Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Racemic tocainide [R,S-T], which is used in the treatment of ventricular arrhythmias, consists of an R(-)-enantiomer [R-T] and an S(+)-enantiomer [S-T]. The present experiments examined these substances for pharmacodynamic differences. The ability of various doses of R-T, S-T, and R,S-T to both induce ataxia (A) and protect against chloroform-induced ventricular arrhythmias (P) in mice were compared at 20 min after subcutaneous treatment. For A effects, the ED50S (95% Fieller Limits) of R-T, S-T, and R,S-T were 125 (78-802), 125 (84-283), and 90 (61-149) mg/kg, respectively. For P effects, the ED50S were 40 (11-71), 116 (82-204), and 86 (55-187) mg/kg. The ratios of A/P, a measure of the margin of safety, were 3.1, 1.1, and 1.0. Effects upon intracardiac conduction in isolated rabbit hearts also exhibited, qualitatively, similar patterns of selectivity. At 1 X 10(-4) M intraatrial, His-Purkinje, intraventricular conduction times, and the QT interval were prolonged with the following order of potency: R-T greater than R,S-T greater than S-T; A-V nodal conduction was unchanged. R-T also evoked the greatest decrease in contractility. With respect to separation of antiarrhythmic action and the production of ataxia, R-T has a greater margin of safety than either S-T or R,S-T.
J Cardiovasc Pharmacol 1988 Feb
PMID:Stereoselectivity of tocainide pharmacodynamics in vivo and in vitro. 245 17

Cell-specific RNA-binding proteins (RBPs) are involved in a variety of processes that are critical for appropriate protein expression (e.g., alternative splicing of messenger RNAs and translational control). Perturbation of the normal functions of RBPs has been implicated in a number of clinical disorders. Disease-related RBPs include the CELF proteins, which are believed to play roles in normal heart and skeletal muscle development and in the pathology of myotonic dystrophy; the Nova autoimmune antigens, which are neuron-specific proteins involved in the pathogenesis of the neurodegenerative syndrome paraneoplastic opsoclonus-myoclonus ataxia; and the alphaCP proteins, which were originally discovered by virtue of their connection to alpha thalassemia. These proteins are representative of a potentially large repertoire of cell-specific RBPs that, together, help to distinguish among the various cell types. Structure/function studies of these RBPs have begun to yield important insights into how they help to shape the protein expression programs unique to heart, skeletal muscle, brain, and other tissues.
Trends Cardiovasc Med 2003 Jul
PMID:Cell-specific RNA-binding proteins in human disease. 1283 81

Ankyrins are intracellular proteins required for the biogenesis and maintenance of membrane domains in both excitable and non-excitable cells. Ankyrin family polypeptides have been implicated in the targeting and stabilization of membrane proteins including ion channels, transporters, exchangers and cell adhesion molecules in diverse tissues and cell types including the erythrocyte, kidney, lung and brain. Dysfunction in ankyrin-based pathways has previously been linked to abnormalities in vertebrate physiology including spherocytosis and anemia, ataxia and axonal degeneration. Recent findings have illuminated the importance of ankyrin-based pathways in excitable cells of the heart. Specifically, two ankyrin gene products, 220-kDa ankyrin-B and 190-kDa ankyrin-G, have been implicated in the targeting of structurally diverse membrane ion channels and transporters to excitable membrane domains in cardiomyocytes. Moreover, findings in humans and mice have determined the critical nature of ankyrin-based pathways for normal cardiac excitability. Reduction of ankyrin-B expression levels in mice or the presence of ankyrin-B loss-of-function mutations in humans leads to 'ankyrin-B syndrome', a cardiac disease with a spectrum of clinical presentations including bradycardia, ventricular tachycardia and sudden cardiac death in response to catecholaminergic stimuli. Ankyrin-G is required for expression of the major cardiac voltage-gated Na(v) channel, Na(v)1.5, at specialized cardiac membrane domains. Human variants in SCN5A (encodes Na(v)1.5) that block Na(v)1.5 interaction with ankyrin-G lead to loss of Na(v)1.5 membrane expression and Brugada syndrome. Together, these recent findings in heart reinforce the importance of ankyrin-based pathways for normal vertebrate physiology and raise exciting new questions regarding the cellular roles for ankyrin polypeptides in cardiac and other excitable cells. While ankyrins have only been recently identified in heart, our current understanding suggests that elucidating the roles of ankyrins in organizing and targeting protein complexes to excitable membrane domains will yield important insights into the molecular basis of cardiac arrhythmias.
Cardiovasc Res 2006 Jul 01
PMID:Cardiac ankyrins: Essential components for development and maintenance of excitable membrane domains in heart. 1665 Aug 39

