Göran Wettrell
Lund, Sweden

As a pediatrician specializing in pediatric cardiology, I met in 1982 a twelve-year-old-boy with syncope when playing football. He had four previous episode of losing consciousness during physical activity and once during a fire alarm. His resting ECG was normal but his long-term ECG registration revealed exercised-induced ventricular extrasystoles of increasing complexity. The family history included an older brother and sister who also had a history of repeated syncope and a brother who had drowned during outdoor swimming.1 The idea that the patients might have long QT syndrome (LQTS) with a normal QT interval was the hypothesis in the 1980s, and twenty years later had been confirmed.2 This is what was presumed in this patient, and he was treated with a beta blocker.
Over the next twenty-five years, twelve other members in four generations of this family were affected. They all experienced syncope during physical activities and were treated with beta blockers. Despite treatment, one family member suffered sudden death, and another had a cardiac arrest but was successfully revived.
Clinical knowledge about LQTS evolved following the establishment of the International LQTS Registry in 1979. Diagnostic criteria for LQTS were introduced in 1975 as the “Schwartz criteria” and were updated in 2011.3
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is another inherited arrhythmogenic disorder of the structurally normal heart. It was first characterized by Coumel et al. in 1970s.4,5 The arrhythmic pattern ranges from polymorphic premature ventricular contractions to ventricular fibrillation.
The development of genetic science between 1990–2003 culminating in the Human Genome Project mapped over 20,000 human genes. This milestone laid the groundwork for identifying genes associated with specific diseases.
Molecular discoveries in calmodulin
The 1990s provided favorable conditions for studying molecular genetics, including members of the Mormon church in Utah in the US. Mark T. Keating’s research group identified mutations in genes encoding specific ion channels of sodium and potassium linked to LQTS in individuals with the syndrome.6 In 2001, CPVT was associated with pathogenic sequence variants in genes encoding cardiac intracellular proteins such as ryanodine receptor 2 and calsequestrin 2. These proteins affected intracellular calcium handling during adrenergic stimulation, potentially triggering cardiac arrhythmias.7,8
Blood samples from our index case—the young boy—and some other family members were screened as part of the clinical workup for mutations in a panel of arrythmia-associated genes. No mutations were found. With our clinical insights and collaboration with a Danish research group equipped with advanced molecular genetic technique, we were prepared to explore further.1,9 As Louis Pasteur said, “Chance favors the prepared mind.”
A genome-wide linkage analysis in the large family with a severe, dominantly inherited form of CPVT-like arrythmias mapped the disease locus to chromosome 14. Sequencing the gene CALM 1 from the index case revealed a heterozygous missense mutation. This mutation altered the gene`s amino acid sequence substituting asparagine with isoleucine. The mutation was present in all affected individuals in the family (Figure 1). This single amino acid substitution seemed functional to disrupt intracellular dynamics and the interaction of the calmodulin N-domain with the ryanodine receptor.10 Our identification of the first human calmodulin missense mutations in 2012 was a dramatic revelation.1 Calmodulin (CaM) is an essential calcium sensing protein that modulates many cellular processes. Three genes (CALM 1-3) located on different chromosomes encode a completely identical CaM protein, and this protein sequence is conserved across all vertebrates. Alterations in the amino sequence were thought to be incompatible with life. Calmodulin genes subsequently became candidates for genetic screening of individuals with CPVT-like arrythmias and unexpected cardiac death.
It also led to the start of the International Calmodulinopathy Registry (ICalmR) in 2015, modeled after the International LQTS Registry launched forty-five years earlier. In 2023, the ICalmR had enrolled 140 subjects with calmodulin-LQTS and Calmodulin- CPVT, as the prevalent phenotypes.11 Although calmodulinopathy remains a severe, life-threatening cardiac disease, its clinical presentations appeared increasingly pleotropic. Neurological and neurodevelopmental deficits, structural cardiac abnormalities, and cardiomyopathies have also been observed. Current recommended treatments of symptomatic cardiac calmodulinopathy include full doses of mainly beta blockers, or sometimes flecainide and sodium channel blockers. Severe cases may require an implantable cardioverter (ICD) and surgical antiadrenergic therapy.
