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Neurology International Jun 2019Andersen-Tawil syndrome (ATS) is characterized by a triad of periodic paralysis, cardiac arrhythmias and distinctive dysmorphic features. Due to its rarity and high...
Andersen-Tawil syndrome (ATS) is characterized by a triad of periodic paralysis, cardiac arrhythmias and distinctive dysmorphic features. Due to its rarity and high degree of clinical and phenotypic variability, a diagnosis of ATS can be very perplexing and challenging. Herein, an atypical case of ATS with a complicated presentation that caused an approximately 11-year delay in diagnosis is reported. The patient made a full recovery with acetazolamide after the diagnosis. The case and its management are presented with an updated literature review.
PubMed: 31281605
DOI: 10.4081/ni.2019.8180 -
International Journal of Applied &... 2019Andersen-Tawil syndrome (ATS) is an autosomal dominant disorder, characterized by the triad of muscular paralysis, skeletal, and craniofacial anomalies and prolonged QT...
Andersen-Tawil syndrome (ATS) is an autosomal dominant disorder, characterized by the triad of muscular paralysis, skeletal, and craniofacial anomalies and prolonged QT interval on echocardiogram with a tendency toward malignant ventricular arrhythmia. Although the patient may express one or two of the three components of triad, hypothyroidism is an endocrine disorder resulting in the delayed eruption of teeth, defective mineralization of bone and teeth, and speech and hearing deformity. Here, we report a case of ATS with hypothyroidism. To the best of authors' knowledge, no such association has been reported in the literature.
PubMed: 31392183
DOI: 10.4103/ijabmr.IJABMR_164_18 -
Europace : European Pacing,... Apr 2023
Topics: Humans; Andersen Syndrome; Heart; Potassium Channels, Inwardly Rectifying; Mutation
PubMed: 36857319
DOI: 10.1093/europace/euac247 -
Clinical and Experimental Immunology Feb 2007Inflammation is part of the non-specific immune response that occurs in reaction to any type of bodily injury. In some disorders, the inflammatory process - which under... (Review)
Review
Inflammation is part of the non-specific immune response that occurs in reaction to any type of bodily injury. In some disorders, the inflammatory process - which under normal conditions is self-limiting - becomes continuous and chronic inflammatory diseases might develop subsequently. Pattern recognition molecules (PRMs) represent a diverse collection of molecules responsible for sensing danger signals, and together with other immune components they are involved in the first line of defence. NALP3 and NOD2, which belong to a cytosolic subgroup of PRMs, dubbed Nod-like-receptors (NLRs), have been associated recently with inflammatory diseases, specifically Crohn's disease and Blau syndrome (NOD2) and familial cold autoinflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurological cutaneous and articular syndrome (NALP3). The exact effects of the defective proteins are not fully understood, but activation of nuclear factor (NF)-kappaB, transcription, production and secretion of interleukin (IL)-1beta and activation of the inflammasome are some of the processes that might hold clues, and the present review will provide a thorough update in this area.
Topics: Carrier Proteins; Chronic Disease; Crohn Disease; Humans; Inflammation; Interleukin-1beta; NLR Family, Pyrin Domain-Containing 3 Protein; Nod2 Signaling Adaptor Protein; Signal Transduction
PubMed: 17223962
DOI: 10.1111/j.1365-2249.2006.03261.x -
Cardiovascular Research May 2023Andersen-Tawil syndrome (ATS) is a rare inheritable disease associated with loss-of-function mutations in KCNJ2, the gene coding the strong inward rectifier potassium...
Andersen-Tawil syndrome (ATS) is a rare inheritable disease associated with loss-of-function mutations in KCNJ2, the gene coding the strong inward rectifier potassium channel Kir2.1, which forms an essential membrane protein controlling cardiac excitability. ATS is usually marked by a triad of periodic paralysis, life-threatening cardiac arrhythmias and dysmorphic features, but its expression is variable and not all patients with a phenotype linked to ATS have a known genetic alteration. The mechanisms underlying this arrhythmogenic syndrome are poorly understood. Knowing such mechanisms would be essential to distinguish ATS from other channelopathies with overlapping phenotypes and to develop individualized therapies. For example, the recently suggested role of Kir2.1 as a countercurrent to sarcoplasmic calcium reuptake might explain the arrhythmogenic mechanisms of ATS and its overlap with catecholaminergic polymorphic ventricular tachycardia. Here we summarize current knowledge on the mechanisms of arrhythmias leading to sudden cardiac death in ATS. We first provide an overview of the syndrome and its pathophysiology, from the patient's bedside to the protein and discuss the role of essential regulators and interactors that could play a role in cases of ATS. The review highlights novel ideas related to some post-translational channel interactions with partner proteins that might help define the molecular bases of the arrhythmia phenotype. We then propose a new all-embracing classification of the currently known ATS loss-of-function mutations according to their position in the Kir2.1 channel structure and their functional implications. We also discuss specific ATS pathogenic variants, their clinical manifestations, and treatment stratification. The goal is to provide a deeper mechanistic understanding of the syndrome toward the development of novel targets and personalized treatment strategies.
