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Journal of Translational Medicine Mar 2024Long QT syndrome type 7 (Andersen-Tawil syndrome, ATS), which is caused by KCNJ2 gene mutation, often leads to ventricular arrhythmia, periodic paralysis and skeletal...
OBJECTIVE
Long QT syndrome type 7 (Andersen-Tawil syndrome, ATS), which is caused by KCNJ2 gene mutation, often leads to ventricular arrhythmia, periodic paralysis and skeletal malformations. The development, differentiation and electrophysiological maturation of cardiomyocytes (CMs) changes promote the pathophysiology of Long QT syndrome type 7(LQT7). We aimed to specifically reproduce the ATS disease phenotype and study the pathogenic mechanism.
METHODS AND RESULTS
We established a cardiac cell model derived from human induced pluripotent stem cells (hiPSCs) to the phenotypes and electrophysiological function, and the establishment of a human myocardial cell model that specifically reproduces the symptoms of ATS provides a reliable platform for exploring the mechanism of this disease or potential drugs. The spontaneous pulsation rate of myocardial cells in the mutation group was significantly lower than that in the repair CRISPR group, the action potential duration was prolonged, and the Kir2.1 current of the inward rectifier potassium ion channel was decreased, which is consistent with the clinical symptoms of ATS patients. Only ZNF528, a chromatin-accessible TF related to pathogenicity, was continuously regulated beginning from the cardiac mesodermal precursor cell stage (day 4), and continued to be expressed at low levels, which was identified by WGCNA method and verified with ATAC-seq data in the mutation group. Subsequently, it indicated that seven pathways were downregulated (all p < 0.05) by used single sample Gene Set Enrichment Analysis to evaluate the overall regulation of potassium-related pathways enriched in the transcriptome and proteome of late mature CMs. Among them, the three pathways (GO: 0008076, GO: 1990573 and GO: 0030007) containing the mutated gene KCNJ2 is involved that are related to the whole process by which a potassium ion enters the cell via the inward rectifier potassium channel to exert its effect were inhibited. The other four pathways are related to regulation of the potassium transmembrane pathway and sodium:potassium exchange ATPase (p < 0.05). ZNF528 small interfering (si)-RNA was applied to hiPSC-derived cardiomyocytes for CRISPR group to explore changes in potassium ion currents and growth and development related target protein levels that affect disease phenotype. Three consistently downregulated proteins (KCNJ2, CTTN and ATP1B1) associated with pathogenicity were verificated through correlation and intersection analysis.
CONCLUSION
This study uncovers TFs and target proteins related to electrophysiology and developmental pathogenicity in ATS myocardial cells, obtaining novel targets for potential therapeutic candidate development that does not rely on gene editing.
Topics: Humans; Andersen Syndrome; Chromatin; Transcriptome; Induced Pluripotent Stem Cells; Mutation; Myocytes, Cardiac; Potassium
PubMed: 38528561
DOI: 10.1186/s12967-024-05125-7 -
American Journal of Hematology Oct 2019Patients with Evans syndrome have both immune thrombocytopenia and autoimmune hemolytic anemia, but little is known about the epidemiology of this rare syndrome. Evans... (Comparative Study)
Comparative Study
Patients with Evans syndrome have both immune thrombocytopenia and autoimmune hemolytic anemia, but little is known about the epidemiology of this rare syndrome. Evans syndrome can be primary or secondary. This nationwide retrospective study linked health registries to identify 242 patients with Evans syndrome in Denmark in 1977-2017. For comparison, we identified three age-matched and sex-matched cohorts of patients with only immune thrombocytopenia or only autoimmune hemolytic anemia, and a general population cohort. The Evans syndrome cohort had a mean age of 58.5 years at diagnosis, 51.2% were women, and 27.3% were classified as secondary Evans syndrome. The annual Evans syndrome incidence and prevalence rose significantly during the study period, to 1.8 per million person-years and 21.3 per million persons, respectively, in 2016. The median survival with Evans syndrome was 7.2 years (primary Evans syndrome: 10.9 years; secondary Evans syndrome: 1.7 years). Secondary Evans syndrome was associated with higher mortality rates than any of the other cohorts, with a 5-year survival of 38%. Among patients with Evans syndrome, the prevailing causes of death were bleeding, infections, and hematological cancer. In conclusion, we found that both primary and secondary Evans syndrome conferred a poor prognosis. Lethal complications probably derive primarily from manifestations of underlying autoimmune hemolytic anemia and immune thrombocytopenia. Our findings suggested that suspicion of Evans syndrome should prompt vigilant clinical follow-up. International collaborations are warranted to advance our knowledge of optimal management of this rare disease.