Calmodulinopathy has also contributed to reevaluating cases of recurring sudden death in infants and children. For instance, scientific evidence provided by Danish researchers played a major role in overturning the conviction of Kathleen Folbigg ,who had been accused of killing her four children and spent twenty years in jail.12 Thus, the calmodulinopathy emerged as a possible explanation for a natural cause of death.
The gene mutations associated with typical CPVT (ryanodine receptor 2 and casequestrin 2) have also been the focus of gene therapy. Preclinical studies involving animal and induced pluripotent stem cell (iPSC) models combined with artificial intelligence to analyze registry data have shown promising steps towards precision therapies by gene transfer and gene editing.13
Forty years of clinical observation—beginning with the bedside clinical problem of a single patient and culminating in a decade of genomic discoveries in calmodulin—have demonstrated the potential for improved treatments of patient with life-threatening arrhythmias.
References
- Nyegaard, M, Overgaard, MT, Söndergaard, T, Vranas, M, Behr, ER, Hildebrand, LL, Lund, J, Hedley, PL, Comm, AJ, Wettrell, G, Fosdal, I, Christiansen, M and Böglum, AD. Mutations in Calmodulin Cause Ventricular Tachycardia and Sudden Cardiac Death. Am. J. Hum. Genet. 2012: 91; 703-712.
- Priori, SG, Napolitano, C and Schwartz, PJ. Low penetrance in the Long QT syndrome: clinical impact. Circulation. 1999: 99: 529-553.
- Schwartz, PJ and Crotti, L. QTc Behaviour During Exercise and Genetic Testing for the Long QT syndrome. Circulation. 2011: 124; 2181-2184.
- Kallas, D, Lamba, A, Roston, TM et al. Pediatric Cathecholaminergic Polymorphic Ventricular Tachycardia: A Translational Perspective for the Clinician-Scientist. Int. J. Mol. Sci. 2001: 22; 9293.
- Pérez, PR, Hylind, RJ, Roston, TM et al. Gene therapy for Catecholaminergic Polymorphic Ventricular Tachycardia. Heart, Lung and Circulation. 2023: 32: 790-797.
- Wettrell, G. Early clinical and molecular discoveries in Long QT Syndrome. Hektoen International Cardiology Winter 2020.
- Priori, SG, Napolitano, C, Tiso, N et al. Mutations in the Cardiac Ryanodine Receptor Gene (hRYR2) Underlie Catecholaminergic Polymorphic Ventricular Tachycardia. Circulation. 2001: 103; 196-200.
- Lahat, H, Pras, E, Olender, T et al. A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine – induced polymorphic ventricular tachycardia in Bedouin families in Israel. Am. J. Hum. Genet. 2001: 69; 1378-1384.
- Hall, JG. A clinician´s plea. Nature Genetics. 2003: 33; 440-442.
- Wang, K, Brohus, M, Holt, C et al. Arrhythmia mutations in calmodulin can disrupt cooperativity of Ca2+ binding and cause misfolding. J. Physiol. 2020: 598.6: 1169- 1186.
- Crotti, L, Spazzolini, C, Nyegaard, M et al. Clinical presentation of calmodulin mutations: International Calmodulinopathy Registry. Eur. Heart J. 2023: 44; 3357-3370.
- Phillips, N. Trials of the heart. Nature. 2022:611;219-223.
- Priori, SG, Mazzanti, A Santiago, DJ. Precision Medicine in Catecholaminergic Polymorphic Ventricular Tachycardia. JACC. 2021:77; 2592-2612.
GÖRAN WETTRELL, MD, PhD, Associate Professor, FLS, is a senior consultant in pediatric cardiology, University Hospital, Lund, Sweden with a focus on cardiac molecular genetics and primary arrhythmias. His other interests include male choir singing and medical humanities.
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