Geno- and phenotypic characteristics and clinical outcomes of CACNA1C gene mutation associated Timothy syndrome, “cardiac only” Timothy syndrome and isolated long QT syndrome 8: A systematic review

Abstract

BackgroundMutations in the CACNA1C gene–encoding for the major Ca2+ channel of the heart–may exhibit a variety of clinical manifestations. These include typical or atypical Timothy syndromes (TS) which are associated with multiple organ manifestations, and cardiac involvement in form of malignant arrhythmias, QTc prolongation, or AV block. “Cardiac only” Timothy syndrome (COTS) shows no extracardiac manifestation, whereas some CACNA1C gene mutations are associated with QTc prolongation alone (isolated long QT syndrome 8, LQT8).MethodsA systematic search of the literature reporting cases of CACNA1C gene mutation associated syndromes, including TS, COTS and isolated LQT8 via major databases published from 2004 through 2019 was performed. Detailed patient-level phenotypic and genotypic characteristics, as well as long-term outcome measures were collected and compared between pre-specified patient groups, defined both on phenotype and genotype.ResultsA total of 59 TS, 6 COTS, and 20 isolated LQT8 index cases were identified. Apart of syndactyly or baldness, there were no major differences regarding clinical manifestations or outcome measures between TS subtypes, either defining TS subtypes on the genotype or based on the phenotype. Both subtypes were characterized by an extreme degree of QTc prolongation (median ≥600 ms) which were reflected in high major adverse cardiac event rate. On the other hand, there were marked differences between TS, COTS, and isolated LQT8. Timothy syndrome was characterized by a much earlier disease onset, much more pronounced QTc prolongation and much higher mortality rate than COTS or isolated LQT8. Similar differences were observed comparing CACNA1C exon 8/8A vs. non-exon 8/8A mutation carriers. TS showed a high degree of genetic homogeneity, as the p.Gly406Arg mutation either in exon 8 or exon 8A alone was responsible for 70% of the cases.ConclusionsClinical phenotypes associated with mutations in the CACNA1C gene show important clinical differences. Timothy syndrome is associated with the most severe clinical phenotype and with the highest risk of morbidity and mortality. However, distinguishing TS subtypes, in any form, are not supported by our data.Systematic review registration[https://www.crd.york.ac.uk/prospero/], identifier [CRD42020184737].

Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome

“…Thus, not only are the CaV1.2 TS channels expressed in TS2 mice, but their expression recapitulates the canonical prolonged electrographic QTc interval and promotes arrhythmias after adrenergic stimulation. In line with a recent systematic analysis that noted hypoglycemia in TS subjects with either exon 8 or exon 8A mutations (8), this TS2 (exon 8) model thus offers an opportunity to investigate the mechanisms underlying the episodic severe hypoglycemic episodes in TS patients.…”

“…The pivotal role for CaV1.2 in the cardiac action potential provides a ready rationale for how increased Ca 2+ influx through the mutant channels prolongs the electrocardiographic QT interval, thus serving as the substate for ventricular arrhythmias (2). Less clear is the etiology for the episodic severe hypoglycemic episodes, present in subjects with either exon 8 or exon 8A G406R mutations (8), thought to trigger as much as 70% of aborted cardiac arrests or sudden deaths in one well characterized TS cohort (9), and suspected of contributing to unsuccessful resuscitations in another (10). This limited understanding presents an obstacle for development of preventive strategies and therapeutic interventions.…”

A Natural History Study of Timothy Syndrome

“…One group was a cohort of individuals diagnosed with only LQT8. There is extensive literature on CACNA1C variants that selectively cause LQT8 [for review, see 32 ] that suggests individuals with these variants may not have extra-cardiac phenotypes common to individuals diagnosed with TS. In our survey, nine nsLQT8 families encompassing 12 individuals responded.…”

DREAMER: Exploring Common Mechanisms of Adverse Drug Reactions and Disease Phenotypes through Network-Based Analysis

“…Similarly, mutations in CACNA1C alter L-type voltage-gated Ca 2+ -channels and are associated with long QT and short QT syndromes. An example is Timothy syndrome, the complex congenital syndrome caused by CACNA1C mutations (Delinière et al 2023), which involves cardiac manifestations such as long QT, along with one or more non-cardiac phenotypes such as skeletal, facial, and neurodevelopmental abnormalities (Borbás et al 2022).…”