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Cardiac and cardiovascular disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
At least 12 different loci are recognised. The clinical features may differ somewhat, especially the factors that provoke symptomatic episodes (or death), with swimming and sudden, loud noises being hazardous in LQT1 and LQT2, respectively. All affected should avoid competitive sports and drugs that prolong the QT interval. Timothy syndrome also has non-cardiac features including autism, syndactyly and immunodeficiency.
Associated disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
Timothy syndrome is a rare disorder caused by alterations in one of the calcium-channel genes. Calcium channels regulate how much calcium can enter a cell. When these channels are defective, the cells become overwhelmed by an inlux of calcium. The calcium channel related to Timothy syndrome is known as the CaV1.2 channel. This disorder is caused by a defect in the CACNA2C gene, which is located on the short arm of chromosome 12 (12p13.3).
Ion Channels in Human Pluripotent Stem Cells and Their Neural Derivatives
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Ritika Raghavan, Robert Juniewicz, Maharaib Syed, Michael Lin, Peng Jiang
The use of hPSCs, specifically patient-derived hPSCs to model complex nervous system disorders is a new and exciting approach to studying pathology, understanding disease mechanisms, and drug discovery. Researchers have been able to use this technology to study specific channelopathies and devise therapeutic strategies for various Autism Spectrum Disorders (ASD) and motor neuron diseases. Caused by mutations in the X-linked gene encoding the MeCP2 protein, ASD Rett Syndrome (RTT) is a progressive neurological disorder involving impaired motor function, hypotonia, seizures, and autistic behavior from as early as 18 months in individuals (69). Given the importance of intracellular calcium levels in the activation of signaling pathways in neural development, it was found that calcium oscillations were significantly decreased in RTT patient-derived iPSCs (70). This result was consistent with a previous study on MeCP2 KO mouse model and suggests a deficiency in neuronal network connectivity and activity dynamics (70,71). Furthermore, it was revealed that RTT neurons have a significant decrease in frequency and amplitude of spontaneous postsynaptic currents as compared to neurons differentiated from normal individual-derived hiPSCs, further reiterating an altered neuronal network in RTT patients. Another ASD, Timothy syndrome (TS), is caused by a dominant mutation in an alternatively spliced exon of the CACNA1C gene which encodes for the a subunit of the CaV1.2 channel (72). The CaV channel plays an important role in neuronal development by promoting dendritic growth and arborization (73). In TS patient hiPSC-derived neurons, researchers observed a lack of dendrite growth (coupled with dendrite retraction upon depolarization) thus reinforcing the connection between the CaV channel mutation in the disease and calcium’s role in neuron development (74). It was also found that TS hiPSC-derived neurons displayed wider APs, increased calcium signals, and abnormal levels of norepinephrine and dopamine (75). Furthermore, these phenotypes were corrected by the application of roscovitine, which is known to restore calcium and electrical signaling. Dravet syndrome, displaying symptoms of developmental delays in language, motor function, and social skills, is another type of childhood epilepsy and ASD that is caused by the loss-of-function mutation in the SCN1A gene that encodes the NaV1.1 channel (76–78). Using whole-cell patch clamp recording, it was found that the INa amplitude was significantly reduced in Dravet syndrome hiPSC-derived telencephalic inhibitory neurons (79). The maximal firing frequency was also reduced by 40% in patient hiPSC-derived inhibitory neurons. These phenotypes were recapitulated in control neurons where NaV1.1 expression was suppressed using shRNAs, and again rescued in patient hiPSC-derived neurons by forced expression of NaV1.1 expression, highlighting the importance of NaV1.1 in controlling the excitability of inhibitory neurons.