A 66-year-old man presented with mild amnesia, progressive fatigue, ataxia, visual hallucinations, and debility. His past medical history included right-sided carotid endarterectomy performed elsewhere 6 years previously. Cranial magnetic resonance imaging showed left parieto-occipital arteriovenous malformation-like tortous vessels, venous congestion, and ischemic areas. Cerebral angiography showed right-sided compound external carotid artery-internal jugular vein (IJV) fistula, and distal occlusion of the right IJV. Transvenous embolization via contralateral IJV was performed, and the fistula, together with fistulous portion of the distal IJV, was sealed using coils. Two years later, patient is well with normal neurologic examination findings. The presence of an arteriovenous communication after vascular surgery is a serious complication with potential long-term effects and therefore should be diagnosed and treated as promptly as possible.
Cardiovasc Intervent Radiol 2011 Feb
PMID:External carotid-internal jugular fistula as a late complication after carotid endarterectomy: a rare case. 2055 93

The autosomal-recessive disorder Friedreich's ataxia is characterized by progressive ataxia, often in association with cardiomyopathy. The most frequent cause of death is cardiac dysfunction, reflecting congestive heart failure, ventricular arrhythmias and cardio-embolic stroke. With the discovery of the underlying genetic mutation, a variety of novel therapies are now progressing into clinical trials. Consequently, it is crucial to understand the features of cardiomyopathy in this disease and how new treatments may improve cardiac function. The present artcle reviews the molecular basis of the disease, the clinical features of cardiomyopathy in Friedreich's ataxia and the upcoming therapies.
Expert Rev Cardiovasc Ther 2012 Jun
PMID:Management and therapy for cardiomyopathy in Friedreich's ataxia. 2289 32

Most cardiovascular researchers are familiar with intermediate-conductance KCa3.1 and small-conductance KCa2.3 channels because of their contribution to endothelium-derived hyperpolarization. However, to immunologists and neuroscientists, these channels are primarily known for their role in lymphocyte activation and neuronal excitability. KCa3.1 is involved in the proliferation and migration of T cells, B cells, mast cells, macrophages, fibroblasts, and dedifferentiated vascular smooth muscle cells and is, therefore, being pursued as a potential target for use in asthma, immunosuppression, and fibroproliferative disorders. In contrast, the 3 KCa2 channels (KCa2.1, KCa2.2, and KCa2.3) contribute to the neuronal medium afterhyperpolarization and, depending on the type of neuron, are involved in determining firing rates and frequencies or in regulating bursting. KCa2 activators are accordingly being studied as potential therapeutics for ataxia and epilepsy, whereas KCa2 channel inhibitors like apamin have long been known to improve learning and memory in rodents. Given this background, we review the recent discoveries of novel KCa3.1 and KCa2.3 modulators and critically assess the potential of KCa activators for the treatment of diabetes and cardiovascular diseases by improving endothelium-derived hyperpolarizations.
J Cardiovasc Pharmacol 2013 Feb
PMID:Endothelial small-conductance and intermediate-conductance KCa channels: an update on their pharmacology and usefulness as cardiovascular targets. 2310 76

