Browsing by Author "Ohno, Seiko"

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    Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry
    (Oxford University Press, 2016-06-06) Crotti, Lia; Spazzolini, Carla; Tester, David J; Ghidoni, Alice; Baruteau, Alban-Elouen; Beckmann, Britt-Maria; Behr, Elijah R; Bennett, Jeffrey S; Bezzina, Connie R; Bhuiyan, Zahurul A; Celiker, Alpay; Cerrone, Marina; Dagradi, Federica; De Ferrari, Gaetano M; Etheridge, Susan P; Fatah, Meena; Garcia-Pavia, Pablo; Al-Ghamdi, Saleh; Hamilton, Robert M; Al-Hassnan, Zuhair N; Horie, Minoru; Jimenez-Jaimez, Juan; Kanter, Ronald J.; Kaski, Juan P.; Kotta, Maria-Christina; Lahrouchi, Najim; Makita, Naomasa; Norrish, Gabrielle; Odland, Hans H.; Ohno, Seiko; Papagiannis, John; Parati, Gianfranco; Sekarski, Nicole; Tveten, Kristian; Vatta, Matteo; Webster, Gregory; Wilde, Arthur A. M.; Wojciak, Julianne; George, Alfred L., Jr; Ackerman, Michael J.; Schwartz, Peter J.; Medical and Molecular Genetics, School of Medicine
    Aims Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1–5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. Conclusion Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.
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    Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry
    (Oxford University Press, 2023) Crotti, Lia; Spazzolini, Carla; Nyegaard, Mette; Overgaard, Michael T.; Kotta, Maria-Christina; Dagradi, Federica; Sala, Luca; Aiba, Takeshi; Ayers, Mark D.; Baban, Anwar; Barc, Julien; Beach, Cheyenne M.; Behr, Elijah R.; Bos, J. Martijn; Cerrone, Marina; Covi, Peter; Cuneo, Bettina; Denjoy, Isabelle; Donner, Birgit; Elbert, Adrienne; Eliasson, Håkan; Etheridge, Susan P.; Fukuyama, Megumi; Girolami, Francesca; Hamilton, Robert; Horie, Minoru; Iascone, Maria; Jiménez-Jaimez, Juan; Jensen, Henrik Kjærulf; Kannankeril, Prince J.; Kaski, Juan P.; Makita, Naomasa; Muñoz-Esparza, Carmen; Odland, Hans H.; Ohno, Seiko; Papagiannis, John; Porretta, Alessandra Pia; Prandstetter, Christopher; Probst, Vincent; Robyns, Tomas; Rosenthal, Eric; Rosés-Noguer, Ferran; Sekarski, Nicole; Singh, Anoop; Spentzou, Georgia; Stute, Fridrike; Tfelt-Hansen, Jacob; Till, Jan; Tobert, Kathryn E.; Vinocur, Jeffrey M.; Webster, Gregory; Wilde, Arthur A. M.; Wolf, Cordula M.; Ackerman, Michael J.; Schwartz, Peter J.; Pediatrics, School of Medicine
    Aims: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. Methods and results: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. Conclusion: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator.
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    Increased CaV1.2 late current by a CACNA1C p.R412M variant causes an atypical Timothy syndrome without syndactyly
    (Springer Nature, 2022-11-08) Ozawa, Junichi; Ohno, Seiko; Melgari, Dario; Fukuyama, Megumi; Toyoda, Futoshi; Makiyama, Takeru; Yoshinaga, Masao; Suzuki, Hiroshi; Saitoh, Akihiko; Ai, Tomohiko; Horie, Minoru; Medicine, School of Medicine
    Timothy syndrome (TS) is a rare pleiotropic disorder associated with long QT syndrome, syndactyly, dysmorphic features, and neurological symptoms. Several variants in exon 8 or 8a of CACNA1C, a gene encoding the α-subunit of voltage-gated Ca2+ channels (Cav1.2), are known to cause classical TS. We identified a p.R412M (exon 9) variant in an atypical TS case. The aim of this study was to examine the functional effects of CACNA1C p.R412M on CaV1.2 in comparison with those of p.G406R. The index patient was a 2-month-old female infant who suffered from a cardio-pulmonary arrest in association with prolonged QT intervals. She showed dysmorphic facial features and developmental delay, but not syndactyly. Interestingly, she also presented recurrent seizures from 4 months. Genetic tests identified a novel heterozygous CACNA1C variant, p.R412M. Using heterologous expression system with HEK-293 cells, analyses with whole-cell patch-clamp technique revealed that p.R412M caused late Ca2+ currents by significantly delaying CaV1.2 channel inactivation, consistent with the underlying mechanisms of classical TS. A novel CACNA1C variant, p.R412M, was found to be associated with atypical TS through the same mechanism as p.G406R, the variant responsible for classical TS.