{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T17:09:23Z","timestamp":1774026563239,"version":"3.50.1"},"reference-count":11,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Marked intellectual and neurodevelopmental delay (INDD) was noted in 6 unrelated patients diagnosed with\n                      <jats:italic toggle=\"yes\">RYR2<\/jats:italic>\n                      -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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Retrospective combined review of patients with\n                      <jats:italic toggle=\"yes\">RYR2<\/jats:italic>\n                      -related CPVT diagnosed \u226418 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Among a total of 168 patients, INDD was reported in 19 (11.3% [95% CI, 7.0%\u201317.1%]). 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;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.04); (2) higher frequency of atrial tachyarrhythmias (84.2% versus 16.3%,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.001); (3) atrial or ventricular tachycardia without adrenergic stimulation (81.3% versus 2.2%,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.001, 31.6% versus 4.5%,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.001 respectively); (4) cardiac structural changes or systolic dysfunction (36.8% versus 1.3%,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.001); and (5) higher incidence of cardiac arrest or sudden death after diagnosis (26.3% versus 2.7%,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.001). INDD-related\n                      <jats:italic toggle=\"yes\">RYR2<\/jats:italic>\n                      genetic variants clustered within the central and channel domains and may be specific to certain variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      This study demonstrates a wider spectrum of\n                      <jats:italic toggle=\"yes\">RYR2<\/jats:italic>\n                      -related disease, with a subset associated with extracardiac manifestations. Certain\n                      <jats:italic toggle=\"yes\">RYR2<\/jats:italic>\n                      variants may lead to a neurocardiac phenotype with distinct features that are important to recognize, as these patients may be at higher risk.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circep.124.013437","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T09:00:35Z","timestamp":1758877235000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Intellectual and Neurodevelopmental Delays in Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: Distinct Characteristics and a More Malignant Neurocardiac Phenotype"],"prefix":"10.1161","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3120-9320","authenticated-orcid":true,"given":"Christina Y.","family":"Miyake","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics, Texas Children\u2019s Hospital and Baylor College of Medicine, Houston (C.Y.M., S.B.S.,T.S.H., S.O.V., T.D.N.P., J.J.K.)."},{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (C.Y.M., O.M.M., X.H.T.W.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dania","family":"Kallas","sequence":"additional","affiliation":[{"name":"British Columbia Children\u2019s Hospital, University of British Columbia, Vancouver, Canada (D.K., S.S.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2180-2198","authenticated-orcid":true,"given":"Sara B.","family":"Stephens","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics, Texas Children\u2019s Hospital and Baylor College of Medicine, Houston (C.Y.M., S.B.S.,T.S.H., S.O.V., T.D.N.P., J.J.K.)."},{"name":"British Columbia Children\u2019s Hospital, University of British Columbia, Vancouver, Canada (D.K., S.S.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3986-7982","authenticated-orcid":true,"given":"Oliver M.","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (C.Y.M., O.M.M., X.H.T.W.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5044-672X","authenticated-orcid":true,"given":"Xander H.T.","family":"Wehrens","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (C.Y.M., O.M.M., X.H.T.W.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5201-0006","authenticated-orcid":true,"given":"Peter S.","family":"Fischbach","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics, Emory University Children\u2019s Healthcare of Atlanta, GA (P.S.F.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5694-6570","authenticated-orcid":true,"given":"Martin J.","family":"LaPage","sequence":"additional","affiliation":[{"name":"University of Michigan, Ann Arbor (M.J.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1878-9631","authenticated-orcid":true,"given":"Andrew P.","family":"Landstrom","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics (A.P.L.), Duke University School of Medicine, Durham, NC."},{"name":"Department of Cell Biology (A.P.L.), Duke University School of Medicine, Durham, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7309-6005","authenticated-orcid":true,"given":"Ian H.","family":"Law","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Iowa Stead Family (I.H.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1166-0042","authenticated-orcid":true,"given":"Allison C.","family":"Hill","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics, Children\u2019s Hospital Los Angeles, Keck School of Medicine, University of Southern California (A.C.H.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1529-9872","authenticated-orcid":true,"given":"Prince J.","family":"Kannankeril","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics, Children\u2019s Hospital at Vanderbilt and Vanderbilt University Medical Center, Nashville, TN (P.J.K., F.A.F.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4054-6262","authenticated-orcid":true,"given":"Frank A.","family":"Fish","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics, Children\u2019s Hospital at Vanderbilt and Vanderbilt University Medical Center, Nashville, TN (P.J.K., F.A.F.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3221-2000","authenticated-orcid":true,"given":"Taylor S.","family":"Howard","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics, Texas Children\u2019s Hospital and Baylor College of Medicine, Houston (C.Y.M., S.B.S.,T.S.H., S.O.V., T.D.N.P., J.J.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9430-4147","authenticated-orcid":true,"given":"Santiago O.","family":"Valdes","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics, Texas Children\u2019s Hospital and Baylor College of Medicine, Houston (C.Y.M., S.B.S.,T.S.H., S.O.V., T.D.N.P., J.J.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tam Dan N.","family":"Pham","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics, Texas Children\u2019s Hospital and Baylor College of Medicine, Houston (C.Y.M., S.B.S.,T.S.H., S.O.V., T.D.N.P., J.J.