Topics: Humans; Andersen Syndrome; Tachycardia, Ventricular; Mutation; Phenotype; Death, Sudden, Cardiac
PubMed: 35892314
DOI: 10.1093/cvr/cvac118 -
Ugeskrift For Laeger Mar 2016Dissection of the cervical arteries is an important cause of stroke in young adults. A haematoma in the wall of the cervical vessel leads to stenosis or occlusion and... (Review)
Review
Dissection of the cervical arteries is an important cause of stroke in young adults. A haematoma in the wall of the cervical vessel leads to stenosis or occlusion and thereby risk of stroke. The most frequent local symptoms in carotid-artery dissection are head- and neck pain accompanied by Horner's syndrome, while typical symptoms in vertebral-artery dissection are pain in the back of the neck and head. The mural haematoma is best visualized by magnetic resonance imaging. Antithrombotic versus anticoagulation treatment to prevent stroke have recently shown to be equally effective.
Topics: Anticoagulants; Back Pain; Carotid Artery, Internal, Dissection; Fibrinolytic Agents; Headache; Horner Syndrome; Humans; Magnetic Resonance Imaging; Neck Pain; Stroke; Tomography, X-Ray Computed; Vertebral Artery Dissection; Young Adult
PubMed: 27045796
DOI: No ID Found -
The Journal of Physiology Jun 2005The inward rectifier K(+) channel Kir2.1 carries all Andersen's syndrome mutations identified to date. Patients exhibit symptoms of periodic paralysis, cardiac...
The inward rectifier K(+) channel Kir2.1 carries all Andersen's syndrome mutations identified to date. Patients exhibit symptoms of periodic paralysis, cardiac dysrhythmia and multiple dysmorphic features. Here, we report the clinical manifestations found in three families with Andersen's syndrome. Molecular genetics analysis identified two novel missense mutations in the KCNJ2 gene leading to amino acid changes C154F and T309I of the Kir2.1 open reading frame. Patch clamp experiments showed that the two mutations produced a loss of channel function. When co-expressed with Kir2.1 wild-type (WT) channels, both mutations exerted a dominant-negative effect leading to a loss of the inward rectifying K(+) current. Confocal microscopy imaging in HEK293 cells is consistent with a co-assembly of the EGFP-fused mutant proteins with WT channels and proper traffick to the plasma membrane to produce silent channels alone or as hetero-tetramers with WT. Functional expression in C2C12 muscle cell line of newly as well as previously reported Andersen's syndrome mutations confirmed that these mutations act through a dominant-negative effect by altering channel gating or trafficking. Finally, in vivo electromyographic evaluation showed a decrease in muscle excitability in Andersen's syndrome patients. We hypothesize that Andersen's syndrome-associated mutations and hypokalaemic periodic paralysis-associated calcium channel mutations may lead to muscle membrane hypoexcitability via a common mechanism.
Topics: Action Potentials; Adult; Amino Acid Sequence; Animals; COS Cells; Chlorocebus aethiops; Electromyography; Humans; Kidney; Male; Mice; Molecular Sequence Data; Muscle Cells; Muscle, Skeletal; Mutation, Missense; Paralyses, Familial Periodic; Patch-Clamp Techniques; Pedigree; Potassium Channels, Inwardly Rectifying
PubMed: 15831539
DOI: 10.1113/jphysiol.2004.081620 -
Genetics in Medicine : Official Journal... Jan 2016The diagnostic criteria of Marfan syndrome (MFS) highlight the importance of a FBN1 mutation test in diagnosing MFS. As genetic sequencing becomes better, cheaper, and... (Review)
Review
PURPOSE
The diagnostic criteria of Marfan syndrome (MFS) highlight the importance of a FBN1 mutation test in diagnosing MFS. As genetic sequencing becomes better, cheaper, and more accessible, the expected increase in the number of genetic tests will become evident, resulting in numerous genetic variants that need to be evaluated for disease-causing effects based on database information. The aim of this study was to evaluate genetic variants in four databases and review the relevant literature.
METHODS
We assessed background data on 23 common variants registered in ESP6500 and classified as causing MFS in the Human Gene Mutation Database (HGMD). We evaluated data in four variant databases (HGMD, UMD-FBN1, ClinVar, and UniProt) according to the diagnostic criteria for MFS and compared the results with the classification of each variant in the four databases.
RESULTS
None of the 23 variants was clearly associated with MFS, even though all classifications in the databases stated otherwise.
CONCLUSION
A genetic diagnosis of MFS cannot reliably be based on current variant databases because they contain incorrectly interpreted conclusions on variants. Variants must be evaluated by time-consuming review of the background material in the databases and by combining these data with expert knowledge on MFS. This is a major problem because we expect even more genetic test results in the near future as a result of the reduced cost and process time for next-generation sequencing.Genet Med 18 1, 98-102.
