Calmodulinopathy in Japanese Children　― Their Cardiac Phenotypes Are Severe and Show Early Onset in Fetal Life and Infancy ―

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  • Fukuyama Megumi
    Department of Cardiovascular Medicine, Shiga University of Medical Science
  • Horie Minoru
    Department of Cardiovascular Medicine, Shiga University of Medical Science
  • Kato Koichi
    Department of Cardiovascular Medicine, Shiga University of Medical Science
  • Aoki Hisaaki
    Department of Pediatric Cardiology, Osaka Women’s and Children’s Hospital
  • Fujita Shuhei
    Department of Pediatrics, Toyama Prefectural Central Hospital
  • Yoshida Yoko
    Division of Pediatric Electrophysiology, Osaka City General Hospital
  • Sakazaki Hisanori
    Department of Pediatric Cardiology, Hyogo Prefectural Amagasaki Hospital
  • Toda Takako
    Department of Pediatrics, University of Yamanashi, Faculty of Medicine Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center
  • Ueno Michihiko
    Department of Pediatrics, Teine Keijinkai Hospital
  • Izumi Gaku
    Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University
  • Momoi Nobuo
    Department of Pediatrics, Fukushima Medical University School of Medicine
  • Muneuchi Jun
    Division of Pediatric Cardiology, Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization
  • Makiyama Takeru
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
  • Nakagawa Yoshihisa
    Department of Cardiovascular Medicine, Shiga University of Medical Science
  • Ohno Seiko
    Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center

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<p>Background: Cardiac calmodulinopathy, characterized by a life-threatening arrhythmia and sudden death in the young, is extremely rare and caused by genes encoding calmodulin, namely calmodulin 1 (CALM1), CALM2, and CALM3.</p><p>Methods and Results: We screened 195 symptomatic children (age 0–12 years) who were suspected of inherited arrhythmias for 48 candidate genes, using a next-generation sequencer. Ten probands were identified as carrying variants in any of CALM1–3 (5%; median age 5 years), who were initially diagnosed with long QT syndrome (LQTS; n=5), catecholaminergic polymorphic ventricular tachycardia (CPVT; n=3), and overlap syndrome (n=2). Two probands harbored a CALM1 variant and 8 probands harbored 6 CALM2 variants. There were 4 clinical phenotypes: (1) documented lethal arrhythmic events (LAEs): 4 carriers of N98S in CALM1 or CALM2; (2) suspected LAEs: CALM2 p.D96G and D132G carriers experienced syncope and transient cardiopulmonary arrest under emotional stimulation; (3) critical cardiac complication: CALM2 p.D96V and p.E141K carriers showed severe cardiac dysfunction with QTc prolongation; and (4) neurological and developmental disorders: 2 carriers of CALM2 p.E46K showed cardiac phenotypes of CPVT. Beta-blocker therapy was effective in all cases except cardiac dysfunction, especially in combination with flecainide (CPVT-like phenotype) and mexiletine (LQTS-like).</p><p>Conclusions: Calmodulinopathy patients presented severe cardiac features, and their onset of LAEs was earlier in life, requiring diagnosis and treatment at the earliest age possible.</p>

収録刊行物

  • Circulation Journal

    Circulation Journal 87 (12), 1828-1835, 2023-11-24

    一般社団法人 日本循環器学会

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