IVCT protocol with heating of the tissue bath will challenge the
thermal stability of RyR-1.
Study objective
The primary objective is to investigate the effect of a variant in RYR1 on the
thermal stability of RyR-1. The secondary objective of the study is to
investigate whether there is difference in clinical characteristics between
patients with a positive extended protocol IVCT.
Study design
In an open-label controlled study freshly biopsied muscle specimen of patients
with a RYR1 variant and healthy controls are exposed to an extended IVCT
protocol.
Study burden and risks
EHS and ER are severe and life threatening medical conditions. Although several
studies report a high number of RYR1 variants in EHS victims, the role of the
RyR-1 in the pathophysiology remains unclear. This study might confirm that a
variant in RYR1 results in a decrease in thermal stability and a possibly
higher risk for ER and EHS. This knowledge can be used when counselling
patients with a RYR1 variant or ER and EHS victims. Besides, this might be the
first step towards future studies to clarify the role or RyR-1 in the
pathophysiology of ER and EHS or development of treatment strategies.
Although all subjects will have muscle biopsies, all biopsies are taken in
patients who already need to be biopsied or will have surgery in the biopsied
area. The impact of an extra biopsy is minor compared to the trauma of the
surgery or the wound already made for the initial surgical biopsy.
Weg door Jonkerbos 100
Nijmegen 6532 SZ
NL
Weg door Jonkerbos 100
Nijmegen 6532 SZ
NL
Listed location countries
Age
Inclusion criteria
Inclusion criteria RYR1 patients
* Genetically proven RYR1 variant
* Indication for an IVCT in the context of routine clinical care
* Age 18 * 65 years old
Inclusion critera healthy controls
* Indication for surgery of the upper leg in the context of routine clinical
care, e.g. removal of osteosynthesis material or elective orthopaedic surgery
of the upper leg.
* Age 18 * 65 years old
Exclusion criteria
Exclusion criteria RYR1 patients
* Another family member is included in the study
* An MH reaction, EHS, ER, compartment syndrome, ischaemia of the lower
extremities, trauma of the upper legs or rhabdomyolysis due to another
aetiology in the past 4 months.
* A viral infection in the past week
* Other neuromuscular disorders than RYR1 related MH/ER/EHS
* Patients using systemic corticosteroids during the last 3 months
* Pregnancy or lactating
* No written informed consent by the patient
Exclusion criteria healthy controls
* A history of a RYR1 variant
* Another family member is included in the study
* A history or a family history of a RYR1 related disease (MH, EHS, ER, central
core disease, multi-minicore disease)
* A history of a neuromuscular disorder
* Patients using systemic corticosteroids during the last 3 months
* Patients with a current compartment syndrome, planned for fasciotomy
* Patients with current ischaemia of the lower extremities with an indication
for vascular surgery or amputation.
* Patients with current trauma of the upper legs and an indication for surgery.
* A compartment syndrome, ischaemia of the lower extremities, trauma of the
upper legs or rhabdomyolysis due to another aetiology in the past 4 months.
* A viral infection in the past week.
* Pregnancy or lactating
* No written informed consent by the patient
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL74937.091.20 |