Topics: Adult; Anemia, Hemolytic, Autoimmune; Denmark; Female; Hematologic Neoplasms; Hemorrhage; Humans; Incidence; Infections; Male; Middle Aged; Prevalence; Prognosis; Proportional Hazards Models; Purpura, Thrombocytopenic, Idiopathic; Registries; Retrospective Studies; Splenectomy; Survival Analysis; Thrombocytopenia
PubMed: 31292991
DOI: 10.1002/ajh.25574 -
Annals of Noninvasive Electrocardiology... May 2021Andersen-Tawil syndrome (ATS) is a rare disorder characterized by a triad of ventricular arrhythmia (VA), dysmorphic features, and periodic paralysis. Due to the rarity... (Review)
Review
Andersen-Tawil syndrome (ATS) is a rare disorder characterized by a triad of ventricular arrhythmia (VA), dysmorphic features, and periodic paralysis. Due to the rarity of this condition, less is known about physiologic effect of pregnancy to ATS and arrhythmia. There is no established guideline for peripartum or postpartum treatment and prevention of arrhythmia in ATS; thus, the clinical management is challenging. We reported two KCNJ2-associated ATS patients who got pregnant and underwent vaginal birth safely. Both individuals had VA, micrognathia without periodic paralysis. β-blocker plus flecainide could be an effective treatment combination when monotherapy failed to control arrhythmia. VA of two pregnant patients with ATS could be controlled by either physiologic changes associated pregnancy or the combination treatment of β-blocker and flecainide.
Topics: Adrenergic beta-Antagonists; Adult; Andersen Syndrome; Anti-Arrhythmia Agents; Female; Flecainide; Humans; Pregnancy; Pregnancy Complications, Cardiovascular; Tachycardia, Ventricular; Treatment Outcome
PubMed: 32959505
DOI: 10.1111/anec.12798 -
Journal of Neuromuscular Diseases 2021Primary periodic paralysis (PPP) are rare inherited neuromuscular disorders including Hypokalemic periodic paralysis (HypoPP), Hyperkalemic periodic paralysis (HyperPP)... (Review)
Review
BACKGROUND
Primary periodic paralysis (PPP) are rare inherited neuromuscular disorders including Hypokalemic periodic paralysis (HypoPP), Hyperkalemic periodic paralysis (HyperPP) and Andersen-Tawil syndrome (ATS) characterised by attacks of weakness or paralysis of skeletal muscles. Limited effective pharmacological treatments are available, and avoidance of lifestyle related triggers seems important.
OBJECTIVE
Our aim was to search and assess the scientific literature for information on trigger factors related to nutrition and physical activity in PPP.
METHODS
We searched Ovid Medline and Embase database for scientific papers published between January 1, 1990, to January 31, 2020.
RESULTS
We did not identify published observation or intervention studies evaluating effect of lifestyle changes on attacks. Current knowledge is based on case-reports, expert opinions, and retrospective case studies with inadequate methods for description of nutrition and physical activity. In HypoPP, high carbohydrate and salt intake, over-eating, alcohol, dehydration, hard physical activity, and rest after exercise are frequently reported triggers. Regarding HyperPP, fasting, intake of potassium, alcohol, cold foods or beverages, physical activity, and rest after exercise are frequently reported triggers. No nutrition related triggers are reported regarding ATS, exercise can however induce ventricular arrhythmias.
CONCLUSIONS
Our results support that dietary intake and physical activity may play a role in causing paralytic attacks in PPP, although the current scientific evidence is weak. To provide good evidence-based patient care, several lifestyle aspects need to be further assessed and described.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Andersen Syndrome; Diet; Exercise; Female; Humans; Male; Middle Aged; Paralyses, Familial Periodic; Paralysis; Young Adult
PubMed: 33646174
DOI: 10.3233/JND-200604 -
Annals of Noninvasive Electrocardiology... Apr 2004Andersen's Syndrome is a rare disease, hereditary with autosomal dominant transmission, of the ion channels of the sarcolemmal membranes of the cardiac and skeletal... (Review)
Review
Andersen's Syndrome is a rare disease, hereditary with autosomal dominant transmission, of the ion channels of the sarcolemmal membranes of the cardiac and skeletal muscles (channelopathy), which affects chromosome 17 of the KCNJ2 gene, responsible for encoding the outward potassium delayed rectifier current KIR2.1, resulting in a loss or suppression of the function of this channel.
