Unusual retrospective prenatal findings in a male newborn with Timothy syndrome type 1

Corona‐Rivera, Jorge Román; Barrios-Prieto, Ernesto; Nieto-García, Rafael; Bloise, Raffaella; Priori, Silvia G.; Napolitano, Carlo; Bobadilla‐Morales, Lucina; Corona‐Rivera, Alfredo; Zapata‐Aldana, Eugenio; Peña-Padilla, Christian; Rivera-Vargas, Jehú; Chavana-Naranjo, Eva

doi:10.1016/j.ejmg.2015.04.001

Cited by 17 publications

(15 citation statements)

References 13 publications

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“…TS patients are treated clinically with β-adrenergic blockers, calcium channel blockers, and sodium channel blockers (Jacobs et al., 2006, Shah et al., 2012). However, these regimens are insufficient to prevent lethal arrhythmias in TS patients (Corona-Rivera et al., 2015, Kawaida et al., 2016, Philipp and Rodriguez, 2016). Therefore, new therapeutics for TS are still needed.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome

et al. 2017

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SummaryL-type calcium channel CaV1.2 plays an essential role in cardiac function. The gain-of-function mutations in CaV1.2 have been reported to be associated with Timothy syndrome, a disease characterized by QT prolongation and syndactyly. Previously we demonstrated that roscovitine, a cyclin-dependent kinase (CDK) inhibitor, could rescue the phenotypes in induced pluripotent stem cell-derived cardiomyocytes from Timothy syndrome patients. However, exactly how roscovitine rescued the phenotypes remained unclear. Here we report a mechanism potentially underlying the therapeutic effects of roscovitine on Timothy syndrome cardiomyocytes. Our results using roscovitine analogs and CDK inhibitors and constructs demonstrated that roscovitine exhibits its therapeutic effects in part by inhibiting CDK5. The outcomes of this study allowed us to identify a molecular mechanism whereby CaV1.2 channels are regulated by CDK5. This study provides insights into the regulation of cardiac calcium channels and the development of future therapeutics for Timothy syndrome patients.

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Section: Introductionmentioning

confidence: 99%

Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome

et al. 2017

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“…Syndactyly is the most common congenital hand deformity. [ 2 ] QTc prolongation is of clinical significance in different pediatric populations such as in children with hypertrophic cardiomyopathy [ 12 ] or undergoing CHD surgery. [ 13 ] A prolonged QTc interval is an independent risk factor for SCD, [ 14 , 15 ] which is the hallmark of TS.…”

Section: Discussionmentioning

confidence: 99%

“…Syndactyly is a common hereditary hand malformation (incidence > 0.03% [ 1 ] ): adjacent fingers and/or toes are webbed or fused. [ 2 ] Syndactyly can be inherited isolated or as part of a syndrome, like, eg, Timothy Syndrome (TS) (OMIM #601005), also referred to as syndactyly-associated long QT syndrome (LQTS). [ 3 ] LQTS is characterized by prolonged ventricular repolarization, with a prolonged QT interval, which causes syncope and sudden cardiac death (SCD) from ventricular arrhythmias.…”

Section: Introductionmentioning

confidence: 99%

Clinical characterization and outcome of prolonged heart rate-corrected QT interval among children with syndactyly

Hao

Chen

et al. 2020

Medicine

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Prolonged heart rate-corrected QT (QTc) interval is an independent risk factor for sudden cardiac death, which is the hallmark of Timothy syndrome (TS). There are little data on children with syndactyly and QTc prolongation. To evaluate the characteristics and long-term outcomes in children with syndactyly, and to attempt to identify TS in patients with syndactyly and QTc prolongation. This is a retrospective case-control study of children with syndactyly who visited Beijing Jishuitan Hospital between July 2003 and February 2013. The patients with prolonged QTc intervals are matched 1:4 with patients without prolongation. Genetic testing of the CACNA1C gene is routinely performed in patients with QTc prolongation. The mean age at admission is 3.4 ± 2.3 years. Compared with the normal QTc group, those with QTc prolongation showed higher frequencies of congenital heart disease (11.8% vs 1.5%, P = .042), mental retardation and facial dysmorphia (11.8% vs 0, P = .004), and T wave alternans (23.5% vs 4.4%, P = .01). In the multivariable analysis, only T wave alternans (OR = 10.61, 95%CI: 1.39–81.16, P = .023) is independently associated with QTc prolongation in patients with syndactyly. One child with QTc prolongation had a mutation in the CACNA1C gene. No patients with prolonged QTs interval met the threshold for TS. Children with syndactyly and prolonged QTc interval had more multisystem diseases and electrocardiography abnormalities. T wave alternans is independently associated with QTc prolongation in patients with syndactyly.

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“…Most patients were diagnosed during neonatal period or rarely in late infancy, only two cases reported the fetal hydrops as antenatal expression of TS1 [58,59]. …”

Section: Long Qt and Timothy Syndromesmentioning

confidence: 99%

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

et al. 2018

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The voltage-gated L-type calcium channel (LTCC) is essential for multiple cellular processes. In the heart, calcium influx through LTCC plays an important role in cardiac electrical excitation. Mutations in LTCC genes, including CACNA1C, CACNA1D, CACNB2 and CACNA2D, will induce the dysfunctions of calcium channels, which result in the abnormal excitations of cardiomyocytes, and finally lead to cardiac arrhythmias. Nevertheless, the newly found mutations in LTCC and their functions are continuously being elucidated. This review summarizes recent findings on the mutations of LTCC, which are associated with long QT syndromes, Timothy syndromes, Brugada syndromes, short QT syndromes, and some other cardiac arrhythmias. Indeed, we describe the gain/loss-of-functions of these mutations in LTCC, which can give an explanation for the phenotypes of cardiac arrhythmias. Moreover, we present several challenges in the field at present, and propose some diagnostic or therapeutic approaches to these mutation-associated cardiac diseases in the future.

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Unusual retrospective prenatal findings in a male newborn with Timothy syndrome type 1

Cited by 17 publications

References 13 publications

Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome

Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome

Clinical characterization and outcome of prolonged heart rate-corrected QT interval among children with syndactyly

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

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