Intellectual and Neurodevelopmental Delays in Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: Distinct Characteristics and a More Malignant Neurocardiac Phenotype

Christina Y. Miyake; Dania Kallas; Sara B. Stephens; Oliver M. Moore; Xander H.T. Wehrens; Peter S. Fischbach; Martin J. LaPage; Andrew P. Landstrom; Ian H. Law; Allison C. Hill; Prince J. Kannankeril; Frank A. Fish; Taylor S. Howard; Santiago O. Valdes; Tam Dan N. Pham; Jeffrey J. Kim; Santokh S. Dhillon; Christopher L. Johnsrude; Ulrich Krause; Georgia Sarquella-Brugada; Peter Kubuš; Terezia Tavacova; Sit Yee Kwok; Susan P. Etheridge; Svjetlana Tisma-Dupanovic; Adam C. Kean; Andrew D. Krahn; Mohammed A. Ebrahim; Joseph Atallah; Anne Fournier; Anjan S. Batra; Ming Lon Young; James Perry; Joshua R. Kovach; Anna N. Kamp; Bradley C. Clark; Erick Jimenez; Fatme Charafeddine; Robert M. Hamilton; Seshadri Balaji; Shubhayan Sanatani

doi:10.1161/CIRCEP.124.013437

Intellectual and Neurodevelopmental Delays in Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: Distinct Characteristics and a More Malignant Neurocardiac Phenotype

Christina Y. Miyake
, Dania Kallas
, Sara B. Stephens
, Oliver M. Moore
, Xander H.T. Wehrens
, Peter S. Fischbach
, Martin J. LaPage
, Andrew P. Landstrom
, Ian H. Law
, Allison C. Hill
, Prince J. Kannankeril
, Frank A. Fish
, Taylor S. Howard
, Santiago O. Valdes
, Tam Dan N. Pham
, Jeffrey J. Kim
, Santokh S. Dhillon
, Christopher L. Johnsrude
, Ulrich Krause
, Georgia Sarquella-Brugada

Peter Kubuš, Terezia Tavacova, Sit Yee Kwok, Susan P. Etheridge, Svjetlana Tisma-Dupanovic, Adam C. Kean, Andrew D. Krahn, Mohammed A. Ebrahim, Joseph Atallah, Anne Fournier, Anjan S. Batra, Ming Lon Young, James Perry, Joshua R. Kovach, Anna N. Kamp, Bradley C. Clark, Erick Jimenez, Fatme Charafeddine, Robert M. Hamilton, Seshadri Balaji, Shubhayan Sanatani

Baylor College of Medicine
University of British Columbia
Children's Healthcare of Atlanta
University of Michigan, Ann Arbor
Duke University
University of Iowa
University of Southern California
Vanderbilt University
Dalhousie University
University of Louisville
University of Göttingen
University of Barcelona
University of Girona
Charles University
Hong Kong Children's Hospital
University of Utah
Nemours Children's Health System
Indiana University Bloomington
Kuwait University
Stollery Children's Hospital
University of Montreal
University of California at Irvine
Memorial Regional Hospital
Rady Children's Hospital
Medical College of Wisconsin
Ohio State University
University of Minnesota Twin Cities
American University of Beirut
University of Toronto
Oregon Health and Science University

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

BACKGROUND: Marked intellectual and neurodevelopmental delay (INDD) was noted in 6 unrelated patients diagnosed with RYR2-related catecholaminergic polymorphic ventricular tachycardia (CPVT) from a single center. Patients exhibited similar distinct phenotypic features not previously described. We aimed to determine the prevalence of INDD in CPVT, compare clinical characteristics between patients with CPVT with and without INDD, and investigate the possibility of a unique neurocardiac CPVT phenotype.

METHODS: Retrospective combined review of patients with RYR2-related CPVT diagnosed ≤18 years with and without INDD from a single center and the International Pediatric CPVT Registry. Patients with hypoxic ischemic insult were excluded unless INDD preceded injury.

RESULTS: Among a total of 168 patients, INDD was reported in 19 (11.3% [95% CI, 7.0%-17.1%]). When compared with cases without INDD, patients with INDD exhibited distinct features including (1) younger age at onset of symptoms (median 7.0 versus 10.0 years; P=0.04); (2) higher frequency of atrial tachyarrhythmias (84.2% versus 16.3%, P<0.001); (3) atrial or ventricular tachycardia without adrenergic stimulation (81.3% versus 2.2%, P<0.001, 31.6% versus 4.5%, P=0.001 respectively); (4) cardiac structural changes or systolic dysfunction (36.8% versus 1.3%, P<0.001); and (5) higher incidence of cardiac arrest or sudden death after diagnosis (26.3% versus 2.7%, P=0.001). INDD-related RYR2 genetic variants clustered within the central and channel domains and may be specific to certain variants.