Topics: Action Potentials; Carbonic Anhydrase Inhibitors; Electrocardiography; Genetic Predisposition to Disease; Glycogen Storage Disease Type IV; Heart Conduction System; Humans; Long QT Syndrome; Paralyses, Familial Periodic; Potassium Channels
PubMed: 15084216
DOI: 10.1111/j.1542-474X.2004.92552.x -
Danish Medical Journal Oct 2016HIV-associated lipodystrophy syndrome frequently presents as a relative lack of peripheral adipose tissue storage combined with an increase in visceral fat, associated... (Review)
Review
HIV-associated lipodystrophy syndrome frequently presents as a relative lack of peripheral adipose tissue storage combined with an increase in visceral fat, associated with insulin resistance and dyslipidaemia. This thesis discusses explanations for the links between abnormalities in glucose metabolism, the steroid synthesis pathway, the growth hormone-insulin growth factor-1 axis, and chronic changes in adipose tissue distribution. Specifically, the mechanisms by which low-grade inflammation may affect the normal stimulatory effect of insulin on glucose and fat storage are reviewed. We propose that both chronic low-grade inflammation from HIV infection and treatment with HAART trigger cellular homeostatic stress responses with adverse effects on glucose metabolism. The physiological outcome is such that the total energy storage in the adipocytes is decreased, and the remaining adipocytes resist further energy storage. The excess circulating and dietary lipid metabolites, normally metabolised by adipose tissue, are deposited ectopically in the muscle, liver, or visceral adipose tissue, where they impair insulin action. This deposition of lipid metabolites leads to a vicious circle of insulin resistance and lipotoxicity leading to lipoatrophy or a mixed-type with increased visceral adipose tissue and a clinical phenotype of HIV-associated lipodystrophy syndrome with an elevated waist-to-hip ratio. This HIV-associated inflamm-ageing syndrome can provide a platform for further studies in HIV-infected patients and act as a model for biological accelerated ageing.
Topics: Global Health; HIV Infections; Humans; Inflammation; Metabolic Diseases; Morbidity; Severity of Illness Index
PubMed: 27697134
DOI: No ID Found -
Cureus May 2020Thyrotoxic periodic paralysis (TPP) is a rare manifestation of hyperthyroidism. The pathophysiology of hyperthyroidism causing periodic paralysis involves the Na+/K+...
Thyrotoxic periodic paralysis (TPP) is a rare manifestation of hyperthyroidism. The pathophysiology of hyperthyroidism causing periodic paralysis involves the Na+/K+ ATPase and potassium channels. We present a case of a 30-year-old male who presented to the ED with acute onset of upper and lower limb weakness. The patient was found to have bilateral weakness in the upper and lower limbs, orbital hypertelorism, and mandibular hypoplasia. He was also found to have hypokalemia, low thyroid-stimulating hormone (TSH), elevated thyroid peroxidase antibody, and elevated thyroid-stimulating immunoglobulins. The patient's EKG was remarkable for a prolonged QTc interval. The patient regained his muscle strength after potassium replacement in less than 24 hours. He was started on methimazole and potassium supplements. Our case is unique because it shows the possibility of the presence of Andersen-Tawil syndrome (ATS) (long QT syndrome 7), diagnosed by the presence of periodic paralysis, long QT, and dysmorphic facial features with TPP. In conclusion, thyrotoxicosis can trigger ATS; also the two syndromes can co-exist owing to the similarity in their pathophysiology.
PubMed: 32432016
DOI: 10.7759/cureus.8169 -
Circulation. Cardiovascular Genetics Feb 2011Mutations in KCNJ2, the gene encoding the human inward rectifier potassium channel Kir2.1 (IK1 or IKir2.1), have been identified in Andersen-Tawil syndrome....
Biophysical and molecular characterization of a novel de novo KCNJ2 mutation associated with Andersen-Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia mimicry.
BACKGROUND
Mutations in KCNJ2, the gene encoding the human inward rectifier potassium channel Kir2.1 (IK1 or IKir2.1), have been identified in Andersen-Tawil syndrome. Andersen-Tawil syndrome is a multisystem inherited disease exhibiting periodic paralysis, cardiac arrhythmias, and dysmorphic features at times mimicking catecholaminergic polymorphic ventricular tachycardia.
METHODS AND RESULTS
Our proband displayed dysmorphic features including micrognathia, clinodactyly, and syndactyly and exhibited multiform extrasystoles and bidirectional ventricular tachycardia both at rest and during exercise testing. The patient's symptoms continued after administration of nadolol but subsided after treatment with flecainide. Molecular genetic screening revealed a novel heterozygous mutation (c.779G>C/p.R260P) in KCNJ2. Whole-cell patch-clamp studies conducted in TSA201 cells transfected with wild-type human KCNJ2 cDNA (WT-KCNJ2) yielded robust IKir2.1 but no measurable current in cells expressing the R260P mutant. Coexpression of WT and R260P-KCNJ2 (heterozygous expression) yielded a markedly reduced inward IKir2.1 compared with WT alone (-36.5±9.8 pA/pF versus -143.5±11.4 pA/pF, n=8 for both, P<0.001, respectively, at -90 mV), indicating a strong dominant negative effect of the mutant. The outward component of IKir2.1 measured at -50 mV was also markedly reduced with the heterozygous expression versus WT (0.52±5.5 pA/pF versus 23.4±6.7 pA/pF, n=8 for both, P<0.001, respectively). Immunocytochemical analysis indicates that impaired trafficking of R260P-KCNJ2 channels.
