ArticleOrphanet journal of rare diseases2024
A Natural History Study of Timothy Syndrome.
Article in Orphanet journal of rare diseases, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers, 1 of them a synthesis that pooled it.
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Who cites it
10 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Diagnosis and management of very rare primary arrhythmia syndromes in children and adults: a Clinical Consensus Statement of the European Heart Rhythm Association of the ESC and the Association of Cardiovascular Nursing & Allied Professions of the ESC, endorsed by the Association for European Paediatric and Congenital Cardiology.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2026Guideline
- Modeling ventricular tachycardia in genetic long QT syndrome using engineered cardiac tissues.Bioactive materials · 2026Article
- A Chinese infant with CACNA1C p.C1021R variant expands clinical phenotype of CACNA1C-related disorder.Molecular genetics and metabolism reports · 2026Article
- Timothy syndrome and CACNA1C-Related Disorder: first international language and management guidelines consensus statement.European journal of human genetics : EJHG · 2026Review
- Genome x Environment analysis of Sudden Unexpected Infant Death unveils etiologic heterogeneity and strong cannabis and genetic disease risks.medRxiv : the preprint server for health sciences · 2025Article
- Timothy Syndrome and CACNA1C-Related Disorder: First International Language and Management Guidelines Consensus Statement.Research square · 2025Article
- Inactivation of CaV1 and CaV2 channels.The Journal of general physiology · 2025Review
- Synaptic plasticity deficits in a mouse model of Timothy syndrome: LTP saturation and its pharmacological rescue by nifedipine.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Article
- Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome.Nature communications · 2024Article
- Alternative Splicing and CaV-Associated Channelopathies.Wiley interdisciplinary reviews. RNAReview
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10 authors.
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Abstract
backgroundTimothy syndrome (OMIM #601005) is a rare disease caused by variants in the gene CACNA1C. Initially, Timothy syndrome was characterized by a cardiac presentation of long QT syndrome and syndactyly of the fingers and/or toes, all associated with the CACNA1C variant, Gly406Arg. However, subsequent identification of diverse variants in CACNA1C has expanded the clinical spectrum, revealing various cardiac and extra-cardiac manifestations. It remains underexplored whether individuals with the canonical Gly406Arg variants in mutually exclusive exon 8A (Timothy syndrome 1) or exon 8 (Timothy syndrome 2) exhibit overlapping symptoms. Moreover, case reports have indicated that some CACNA1C variants may produce a cardiac-selective form of Timothy syndrome often referred to as non-syndromic long QT type 8 or cardiac-only Timothy syndrome, however few reports follow up on these patients to confirm the cardiac selectivity of the phenotype over time.
methodsA survey was administered to the parents of patients with Timothy syndrome, querying a broad range of symptoms and clinical features. Study participants were organized into 5 separate categories based on genotype and initial diagnosis, enabling comparison between groups of patients which have been described differentially in the literature.
resultsOur findings reveal that Timothy syndrome patients commonly exhibit both cardiac and extra-cardiac features, with long QT syndrome, neurodevelopmental impairments, hypoglycemia, and respiratory issues being frequently reported. Notably, the incidence of these features was similar across all patient categories, including those diagnosed with non-syndromic long QT type 8, suggesting that the 'non-syndromic' classification may be incomplete.
conclusionsThis study represents the first Natural History Study of Timothy syndrome, offering a comprehensive overview of the disease's clinical manifestations. We demonstrate that both cardiac and extra-cardiac features are prevalent across all patient groups, underscoring the syndromic nature of CACNA1C variants. While the critical role of long QT syndrome and cardiac arrhythmias in Timothy syndrome has been well recognized, our findings indicate that hypoglycemia and respiratory dysfunction also pose significant life-threatening risks, emphasizing the need for comprehensive therapeutic management of affected individuals.
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