CONCLUSIONS: This study demonstrates a wider spectrum of RYR2-related disease, with a subset associated with extracardiac manifestations. Certain RYR2 variants may lead to a neurocardiac phenotype with distinct features that are important to recognize, as these patients may be at higher risk.

Original language	English
Pages (from-to)	e013437
Journal	Circulation. Arrhythmia and electrophysiology
Volume	18
Issue number	10
DOIs	https://doi.org/10.1161/CIRCEP.124.013437
State	Published - 1 Oct 2025

Keywords

Adolescent
Age of Onset
Child
Child, Preschool
Female
Genetic Predisposition to Disease
Humans
Infant
Intellectual Disability/epidemiology
Male
Mutation
Neurodevelopmental Disorders/epidemiology
Phenotype
Polymorphic Catecholaminergic Ventricular Tachycardia
Prevalence
Registries
Retrospective Studies
Risk Factors
Ryanodine Receptor Calcium Release Channel/genetics
Tachycardia, Ventricular/genetics

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10.1161/CIRCEP.124.013437

Cite this

Miyake, C. Y., Kallas, D., Stephens, S. B., Moore, O. M., Wehrens, X. H. T., Fischbach, P. S., LaPage, M. J., Landstrom, A. P., Law, I. H., Hill, A. C., Kannankeril, P. J., Fish, F. A., Howard, T. S., Valdes, S. O., Pham, T. D. N., Kim, J. J., Dhillon, S. S., Johnsrude, C. L., Krause, U., ... Sanatani, S. (2025). Intellectual and Neurodevelopmental Delays in Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: Distinct Characteristics and a More Malignant Neurocardiac Phenotype. Circulation. Arrhythmia and electrophysiology, 18(10), e013437. https://doi.org/10.1161/CIRCEP.124.013437

@article{8cdd65e796db42b99b1673008710ef44,

title = "Intellectual and Neurodevelopmental Delays in Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: Distinct Characteristics and a More Malignant Neurocardiac Phenotype",

abstract = "BACKGROUND: Marked intellectual and neurodevelopmental delay (INDD) was noted in 6 unrelated patients diagnosed with RYR2-related catecholaminergic polymorphic ventricular tachycardia (CPVT) from a single center. Patients exhibited similar distinct phenotypic features not previously described. We aimed to determine the prevalence of INDD in CPVT, compare clinical characteristics between patients with CPVT with and without INDD, and investigate the possibility of a unique neurocardiac CPVT phenotype. METHODS: Retrospective combined review of patients with RYR2-related CPVT diagnosed ≤18 years with and without INDD from a single center and the International Pediatric CPVT Registry. Patients with hypoxic ischemic insult were excluded unless INDD preceded injury. RESULTS: Among a total of 168 patients, INDD was reported in 19 (11.3\% [95\% CI, 7.0\%-17.1\%]). When compared with cases without INDD, patients with INDD exhibited distinct features including (1) younger age at onset of symptoms (median 7.0 versus 10.0 years; P=0.04); (2) higher frequency of atrial tachyarrhythmias (84.2\% versus 16.3\%, P<0.001); (3) atrial or ventricular tachycardia without adrenergic stimulation (81.3\% versus 2.2\%, P<0.001, 31.6\% versus 4.5\%, P=0.001 respectively); (4) cardiac structural changes or systolic dysfunction (36.8\% versus 1.3\%, P<0.001); and (5) higher incidence of cardiac arrest or sudden death after diagnosis (26.3\% versus 2.7\%, P=0.001). INDD-related RYR2 genetic variants clustered within the central and channel domains and may be specific to certain variants. CONCLUSIONS: This study demonstrates a wider spectrum of RYR2-related disease, with a subset associated with extracardiac manifestations. Certain RYR2 variants may lead to a neurocardiac phenotype with distinct features that are important to recognize, as these patients may be at higher risk. ",

keywords = "Adolescent, Age of Onset, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Humans, Infant, Intellectual Disability/epidemiology, Male, Mutation, Neurodevelopmental Disorders/epidemiology, Phenotype, Polymorphic Catecholaminergic Ventricular Tachycardia, Prevalence, Registries, Retrospective Studies, Risk Factors, Ryanodine Receptor Calcium Release Channel/genetics, Tachycardia, Ventricular/genetics",