Miller-Fisher syndrome (MFS) is an uncommon neurological disorder that is considered a variant of the Guillain-Barre syndrome (GBS). It is clinically defined by a triad of symptoms, namely ataxia, areflexia and ophthalmoplegia. These acute inflammatory polyradiculopathic syndromes can be triggered by viral infections, major surgery, pregnancy or vaccination. While the overall incidence of GBS is 1.2-2.3 per 100 000 per year, MFS is a relatively rare disorder. Only six cases of GBS after cardiac surgery have been reported, and to our knowledge, we describe the first case of MFS after coronary artery bypass surgery. Although cardiac surgery with cardiopulmonary bypass may increase the incidence of MFS and GBS, the pathological mechanism is unclear. Cardiac surgery may be a trigger for the immune-mediated response and may cause devastating complications. It is also important to be alert to de novo autoimmune and unexpected neurological disorders such as MFS after coronary bypass surgery.
Cardiovasc J Afr 2017 11 23
PMID:Miller-Fisher syndrome after coronary artery bypass surgery. 2929 41

A 76-year-old woman who had been on hemodialysis for 3 years developed ischemic mitral valve insufficiency, tricuspid insufficiency, and chronic atrial fibrillation, and underwent cardiac surgery. On the 4th postoperative day, she experienced a sudden disturbance of consciousness, aphasia, and limb ataxia. Brain computed tomography and magnetic resonance imaging showed no abnormalities. Wernicke's encephalopathy was suspected and the patient was given vitamin B1, whereupon her symptoms gradually improved. On the 42nd postoperative day, she was free of neurological symptoms and discharged.
Asian Cardiovasc Thorac Ann 2018 May
PMID:Wernicke's encephalopathy after cardiac surgery. 2966 98

Cardiac papillary fibroelastoma is a rare but increasingly recognized cause of embolic stroke that is prevalent in the older population and requires prompt surgical management. We report an unusual case of left atrial appendage cardiac fibroelastoma in a 76-year-old gentleman who presented with left internuclear ophthalmoplegia and ataxia, with corresponding diffusion-weighted imaging on magnetic resonance imaging of the brain. This case illustrates the importance of echocardiographic imaging in the workup of cardioembolic stroke in the older adult population in the acute setting.
Cardiovasc Pathol
PMID:Brainstem stroke caused by left atrial cardiac papillary fibroelastoma: an increasingly recognized rare cause of stroke. 3092 17

We used patient dermal fibroblasts to characterize the mitochondrial abnormalities associated with the dilated cardiomyopathy with ataxia syndrome (DCMA) and to study the effect of the mitochondrially-targeted peptide SS-31 as a potential novel therapeutic. DCMA is a rare and understudied autosomal recessive disorder thought to be related to Barth syndrome but caused by mutations in DNAJC19, a protein of unknown function localized to the mitochondria. The clinical disease is characterized by 3-methylglutaconic aciduria, dilated cardiomyopathy, abnormal neurological development, and other heterogeneous features. Until recently no effective therapies had been identified and affected patients frequently died in early childhood from intractable heart failure. Skin fibroblasts from four pediatric patients with DCMA were used to establish parameters of mitochondrial dysfunction. Mitochondrial structure, reactive oxygen species (ROS) production, cardiolipin composition, and gene expression were evaluated. Immunocytochemistry with semi-automated quantification of mitochondrial structural metrics and transmission electron microscopy demonstrated mitochondria to be highly fragmented in DCMA fibroblasts compared to healthy control cells. Live-cell imaging demonstrated significantly increased ROS production in patient cells. These abnormalities were reversed by treating DCMA fibroblasts with SS-31, a synthetic peptide that localizes to the inner mitochondrial membrane. Levels of cardiolipin were not significantly different between control and DCMA cells and were unaffected by SS-31 treatment. Our results demonstrate the abnormal mitochondria in fibroblasts from patients with DCMA and suggest that SS-31 may represent a potential therapy for this devastating disease.
Front Cardiovasc Med 2019
PMID:SS-31 Peptide Reverses the Mitochondrial Fragmentation Present in Fibroblasts From Patients With DCMA, a Mitochondrial Cardiomyopathy. 3180 60


1