Characteristics of rare RYR2 variants which can cause a reduced performance of the RYR2 protein, leading to a so called Calcium-Release Deficiency Syndrome
Ventricular fibrillation, the most important (potential) lethal arrhythmia of the heart, can occasionally occur in patients without any structural abnormalities in the heart. In these patients usually genetic variants in genes that are important for appropriate electrical activity in the heart are identified. In a subset of these patients this involves the gene that is responsible for the protein that regulates transport of calcium ions from their stores in the cell to the cell interior where calcium has a critical role for contraction of the cell (mandatory for proper pumping of the heart). This protein is referred to as the Ryanodine receptor type 2 (RyR2; type 1 is in the other muscles in the body and type 2 is in the heart).
Variants in RyR2 can lead to better function of the protein (i.e. increased transport of calcium) or to reduced function of the protein (decreased transport of calcium). It is one of the one, so either gain (better) of function or loss (reduced) of function. The first abnormality leads to a disease that is characterized by exercise or emotion-induced arrhythmias in the ventricles of the heart. This disease is referred to as Catecholamine-induced polymorphic ventricular tachycardia (CPVT) and is diagnosed by finding ventricular arrhythmias during an exercise test. These arrhythmias may deteriorate and lead to sudden cardiac death. Reduced function of the RyR2 protein, on the basis of genetic variants in this gene, does not lead to ventricular arrhythmias during exercise but is associated with sudden cardiac death. This disease is only recently described (2020) and is referred to as Calcium-release deficiency syndrome (CRDS).
Through an international collaboration 10 patients with unexplained life-threatening arrhythmic events and an ultrarare RyR2 variant were identified. All these variants were studied in isolated cell system in order to determine whether they led to better of reduced performance of the RyR2 protein. For 6 of them reduced function was proven and family screening in their families identified another 13 carriers of the abnormal gene. Hence, in total 19 patients were identified.
Of these 19 patients, 10 had at least one life-threatening event at presentation and/or during a median follow-up of ±7 years. In patient with documented arrhythmias (in the ICD) a typical onset of the arrhythmia, which has been suggested as an important characteristic for this disease, was observed. The arrhythmia is preceded by a relatively fast heart rate, followed by a pause and an extra beat which immediately follows the beat that terminates the pause. Some of these episodes were triggered by an adrenergic event. Beta blocker therapy, however, which is very effective in CPVT, does not seem to be successful in this disorder.
Conclusions: The results of this study suggest that the two RyR-2 related diseases, i.e. calcium-release deficiency syndrome (CDRS) and CPVT are different although that is not easy to sort out. In particular the response to exercise discriminates them. At present, CRDS remains difficult to recognize clinically, although a specific onset of the arrhythmia may be seen. Beta blocker treatment does not seem to be very effective.
Translated by Arthur Wilde, Amsterdam UMC, Amsterdam, The Netherlands
Roston TM, Wei J, Guo W, Li Y, Zhong X, Wang R, Estillore JP, Peltenburg PJ, Noguer FRI, Till J, Eckhardt LL, Orland KM, Hamilton R, LaPage MJ, Krahn AD, Tadros R, Vinocur JM, Kallas D, Franciosi S, Roberts JD, Wilde AAM, Jensen HK, Sanatani S, Chen SRW. Clinical and Functional Characterization of Ryanodine Receptor 2 Variants Implicated in Calcium-Release Deficiency Syndrome. JAMA Cardiol. 7, 84-92, 2022. PMID: 34730774