Topics: Databases, Genetic; Fibrillins; Genetic Variation; High-Throughput Nucleotide Sequencing; Humans; Marfan Syndrome; Microfilament Proteins; Mutation
PubMed: 25812041
DOI: 10.1038/gim.2015.32 -
Revista de Investigacion Clinica;... May 2020Andersen-Tawil syndrome (ATS) is a cardiac channelopathy that is inherited in an autosomal dominant way, and it is characterized by a triad of periodic paralysis,...
BACKGROUND
Andersen-Tawil syndrome (ATS) is a cardiac channelopathy that is inherited in an autosomal dominant way, and it is characterized by a triad of periodic paralysis, ventricular arrhythmias, and includes some dysmorphic features with incom- plete penetrance and variable expression that result in a challenging diagnosis.
OBJECTIVE
The objective of the study was to describe the cardiac and extra-cardiac phenotype in a cohort of patients with ATS at risk of sudden cardiac death (SCD) to improve its early clinical identification.
METHODS
In an observational, transversal study, with a deviant case sampling, four female patients with ATS at high risk of SCD were included in the study. They carried the heterozygous pathogenic variants c.407C>T [p.Ser136Phe], c.652C>T [p.Arg218Trp] (n=2), and c.431G>C [p.Gly144Ala] in the KCNJ2 gene. Patients were evaluated by a cardiologist, a clinical geneticist, and a physiatrist.
RESULTS
One patient had the classical facial phenotype and the other three had subtle manifestations. The group of patients presented a diverse set of clinical data such as: triangular face, broad forehead, broadening of medial eyebrows, auricular pits, low-set ears, eyelid ptosis, thin lips, mandibular hypoplasia, and diverse types of dental alterations, single transverse palmar crease, camptodactyly, and syndactyly. Long-exercise test showed a decrement in the percentage amplitude up to 44%, classifying patients in IV or V types according to Fournier's scale.
CONCLUSIONS
Extra- cardiac manifestations were a common finding in this series of ATS type1 at high risk of SCD. Its recognition could help the clinician in the early identification of patients with ATS, especially for the cardiologist since they are commonly referred only for evaluation of ventricular arrhythmias.
PubMed: 33057326
DOI: 10.24875/RIC.20000310 -
Gynecologic Oncology Sep 2021Lynch syndrome is a multi-tumor syndrome characterized by mismatch repair deficiency (MMR-d), microsatellite instability (MSI), and increased tumor-infiltrating...
INTRODUCTION
Lynch syndrome is a multi-tumor syndrome characterized by mismatch repair deficiency (MMR-d), microsatellite instability (MSI), and increased tumor-infiltrating lymphocytes (TILs) making these tumors candidates for treatment with immune checkpoint inhibitors. However, response may depend on tumor-induced immune evasion mechanisms, e.g. loss of Beta-2-Microglobulin (B2M) or upregulation of programmed death protein ligand 1 (PD-L1). We investigated the immune response and B2M and PD-L1 expression in Lynch syndrome-associated ovarian cancers.
METHODS
We successfully analyzed 30 Lynch syndrome-associated epithelial ovarian cancers collected through the Danish Hereditary Non-Polyposis Colorectal Cancer (HNPCC) register. MMR-d, MSI, immune response (CD3, CD8, and CD68), and immune evasion mechanisms (B2M and PD-L1) were investigated. Statistical associations between these markers were evaluated in addition to survival in relation to B2M/PD-L1.
RESULTS
Of the 29 evaluable tumors, 27 were MMR-d (93.1%). Likewise of 26 evaluable tumors, 14 were MSI (53.8%). MMR-d/MMR-proficiency associated with MSI/MSS in 60.0%. Half of the ovarian tumors presented with high levels of TILs. Loss of B2M expression was observed in 46.7% of the tumors, while expression of PD-L1 was seen in 28.0% of the cases. There was no association between B2M/PD-L1 and MSI/TILs/survival. Loss of B2M was often seen in tumors with low TILs (p = 0.056 or p = 0.059 for CD3 and CD8 positive cells, respectively).
CONCLUSION
MMR-d, MSI, and TILs are also seen in Lynch syndrome-associated ovarian cancers making these potential candidates for checkpoint-based immunotherapy. The clinical impact from immune evasion through loss of B2M needs to be investigated further in larger cohorts.
Topics: Adult; Aged; B7-H1 Antigen; Carcinoma, Ovarian Epithelial; Cohort Studies; Colorectal Neoplasms, Hereditary Nonpolyposis; Female; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Microsatellite Instability; Middle Aged; Ovarian Neoplasms; Registries; beta 2-Microglobulin
PubMed: 34275654
DOI: 10.1016/j.ygyno.2021.07.001