1.
Heterozygous familial hypercholesterolaemia in a pair of identical twins: a case report and updated review.
Mohd Nor, NS, Al-Khateeb, AM, Chua, YA, Mohd Kasim, NA, Mohd Nawawi, H
BMC pediatrics. 2019;(1):106
Abstract
BACKGROUND Familial hypercholesterolaemia (FH) is the most common inherited metabolic disease with an autosomal dominant mode of inheritance. It is characterised by raised serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c), leading to premature coronary artery disease. Children with FH are subjected to early and enhanced atherosclerosis, leading to greater risk of coronary events, including premature coronary artery disease. To the best of our knowledge, this is the first report of a pair of monochorionic diamniotic identical twins with a diagnosis of heterozygous FH, resulting from mutations in both LDLR and ABCG8 genes. CASE PRESENTATION This is a rare case of a pair of 8-year-old monochorionic diamniotic identical twin, who on family cascade screening were diagnosed as definite FH, according to the Dutch Lipid Clinic Criteria (DLCC) with a score of 10. There were no lipid stigmata noted. Baseline lipid profiles revealed severe hypercholesterolaemia, (TC = 10.5 mmol/L, 10.6 mmol/L; LDL-c = 8.8 mmol/L, 8.6 mmol/L respectively). Their father is the index case who initially presented with premature CAD, and subsequently diagnosed as FH. Family cascade screening identified clinical FH in other family members including their paternal grandfather who also had premature CAD, and another elder brother, aged 10 years. Genetic analysis by targeted next-generation sequencing using MiSeq platform (Illumina) was performed to detect mutations in LDLR, APOB100, PCSK9, ABCG5, ABCG8, APOE and LDLRAP1 genes. Results revealed that the twin, their elder brother, father and grandfather are heterozygous for a missense mutation (c.530C > T) in LDLR that was previously reported as a pathogenic mutation. In addition, the twin has heterozygous ABCG8 gene mutation (c.55G > C). Their eldest brother aged 12 years and their mother both had normal lipid profiles with absence of LDLR gene mutation. CONCLUSION A rare case of Asian monochorionic diamniotic identical twin, with clinically diagnosed and molecularly confirmed heterozygous FH, due to LDLR and ABCG8 gene mutations have been reported. Childhood FH may not present with the classical physical manifestations including the pathognomonic lipid stigmata as in adults. Therefore, childhood FH can be diagnosed early using a combination of clinical criteria and molecular analyses.
2.
The biophysical characterization of the first SCN5A mutation R1512W identified in Chinese sudden unexplained nocturnal death syndrome.
Zheng, J, Zhou, F, Su, T, Huang, L, Wu, Y, Yin, K, Wu, Q, Tang, S, Makielski, JC, Cheng, J
Medicine. 2016;(23):e3836
-
-
Free full text
-
Abstract
Increasing evidence observed in clinical phenotypes show that abrupt breathing disorders during sleep may play an important role in the pathogenesis of sudden unexplained nocturnal death syndrome (SUNDS). The reported Brugada syndrome causing mutation R1512W in cardiac sodium channel α subunit encoded gene SCN5A, without obvious loss of function of cardiac sodium channel in previous in vitro study, was identified as the first genetic cause of Chinese SUNDS by us. The R1512W carrier was a 38-year-old male SUNDS victim who died suddenly after tachypnea in nocturnal sleep without any structural heart disease. To test our hypothesis that slight acidosis conditions may contribute to the significant loss of function of mutant cardiac sodium channels underlying SUNDS, the biophysical characterization of SCN5A mutation R1512W was performed under both extracellular and intracellular slight acidosis at pH 7.0. The cDNA of R1512W was created using site-directed mutagenesis methods in the pcDNA3 plasmid vector. The wild type (WT) or mutant cardiac sodium channel R1512W was transiently transfected into HEK293 cells. Macroscopic voltage-gated sodium current (INa) was measured 24 hours after transfection with the whole-cell patch clamp method at room temperature in the HEK293 cells. Under the baseline conditions at pH 7.4, R1512W (-175 ± 15 pA/pF) showed about 30% of reduction in peak INa compared to WT (-254 ± 23 pA/pF, P < 0.05). Under the acidosis condition at pH 7.0, R1512W (-130 ± 17 pA/pF) significantly decreased the peak INa by nearly 50% compared to WT (-243 ± 23 pA/pF, P < 0.005). Compared to baseline condition at pH 7.4, the acidosis at pH 7.0 did not affect the peak INa in WT (P > 0.05) but decreased peak INa in R1512W (P < 0.05). This initial functional study for SCN5A mutation in the Chinese SUNDS victim revealed that the acidosis aggravated the loss of function of mutant channel R1512W and suggested that nocturnal sleep disorders-associated slight acidosis may trigger the lethal arrhythmia underlying the sudden death of SUNDS cases in the setting of genetic defect.
3.
CALM3 mutation associated with long QT syndrome.
Reed, GJ, Boczek, NJ, Etheridge, SP, Ackerman, MJ
Heart rhythm. 2015;(2):419-22
4.
Short-coupled polymorphic ventricular tachycardia at rest linked to a novel ryanodine receptor (RyR2) mutation: leaky RyR2 channels under non-stress conditions.
Cheung, JW, Meli, AC, Xie, W, Mittal, S, Reiken, S, Wronska, A, Xu, L, Steinberg, JS, Markowitz, SM, Iwai, S, et al
International journal of cardiology. 2015;:228-36
-
-
Free full text
-
Abstract
BACKGROUND Ryanodine receptor (RyR2) mutations have largely been associated with catecholaminergic polymorphic ventricular tachycardia (PMVT). The role of RyR2 mutations in the pathogenesis of arrhythmias and syncope at rest is unknown. We sought to characterize the clinical and functional characteristics associated with a novel RyR2 mutation found in a mother and daughter with PMVT at rest. METHODS AND RESULTS A 31-year-old female with syncope at rest and recurrent short-coupled premature ventricular contractions (PVCs) initiating PMVT was found to be heterozygous for a novel RyR2-H29D mutation. Her mother, who also had syncope at rest and short-coupled PMVT, was found to harbor the same mutation. Human RyR2-H29D mutant channels were generated using site-directed mutagenesis and heterologously expressed in HEK293 cells together with the stabilizing protein calstabin2 (FKPB12.6). Single channel measurements of RyR2-H29D mutant channels and wild type (WT) RyR2 channels were compared at varying concentrations of cytosolic Ca(2+). Binding affinities of the RyR2-H29D channels and RyR2-WT channels to calstabin2 were compared. Functional characterization of the RyR2-H29D mutant channel revealed significantly higher open probability and opening frequency at diastolic levels of cytosolic Ca(2+) under non-stress conditions without protein kinase A treatment. This was associated with a modest depletion of calstabin2 binding under resting conditions. CONCLUSIONS The RyR2-H29D mutation is associated with a clinical phenotype of short-coupled PMVT at rest. In contrast to catecholaminergic PMVT-associated RyR2 mutations, RyR2-H29D causes a leaky channel at diastolic levels of Ca(2+) under non-stress conditions. Leaky RyR2 may be an under-recognized mechanism for idiopathic PMVT at rest.