Timothy syndrome 1 genotype without syndactyly and major extracardiac manifestations

Abstract

Timothy syndrome 1 (TS1) is a rare genetic disorder characterized by multisystem abnormalities including QT prolongation, congenital heart defects, facial dysmorphism, episodic hypoglycemia, and neurological symptoms. A morphological hallmark of TS1 is syndactyly, present in all cases. TS1 is caused by the canonical p.Gly406Arg mutation in the alternatively spliced exon 8A in the CACNA1C gene, encoding for the main cardiac L-type calcium channel. A variant case of TS1 is reported. The proband had intermittent fetal bradycardia with heart rate of 72 bpm. On the first day of life bradycardia due to 2:1 atrioventricular (AV) block and marked QTc prolongation of 600 ms was noted. On medical therapy with propranolol and mexiletine 1:1 AV conduction returned with QTc prolongation of 470-580 ms. The patient lacked other extracardiac manifestations, most importantly syndactyly, neurological complications or autism. On genetic analysis, the canonical TS1 causing mutation, p.Gly406Arg in exon 8A of the CACNA1C gene was detected. The CACNA1C p.Gly406Arg variant was not present in the parents, but was detected in different DNA samples of the index patient. Our case highlight further phenotypic variability in TS. Most importantly, it underlines that the lack of syndactyly does not exclude the presence of a TS1 genotype. © 2017 Wiley Periodicals, Inc.

Expanding clinical phenotype in CACNA1C related disorders: From neonatal onset severe epileptic encephalopathy to late‐onset epilepsy

“…Ca v 1.2 is evolutionally conserved protein that is expressed in the heart, brain, lung and smooth muscles, and is critical for Ca 2+ signaling, cellular and neuronal excitability, muscle contraction, and regulation of gene expression [Dai et al, 2009; Hedley et al, 2009]. The variable clinical spectrum summarized in Table 1 [Splawski et al, 2005; Sepp et al, 2017; Corona-Rivera et al, 2015; Etheridge et al, 2011; Splawski et al, 2004; Gillis et al, 2012; Wemhöner et al, 2015; Boczek et al, 2015; Fukuyama et al, 2014; Liu et al, 2017; Antzelevitch et al, 2007] may be accounted for by the numerous isoforms generated by alternatively spliced exons, variable expression of different transcripts in tissue, and the variant’s location in the protein and structural domain of the Ca v 1.2 channel. For example, in some individuals it is predominantly confined to the heart as seen in Brugada syndrome, while in others there is a predominant neurologic phenotype as seen in Patient 1.…”

Timothy syndrome‐like condition with syndactyly but without prolongation of the QT interval

“…There are reports of patients with other mutations (i.e., non‐Gly406Arg mutations) in the CACNA1C gene who had Timothy syndrome‐like phenotype (i.e., QT prolongation and syndactyly, Figure ) (Walsh et al, ). To our knowledge, our patient is the first to exhibit syndactyly and to carry a CACNA1C mutation but to not have QT prolongation, which has long been considered an obligatory feature of Timothy syndrome (Sepp et al, ). It would be important to accumulate more data on the risk for arrhythmia in patients with non‐p.Gly406Arg mutations.…”

“…Timothy syndrome (OMIM: 601005) is characterized by a unique combination of QT prolongation and bilateral cutaneous syndactyly of the fingers and toes (Splawski et al, ). Since the original description of Timothy syndrome, the phenotypic spectrum of this multisystem disorder has expanded to include congenital heart disease, dysmorphic facial features, and neurodevelopmental disorders (Sepp et al, ).…”

Dysfunctional Cav1.2 channel in Timothy syndrome, from cell to bedside

“…Long-term administration of β-blockers is recommended in TS patients. Additional treatment strategies are usually dependent on TS genotypes and clinical phenotypes including late sodium current (I NaL ) blocker, mexiletine, 1,4,24,25,37,89–94 other antiarrhythmic drugs such as verapamil and nicorandil, potassium and/or magnesium supplementation, ICD, pacemakers, and left cardiac sympathetic denervation.…”