author = "Miyake, \{Christina Y.\} and Dania Kallas and Stephens, \{Sara B.\} and Moore, \{Oliver M.\} and Wehrens, \{Xander H.T.\} and Fischbach, \{Peter S.\} and LaPage, \{Martin J.\} and Landstrom, \{Andrew P.\} and Law, \{Ian H.\} and Hill, \{Allison C.\} and Kannankeril, \{Prince J.\} and Fish, \{Frank A.\} and Howard, \{Taylor S.\} and Valdes, \{Santiago O.\} and Pham, \{Tam Dan N.\} and Kim, \{Jeffrey J.\} and Dhillon, \{Santokh S.\} and Johnsrude, \{Christopher L.\} and Ulrich Krause and Georgia Sarquella-Brugada and Peter Kubu{\v s} and Terezia Tavacova and Kwok, \{Sit Yee\} and Etheridge, \{Susan P.\} and Svjetlana Tisma-Dupanovic and Kean, \{Adam C.\} and Krahn, \{Andrew D.\} and Ebrahim, \{Mohammed A.\} and Joseph Atallah and Anne Fournier and Batra, \{Anjan S.\} and Young, \{Ming Lon\} and James Perry and Kovach, \{Joshua R.\} and Kamp, \{Anna N.\} and Clark, \{Bradley C.\} and Erick Jimenez and Fatme Charafeddine and Hamilton, \{Robert M.\} and Seshadri Balaji and Shubhayan Sanatani",

note = "Publisher Copyright: {\textcopyright} 2025",

year = "2025",

month = oct,

day = "1",

doi = "10.1161/CIRCEP.124.013437",

language = "English",

volume = "18",

pages = "e013437",

journal = "Circulation. Arrhythmia and electrophysiology",

issn = "1941-3149",

publisher = "Lippincott Williams and Wilkins",

number = "10",

}

Miyake, CY, Kallas, D, Stephens, SB, Moore, OM, Wehrens, XHT, Fischbach, PS, LaPage, MJ, Landstrom, AP, Law, IH, Hill, AC, Kannankeril, PJ, Fish, FA, Howard, TS, Valdes, SO, Pham, TDN, Kim, JJ, Dhillon, SS, Johnsrude, CL, Krause, U, Sarquella-Brugada, G, Kubuš, P, Tavacova, T, Kwok, SY, Etheridge, SP, Tisma-Dupanovic, S, Kean, AC, Krahn, AD, Ebrahim, MA, Atallah, J, Fournier, A, Batra, AS, Young, ML, Perry, J, Kovach, JR, Kamp, AN, Clark, BC, Jimenez, E, Charafeddine, F, Hamilton, RM, Balaji, S & Sanatani, S 2025, 'Intellectual and Neurodevelopmental Delays in Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: Distinct Characteristics and a More Malignant Neurocardiac Phenotype', Circulation. Arrhythmia and electrophysiology, vol. 18, no. 10, pp. e013437. https://doi.org/10.1161/CIRCEP.124.013437

Intellectual and Neurodevelopmental Delays in Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: Distinct Characteristics and a More Malignant Neurocardiac Phenotype. / Miyake, Christina Y.; Kallas, Dania; Stephens, Sara B. et al.
In: Circulation. Arrhythmia and electrophysiology, Vol. 18, No. 10, 01.10.2025, p. e013437.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Intellectual and Neurodevelopmental Delays in Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia

T2 - Distinct Characteristics and a More Malignant Neurocardiac Phenotype

AU - Miyake, Christina Y.

AU - Kallas, Dania

AU - Stephens, Sara B.

AU - Moore, Oliver M.

AU - Wehrens, Xander H.T.

AU - Fischbach, Peter S.

AU - LaPage, Martin J.

AU - Landstrom, Andrew P.

AU - Law, Ian H.

AU - Hill, Allison C.

AU - Kannankeril, Prince J.

AU - Fish, Frank A.

AU - Howard, Taylor S.

AU - Valdes, Santiago O.

AU - Pham, Tam Dan N.

AU - Kim, Jeffrey J.

AU - Dhillon, Santokh S.

AU - Johnsrude, Christopher L.

AU - Krause, Ulrich

AU - Sarquella-Brugada, Georgia

AU - Kubuš, Peter

AU - Tavacova, Terezia

AU - Kwok, Sit Yee

AU - Etheridge, Susan P.

AU - Tisma-Dupanovic, Svjetlana

AU - Kean, Adam C.

AU - Krahn, Andrew D.

AU - Ebrahim, Mohammed A.

AU - Atallah, Joseph

AU - Fournier, Anne

AU - Batra, Anjan S.

AU - Young, Ming Lon

AU - Perry, James

AU - Kovach, Joshua R.

AU - Kamp, Anna N.

AU - Clark, Bradley C.

AU - Jimenez, Erick

AU - Charafeddine, Fatme

AU - Hamilton, Robert M.

