Intellectual and Neurodevelopmental Delays in Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: Distinct Characteristics and a More Malignant Neurocardiac Phenotype.
Por:
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 TD, Kim JJ, Dhillon S, Johnsrude CL, Krause U, Sarquella-Brugada G, Kubus P, Tavacova T, Kwok SY, Etheridge SP, Tisma-Dupanovic S, Kean AC, Krahn AD, Ebrahim M, Atallah J, Fournier A, Batra AS, Young ML, Perry J, Kovach JR, Kamp AN, Clark BC, Jimenez E, Charafeddine F, Hamilton RM, Balaji S and Sanatani S
Publicada:
1 oct 2025
Ahead of Print:
26 sep 2025
Resumen:
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.
Filiaciones:
Miyake CY:
Texas Children's Hospital and Baylor College of Medicine, Houston (C.Y.M., S.B.S., O.M.M., X.H.T.W., T.S.H., S.O.V., T.D.P., J.J.K.)
Kallas D:
BC Children's Hospital, Vancouver, Canada (D.K., S.S.)
Stephens SB:
Texas Children's Hospital and Baylor College of Medicine, Houston (C.Y.M., S.B.S., O.M.M., X.H.T.W., T.S.H., S.O.V., T.D.P., J.J.K.)
Moore OM:
Texas Children's Hospital and Baylor College of Medicine, Houston (C.Y.M., S.B.S., O.M.M., X.H.T.W., T.S.H., S.O.V., T.D.P., J.J.K.)
Wehrens XHT:
Texas Children's Hospital and Baylor College of Medicine, Houston (C.Y.M., S.B.S., O.M.M., X.H.T.W., T.S.H., S.O.V., T.D.P., J.J.K.)
Fischbach PS:
Sibley Heart Center, Children's Healthcare of Atlanta, GA (P.S.F.)
LaPage MJ:
University of Michigan, Ann Arbor (M.J.L.)
Landstrom AP:
Department of Pediatrics, Duke University School of Medicine, Durham, NC (A.P.L.)
Law IH:
University of Iowa Stead Family Children's Hospital (I.H.L.)
Hill AC:
Children's Hospital Los Angeles, CA (A.C.H.)
Kannankeril PJ:
Vanderbilt University Medical Center, Nashville, TN (P.J.K., F.A.F.)
Fish FA:
Vanderbilt University Medical Center, Nashville, TN (P.J.K., F.A.F.)
Howard TS:
Texas Children's Hospital and Baylor College of Medicine, Houston (C.Y.M., S.B.S., O.M.M., X.H.T.W., T.S.H., S.O.V., T.D.P., J.J.K.)
Valdes SO:
Texas Children's Hospital and Baylor College of Medicine, Houston (C.Y.M., S.B.S., O.M.M., X.H.T.W., T.S.H., S.O.V., T.D.P., J.J.K.)
Pham TD:
Texas Children's Hospital and Baylor College of Medicine, Houston (C.Y.M., S.B.S., O.M.M., X.H.T.W., T.S.H., S.O.V., T.D.P., J.J.K.)
Kim JJ:
Texas Children's Hospital and Baylor College of Medicine, Houston (C.Y.M., S.B.S., O.M.M., X.H.T.W., T.S.H., S.O.V., T.D.P., J.J.K.)
Dhillon S:
Dalhousie University, Halifax, Canada (S.D.)
Johnsrude CL:
University of Louisville School of Medicine, KY (C.L.J.)
Krause U:
University of Gottingen, Germany (U.K.)
Sarquella-Brugada G:
Hospital Sant Joan de Déu, Barcelona, Spain (G.S.-B.)
Kubus P:
Motol University Hospital, Prague, Czech Republic (P.K., T.T.)
Tavacova T:
Motol University Hospital, Prague, Czech Republic (P.K., T.T.)
Kwok SY:
Hong Kong Children's Hospital, China (S.-Y.K.)
Etheridge SP:
University of Utah, Salt Lake City (S.P.E.)
Tisma-Dupanovic S:
Nemours Children's Clinic, Orlando, FL (S.T.-D.)
Kean AC:
Indiana University School of Medicine, Indianapolis (A.C.K.)
Krahn AD:
Division of Cardiology, The University of British Columbia, Vancouver, Canada (A.D.K.)
Ebrahim M:
University of Kuwait (M.E.)
Atallah J:
Stollery Children's Hospital, Edmonton, Alberta, Canada (J.A.)
Fournier A:
CHU Sante-Justine, Université de Montréal, Quebec, Canada (A.F.)
Batra AS:
Department of Pediatrics, University of California, Irvine (A.S.B.)
Young ML:
Heart Institute, Joe DiMaggio Children's Hospital, Hollywood, FL (M.-L.Y.)
Perry J:
Rady Children's Hospital, San Diego, CA (J.P.)
Kovach JR:
Children's Hospital of Wisconsin, Milwaukee (J.R.K.)
Kamp AN:
Nationwide Children's Hospital, Columbus, OH (A.N.K.)
Clark BC:
University of Minnesota, Minneapolis (B.C.C., E.J.)
Jimenez E:
University of Minnesota, Minneapolis (B.C.C., E.J.)
Charafeddine F:
Division of Pediatric Cardiology, American University of Beirut Medical Center, Lebanon (F.C.)
Hamilton RM:
Hospital for Sick Children, Toronto, Canada (R.M.H.)
Balaji S:
Oregon Health Science University, Portland (S.B.)
Sanatani S:
BC Children's Hospital, Vancouver, Canada (D.K., S.S.)
Green Submitted
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