CONCLUSIONS
We report a novel de novo KCNJ2 mutation associated with classic phenotypic features of Andersen-Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia mimicry. The R260P mutation produces a strong dominant negative effect leading to marked suppression of IK1 secondary to a trafficking defect.
Topics: Amino Acid Sequence; Amino Acid Substitution; Andersen Syndrome; Arrhythmias, Cardiac; Base Sequence; Biophysical Phenomena; Cell Line; Child; DNA Mutational Analysis; Female; Flecainide; Genes, Dominant; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Male; Molecular Sequence Data; Mutation; Pedigree; Potassium Channels, Inwardly Rectifying; Tachycardia, Ventricular; Ultrasonography
PubMed: 21148745
DOI: 10.1161/CIRCGENETICS.110.957696 -
Pharmaceuticals (Basel, Switzerland) Mar 2023Expression and activity of inwardly rectifying potassium (K) channels within the heart are strictly regulated. K channels have an important role in shaping cardiac...
Expression and activity of inwardly rectifying potassium (K) channels within the heart are strictly regulated. K channels have an important role in shaping cardiac action potentials, having a limited conductance at depolarized potentials but contributing to the final stage of repolarization and resting membrane stability. Impaired K2.1 function causes Andersen-Tawil Syndrome (ATS) and is associated with heart failure. Restoring K2.1 function by agonists of K2.1 (AgoKirs) would be beneficial. The class 1c antiarrhythmic drug propafenone is identified as an AgoKir; however, its long-term effects on K2.1 protein expression, subcellular localization, and function are unknown. Propafenone's long-term effect on K2.1 expression and its underlying mechanisms in vitro were investigated. K2.1-carried currents were measured by single-cell patch-clamp electrophysiology. K2.1 protein expression levels were determined by Western blot analysis, whereas conventional immunofluorescence and advanced live-imaging microscopy were used to assess the subcellular localization of K2.1 proteins. Acute propafenone treatment at low concentrations supports the ability of propafenone to function as an AgoKir without disturbing K2.1 protein handling. Chronic propafenone treatment (at 25-100 times higher concentrations than in the acute treatment) increases K2.1 protein expression and K2.1 current densities in vitro, which are potentially associated with pre-lysosomal trafficking inhibition.
PubMed: 36986503
DOI: 10.3390/ph16030404 -
Arthritis Research & Therapy Aug 2021Osteoarthritis (OA) is the most common form of arthritis with multiple risk factors implicated including female sex and obesity. Metabolic dysregulation associated with...
BACKGROUND
Osteoarthritis (OA) is the most common form of arthritis with multiple risk factors implicated including female sex and obesity. Metabolic dysregulation associated with obesity leading to metabolic syndrome is a proposed component of that association. Polycystic ovary syndrome (PCOS) commonly affects women of reproductive age and these women are at higher risk of developing metabolic syndrome and thus likely to represent a high-risk group for early OA development. There are no published studies exploring the epidemiology of knee, hip and hand OA in women diagnosed with PCOS.
STUDY AIM
To assess the prevalence and incidence of knee, hip and hand osteoarthritis (OA) in women with polycystic ovary syndrome (PCOS) when compared with age-matched controls.
METHODS
Prospective Danish national registry-based cohort study. The prevalence of OA in 2015 and incidence rates of OA over 11.1 years were calculated and compared in more than 75,000 Danish women with either a documented diagnosis of PCOS ± hirsutism (during the period of 1995 to 2012) or age-matched females without those diagnoses randomly drawn from the same population register.
RESULTS
In 2015, the prevalence of hospital treated knee, hip and hand OA was 5.2% in women with PCOS diagnosis. It was 73% higher than that seen in age-matched controls. Significantly higher incidence rates were observed in the PCOS cohort compared with the age-matched controls during the follow-up period (up to 20 years), with the following hazard ratios (HR): 1.9 (95% CI 1.7 to 2.1) for knee, 1.8 (95% CI 1.3-2.4) for hand and 1.3 (95% CI 1.1 to 1.6) for hip OA. After excluding women with obesity, similar associations were observed for knee and hand OA. However, risk of developing hip OA was no longer significant.
CONCLUSIONS
In this large prospective study, women with PCOS diagnosis had higher prevalence and accelerated onset of OA of both weight and non-weight bearing joints, when compared with age-matched controls. Further studies are needed to understand the relative effect of metabolic and hormonal changes linked with PCOS and their role in promoting development of OA.
Topics: Cohort Studies; Female; Humans; Osteoarthritis; Polycystic Ovary Syndrome; Prospective Studies; Registries
PubMed: 34461982
DOI: 10.1186/s13075-021-02604-w