AU - Balaji, Seshadri

AU - Sanatani, Shubhayan

PY - 2025/10/1

Y1 - 2025/10/1

N2 - BACKGROUND: Marked intellectual and neurodevelopmental delay (INDD) was noted in 6 unrelated patients diagnosed with RYR2-related catecholaminergic polymorphic ventricular tachycardia (CPVT) from a single center. Patients exhibited similar distinct phenotypic features not previously described. We aimed to determine the prevalence of INDD in CPVT, compare clinical characteristics between patients with CPVT with and without INDD, and investigate the possibility of a unique neurocardiac CPVT phenotype. METHODS: Retrospective combined review of patients with RYR2-related CPVT diagnosed ≤18 years with and without INDD from a single center and the International Pediatric CPVT Registry. Patients with hypoxic ischemic insult were excluded unless INDD preceded injury. RESULTS: Among a total of 168 patients, INDD was reported in 19 (11.3% [95% CI, 7.0%-17.1%]). When compared with cases without INDD, patients with INDD exhibited distinct features including (1) younger age at onset of symptoms (median 7.0 versus 10.0 years; P=0.04); (2) higher frequency of atrial tachyarrhythmias (84.2% versus 16.3%, P<0.001); (3) atrial or ventricular tachycardia without adrenergic stimulation (81.3% versus 2.2%, P<0.001, 31.6% versus 4.5%, P=0.001 respectively); (4) cardiac structural changes or systolic dysfunction (36.8% versus 1.3%, P<0.001); and (5) higher incidence of cardiac arrest or sudden death after diagnosis (26.3% versus 2.7%, P=0.001). INDD-related RYR2 genetic variants clustered within the central and channel domains and may be specific to certain variants. CONCLUSIONS: This study demonstrates a wider spectrum of RYR2-related disease, with a subset associated with extracardiac manifestations. Certain RYR2 variants may lead to a neurocardiac phenotype with distinct features that are important to recognize, as these patients may be at higher risk.

AB - BACKGROUND: Marked intellectual and neurodevelopmental delay (INDD) was noted in 6 unrelated patients diagnosed with RYR2-related catecholaminergic polymorphic ventricular tachycardia (CPVT) from a single center. Patients exhibited similar distinct phenotypic features not previously described. We aimed to determine the prevalence of INDD in CPVT, compare clinical characteristics between patients with CPVT with and without INDD, and investigate the possibility of a unique neurocardiac CPVT phenotype. METHODS: Retrospective combined review of patients with RYR2-related CPVT diagnosed ≤18 years with and without INDD from a single center and the International Pediatric CPVT Registry. Patients with hypoxic ischemic insult were excluded unless INDD preceded injury. RESULTS: Among a total of 168 patients, INDD was reported in 19 (11.3% [95% CI, 7.0%-17.1%]). When compared with cases without INDD, patients with INDD exhibited distinct features including (1) younger age at onset of symptoms (median 7.0 versus 10.0 years; P=0.04); (2) higher frequency of atrial tachyarrhythmias (84.2% versus 16.3%, P<0.001); (3) atrial or ventricular tachycardia without adrenergic stimulation (81.3% versus 2.2%, P<0.001, 31.6% versus 4.5%, P=0.001 respectively); (4) cardiac structural changes or systolic dysfunction (36.8% versus 1.3%, P<0.001); and (5) higher incidence of cardiac arrest or sudden death after diagnosis (26.3% versus 2.7%, P=0.001). INDD-related RYR2 genetic variants clustered within the central and channel domains and may be specific to certain variants. CONCLUSIONS: This study demonstrates a wider spectrum of RYR2-related disease, with a subset associated with extracardiac manifestations. Certain RYR2 variants may lead to a neurocardiac phenotype with distinct features that are important to recognize, as these patients may be at higher risk.

KW - Adolescent

KW - Age of Onset

KW - Child

KW - Child, Preschool

KW - Female

KW - Genetic Predisposition to Disease

KW - Humans

KW - Infant

KW - Intellectual Disability/epidemiology

KW - Male

KW - Mutation

KW - Neurodevelopmental Disorders/epidemiology

KW - Phenotype

KW - Polymorphic Catecholaminergic Ventricular Tachycardia

KW - Prevalence

KW - Registries

KW - Retrospective Studies

KW - Risk Factors

KW - Ryanodine Receptor Calcium Release Channel/genetics

KW - Tachycardia, Ventricular/genetics

UR - https://www.scopus.com/pages/publications/105019822064

U2 - 10.1161/CIRCEP.124.013437

DO - 10.1161/CIRCEP.124.013437

M3 - Article

C2 - 41000018

AN - SCOPUS:105019822064

SN - 1941-3149

VL - 18

SP - e013437

JO - Circulation. Arrhythmia and electrophysiology

JF - Circulation. Arrhythmia and electrophysiology

IS - 10

ER -

Intellectual and Neurodevelopmental Delays in Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: Distinct Characteristics and a More Malignant Neurocardiac Phenotype

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