Related Experiment Video
Updated: May 15, 2025
Pull-down of Calmodulin-binding Proteins
Published on: January 23, 2012
Beyond the blueprint: decoding calmodulinopathy-a case report showcasing the utility of multifaceted treatments
Saikiran Kakarla1, Madhusoodanan Jalaja Aswathy1, Madhusoodanan Pillai Sreelekshmi1
1Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Medical College Junction, Thiruvananthapuram, Kerala 695011, India.
Background:
Calmodulinopathies are adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially for CALM-LQTS (calmodulinopathy-associated long QT syndrome). This case report illustrates a novel mutation in CALM-LQTS and its response to multimodality treatment strategies.
Case Summary:
The proband was the first child born to a nonconsanguineous Indian couple, a 26-year-old woman and a 30-year-old man. The child was delivered prematurely, and at birth, a functional 2:1 atrioventricular block was noted with sinus bradycardia with a corrected QT by Bazzet's of 716 ms. Clinical exome sequencing of the proband revealed a novel missense variant c.287A>G in exon 5 of the CALM3 gene in a heterozygous state, resulting in an Asp96Gly change. The OMIM phenotype associated with it is long QT syndrome 16 (#618782). Despite receiving a dose of 4.5 mg/kg/day of propranolol, the child still had a persistent long QTc. Mexiletine was started at the trial dose of 1.5 mg/kg/day, and after 1 h, QTc was reduced to 507 ms from 560 ms. After a left-cardiac sympathectomy, he remains asymptomatic after 1.3 years of follow-up with a QTc value of 490 ms.
Discussion:
CALM3 pathogenic variants are gain-of-function variants mainly affecting amino acids residing in the Ca2-binding loops. Earlier data suggested the role of the Nav1.5 channel in leading to persistent Na+ leaks resulting in LQTS. However, they only focused on LQTS-CALM1 and CALM2 models and did not include CALM3-related genes. Despite similarities, the precise impact of CaM on Nav1.5 channels still needs to be defined as CaV1.2. The exact role of mexiletine is not fully understood.
Insights
Calmodulinopathies cause dangerous arrhythmias, with limited treatments for CALM-LQTS. This case shows a new CALM3 mutation effectively managed with propranolol, mexiletine, and cardiac sympathectomy.
Area of Science:
- Cardiology
- Genetics
- Pharmacology
Background:
- Calmodulinopathies are life-threatening arrhythmias triggered by adrenergic activity.
- Current therapies for calmodulinopathy-associated long QT syndrome (CALM-LQTS) are insufficient.
- This report details a novel mutation in CALM-LQTS and its treatment response.
Observation:
- A neonate presented with severe bradycardia and a prolonged QTc interval (716 ms).
- Clinical exome sequencing identified a novel heterozygous missense variant (c.287A>G) in the CALM3 gene, linked to Long QT Syndrome 16.
- Initial propranolol treatment was ineffective in correcting the QTc interval.
Findings:
- Mexiletine administration rapidly reduced the QTc interval from 560 ms to 507 ms.
- Following left-cardiac sympathectomy, the patient remained asymptomatic with a QTc of 490 ms at 1.3-year follow-up.
- CALM3 variants are gain-of-function, potentially impacting cardiac ion channels.
Implications:
- This case highlights a novel CALM3 mutation causing severe long QT syndrome.
- Multimodality treatment including mexiletine and sympathectomy can be effective for refractory CALM-LQTS.
- Further research is needed to elucidate the precise role of calmodulin and mexiletine in cardiac electrophysiology.
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