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Provocation Testing and Therapeutic Response in a Newly Described Channelopathy: RyR2 Calcium Release Deficiency Syndrome

Authors :
Julian O.M. Ormerod
Elizabeth Ormondroyd
Yanhui Li
John Taylor
Jinhong Wei
Wenting Guo
Ruiwu Wang
Caroline N.S. Sarton
Karen McGuire
Helene M.P. Dreau
Jenny C. Taylor
Matthew R. Ginks
Kim Rajappan
S.R. Wayne Chen
Hugh Watkins
Source :
Circulation: Genomic and Precision Medicine. 15
Publication Year :
2022
Publisher :
Ovid Technologies (Wolters Kluwer Health), 2022.

Abstract

Background: A novel familial arrhythmia syndrome, cardiac ryanodine receptor (RyR2) calcium release deficiency syndrome (CRDS), has recently been described. We evaluated a large and well characterized family to assess provocation testing, risk factor stratification and response to therapy in CRDS. Methods: We present a family with multiple unheralded sudden cardiac deaths and aborted cardiac arrests, primarily in children and young adults, with no clear phenotype on standard clinical testing. Results: Genetic analysis, including whole genome sequencing, firmly established that a missense mutation in RYR2 , Ala4142Thr, was the underlying cause of disease in the family. Functional study of the variant in a cell model showed RyR2 loss-of-function, indicating that the family was affected by CRDS. EPS (Electrophysiological Study) was undertaken in 9 subjects known to carry the mutation, including a survivor of aborted sudden cardiac death, and the effects of flecainide alone and in combination with metoprolol were tested. There was a clear gradation in inducibility of nonsustained and sustained ventricular arrhythmia between subjects at EPS, with the survivor of aborted sudden cardiac death being the most inducible subject. Administration of flecainide substantially reduced arrhythmia inducibility in this subject and abolished arrhythmia in all others. Finally, the effects of additional metoprolol were tested; it increased inducibility in 4/9 subjects. Conclusions: The Ala4142Thr mutation of RYR2 causes the novel heritable arrhythmia syndrome CRDS, which is characterized by familial sudden death in the absence of prior symptoms or a recognizable phenotype on ambulatory monitoring or exercise stress testing. We increase the experience of a specific EPS protocol in human subjects and show that it is helpful in establishing the clinical status of gene carriers, with potential utility for risk stratification. Our data provide evidence that flecainide is protective in human subjects with CRDS, consistent with the effect previously shown in a mouse model.

Details

ISSN :
25748300
Volume :
15
Database :
OpenAIRE
Journal :
Circulation: Genomic and Precision Medicine
Accession number :
edsair.doi.dedup.....54ec228c079d4f1939915a85ccf34025
Full Text :
https://doi.org/10.1161/circgen.121.003589