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2441-8308","authenticated-orcid":true,"given":"Jeffrey J.","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics, Texas Children\u2019s Hospital and Baylor College of Medicine, Houston (C.Y.M., S.B.S.,T.S.H., S.O.V., T.D.N.P., J.J.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9922-3981","authenticated-orcid":true,"given":"Santokh S.","family":"Dhillon","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Dalhousie University, Halifax, Canada (S.S.D.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7621-4342","authenticated-orcid":true,"given":"Christopher L.","family":"Johnsrude","sequence":"additional","affiliation":[{"name":"University of Louisville School of Medicine, KY (C.L.J.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3673-165X","authenticated-orcid":true,"given":"Ulrich","family":"Krause","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology and Intensive Care Medicine, Department of Pediatrics and Adolescent Medicine, University Medical Center Gottingen, Georg-August-University, Germany (U.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6857-8904","authenticated-orcid":true,"given":"Georgia","family":"Sarquella-Brugada","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hospital Sant Joan de D\u00e9u, University of Barcelona, Spain (G.S.-B.)."},{"name":"Department of Medical Sciences School of Medicine, University of Girona, Spain (G.S.-B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3489-372X","authenticated-orcid":true,"given":"Peter","family":"Kubu\u0161","sequence":"additional","affiliation":[{"name":"Children\u2019s Heart Centre, Charles University and Motol University Hospital, Prague, Czech Republic (P.K., T.T.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0699-8284","authenticated-orcid":true,"given":"Terezia","family":"Tavacova","sequence":"additional","affiliation":[{"name":"Children\u2019s Heart Centre, Charles University and Motol University Hospital, Prague, Czech Republic (P.K., T.T.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8149-8004","authenticated-orcid":true,"given":"Sit-Yee","family":"Kwok","sequence":"additional","affiliation":[{"name":"Hong Kong Children\u2019s Hospital, China (S.-Y.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2492-422X","authenticated-orcid":true,"given":"Susan P.","family":"Etheridge","sequence":"additional","affiliation":[{"name":"University of Utah, Salt Lake City (S.P.E.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7185-4159","authenticated-orcid":true,"given":"Svjetlana","family":"Tisma-Dupanovic","sequence":"additional","affiliation":[{"name":"Nemours Children\u2019s Clinic, Orlando, FL (S.T.-D.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3966-4261","authenticated-orcid":true,"given":"Adam C.","family":"Kean","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis (A.C.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7982-1586","authenticated-orcid":true,"given":"Andrew D.","family":"Krahn","sequence":"additional","affiliation":[{"name":"Division of Cardiology, The University of British Columbia, Vancouver, Canada (A.D.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5503-5193","authenticated-orcid":true,"given":"Mohammed A.","family":"Ebrahim","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kuwait University (M.A.E.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8763-2067","authenticated-orcid":true,"given":"Joseph","family":"Atallah","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics, Stollery Children\u2019s Hospital, University of Alberta, Edmonton, Canada (J.A.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2592-3202","authenticated-orcid":true,"given":"Anne","family":"Fournier","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics, CHU Sante-Justine, University of Montr\u00e9al, Quebec, Canada (A.F.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8223-2631","authenticated-orcid":true,"given":"Anjan S.","family":"Batra","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California Irvine (A.S.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9120-5313","authenticated-orcid":true,"given":"Ming-Lon","family":"Young","sequence":"additional","affiliation":[{"name":"Heart Institute, Joe DiMaggio Children\u2019s Hospital, Hollywood, FL (M.-L.Y.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9520-4660","authenticated-orcid":true,"given":"James","family":"Perry","sequence":"additional","affiliation":[{"name":"Division of Cardiology Department of Pediatrics (J.P.), Rady Children\u2019s Hospital, San Diego, CA."},{"name":"Department of Bioengineering (J.P.), Rady Children\u2019s Hospital, San Diego, CA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0251-9757","authenticated-orcid":true,"given":"Joshua R.","family":"Kovach","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee (J.R.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0095-1044","authenticated-orcid":true,"given":"Anna N.","family":"Kamp","sequence":"additional","affiliation":[{"name":"The Ohio State University Medical Center, Nationwide Children\u2019s Hospital, Columbus (A.N.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8186-8471","authenticated-orcid":true,"given":"Bradley C.","family":"Clark","sequence":"additional","affiliation":[{"name":"Masonic Children\u2019s Hospital, University of Minnesota, Minneapolis (B.C.C., E.J.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6507-7007","authenticated-orcid":true,"given":"Erick","family":"Jimenez","sequence":"additional","affiliation":[{"name":"Masonic Children\u2019s Hospital, University of Minnesota, Minneapolis (B.C.C., 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(S.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9296-7400","authenticated-orcid":true,"given":"Shubhayan","family":"Sanatani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000020013.73106.d8"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.91.5.1512"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2011.01.048"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1253\/circj.71.1606"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0306-4522(97)00612-x"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccep.2023.05.003"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2018.08.025"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.226845"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/petr.14442"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.14503\/THIJ-22-7974"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2021-320220"}],"container-title":["Circulation: 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