CANAC1C encodes for the main cardiac L-type calcium channel and mutations on it lead to a prolonged QT interval in Timothy Syndrome (TS). We provide a new de novo constitutional heterozygote missense variation in CACNA1C in a living adult woman, also carrier of the known c.2146-1G>C heterozygous variation of PKP2 inherited from her father. To our knowledge, this patient is the first to have the two variations in these genes. Theses clinical and molecular findings expand the clinical and molecular spectrum of TS and show the interest of next generation sequencing or whole exome sequencing in rare disorders, atypical or novel phenotype.
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A novel computational model of swine ventricular myocyte reveals new insights into disease mechanisms and therapeutic approaches in Timothy Syndrome.
Sci Rep
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Novel Arrhythmogenic Mechanisms Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Timothy syndrome type 1 (TS1), a malignant variant of Long QT Syndrome, is caused by L-type Ca2+ Channel (LTCC) inactivation defects secondary to the p.Gly406Arg mutation in the CACNA1C gene. Leveraging on the experimental in vitro data from our TS1 knock-in swine model and their wild-type (WT) littermates, we first developed a mathematical model of WT large white swine ventricular cardiomyocyte electrophysiology that reproduces a wide range of experimental data, including ionic current properties, action potential (AP) dynamics, and handling.
View Article and Find Full Text PDFA Natural History Study of Timothy Syndrome.
Orphanet J Rare Dis
November 2024
Laboratory of Biochemistry and Genetics, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institute of Health, Bethesda, MD, USA.
Article Synopsis
- - Timothy syndrome, caused by variants in the CACNA1C gene, was originally recognized for its cardiac symptoms (long QT syndrome) and physical abnormalities (syndactyly), but more recent research has unveiled a wider range of symptoms associated with different CACNA1C variants.
- - A survey was conducted with parents of Timothy syndrome patients to gather information on various symptoms, grouping participants by genetic type and initial diagnosis to compare their conditions.
- - The study found that patients commonly show both cardiac and extra-cardiac symptoms, such as neurodevelopmental issues and respiratory problems, regardless of their classification, indicating that the current understanding of "non-syndromic" cases may not fully capture the complexity of the disease.
A case of pioneering subcutaneous implantable cardioverter defibrillator intervention in Timothy syndrome.
BMC Pediatr
November 2024
Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Furong District, Changsha, 410011, Hunan Province, People's Republic of China.
Article Synopsis
- - A 9-year-old with Timothy syndrome, a rare genetic condition linked to the CACNA1c gene, underwent subcutaneous implantable cardioverter defibrillator (S-ICD) implantation, marking the youngest known case in mainland China.
- - While the patient showed no ventricular arrhythmias during hospitalization or follow-up, this result alone doesn't confirm the safety of S-ICD for young TS patients.
- - Further research is needed to assess long-term effects of S-ICD and explore gene therapy options to improve treatment strategies for Timothy syndrome.
Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome.
Nat Commun
October 2024
Cardiovascular Research Institute, Weill Cornell Medicine, 413 E. 69th St., New York, NY, 10021, USA.
Article Synopsis
- * Researchers created a G406R knockin mouse model that exhibits TS features, including hypoglycemia, but surprisingly does not show increased beta cell activity or hyperinsulinism.
- * The study unveils alternative mechanisms for hypoglycemia, such as impaired hormone responses and disrupted hypothalamic regulation of glucose levels, enhancing our understanding of how mutant channels impact TS.
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