Nitric oxide pathway as a plausible therapeutic target in autism spectrum disorders
Published in Expert Opinion on Therapeutic Targets, 2022
Rishab Mehta, Anurag Kuhad, Ranjana Bhandari
The disturbed calcium signaling pathway due to the mutation of gene CACNA1C was found to be associated with Timothy syndrome [32,33]. Altered MAPK signaling has been implicated in ASD leading to a direct effect on fundamental cellular processes such as gene expression, proliferation, differentiation, cell survival, and apoptosis [34,35]. The role of the PI3k-Akt pathway has been well implicated in ASD. It has been reported that the Akt is responsible for phosphorylation of various substrates associated with cellular metabolism, protein synthesis, and cell cycle with the help of PiP3 (phosphatidylinositol-3,4,5-triphosphate) [36,37]. Mutation in genes such as PTEN, TSC1, and TSC2 are considered to be associated with altered PI3K-Akt pathway thus, altering transcription, translation, proliferation, and survival of neurons [37]. Various studies have also implicated the role of mTOR and Ras signaling pathways where they also tend to affect normal cellular signaling and functions [8]. The mTOR pathway is known to be affected by tuberous sclerosis complex genes (TSC 1 and TCS 2), which tend to inhibit the aforementioned pathway thus having a downstream effect on synaptic and neuronal structures, which may lead to alteration in fundamental circuitry and may cause an imbalance of excitatory and inhibitory neurotransmitters [38,39]
Precision medicine in cardiac electrophysiology: where we are and where we need to go
Published in Expert Review of Precision Medicine and Drug Development, 2020
Ashish Correa, Syed Waqas Haider, Wilbert S. Aronow
Congenital LQTS is an inherited arrhythmia syndrome characterized by a prolonged QT interval on the surface electrocardiogram (EKG) resulting from abnormal cardiac repolarization that puts an individual at an increased risk for a particular type of polymorphic ventricular tachycardia known as torsades des pointes [20,21]. LQTS are divided into 13 subtypes based on 13 genotypes that have been identified. Each genotype is due to a mutation of a discrete gene. Phenotypically, the disease may present as a cardiac arrhythmia syndrome alone or one associated with other conditions. When occurring without any other associated conditions, it is known as Romano-Ward Syndrome – an LQTS that can be caused by mutations of any the 13 identified genes and with autosomal dominant inheritance [20,22,23]. Other rarer phenotypes of LQTS include Jervell and Lange-Nielsen Syndrome, Andersen-Tawil Syndrome, and Timothy Syndrome. Jervell and Lange-Nielsen Syndrome (JLNS) is an extremely severe and rare autosomal recessive disorder characterized by marked QT prolongation with high rates of SCD as well as sensorineural deafness [24]. Andersen-Tawil Syndrome, also known as hypokalemic periodic paralysis or long QT syndrome 7 (LQT7) is an autosomal dominant disorder characterized by a triad of a prolonged QT interval with ventricular arrhythmias, potassium-sensitive periodic paralysis and various dysmorphic features [25,26]. Timothy Syndrome or LQT8 is an extremely rare autosomal recessive arrhythmia syndrome characterized by various arrhythmias, QT prolongation, and developmental disorders [27].
Pharmacotherapy in inherited and acquired ventricular arrhythmia in structurally normal adult hearts
Published in Expert Opinion on Pharmacotherapy, 2019
Staniel Ortmans, Charline Daval, Martin Aguilar, Pablo Compagno, Julia Cadrin-Tourigny, Katia Dyrda, Lena Rivard, Rafik Tadros
Second, the Timothy syndrome (TS), also known as LQT8, is an extremely rare disease and is characterized by prolonged QT interval, syndactyly, cardiac malformations, autism spectrum disorders and facial dysmorphism [42]. It is caused by a gain of function mutation, usually non-inherited (i.e. de novo), in the ICa gene CACNA1C, resulting in intracellular calcium overload and marked QTc interval prolongation. Data regarding pharmacologic therapy of TS is limited to small case series. Considering the pathophysiology, calcium-channel blockade such as with verapamil has been used with variable response [43]. Ranolazine and mexiletine have also been shown to shorten QTc in patients with the TS [44,45]. β-blockers have also been used with insufficient protection and the arrhythmic course of patients with the TS is highly malignant with high mortality despite antiarrhythmic therapy [46]. Prophylactic ICD therapy may be considered in TS patients despite the absence of randomized studies.