Home About us Contact
|
Home About us Contact | ||
|
|
||
Myopathy
Kinds of Myopathy Selected AbstractsEffect of Inotropic Stimulation on Left Atrial Appendage Function in Atrial Myopathy of Chronic Atrial FibrillationECHOCARDIOGRAPHY, Issue 4 2000MASOOR KAMALESH M.D. Atrial fibrillation (AF) leads to remodeling of the left atrium (LA) and left atrial appendage (LAA), resulting in atrial myopathy. Reduced LA and LAA function in chronic AF leads to thrombus formation and spontaneous echo contrast (SEC). The effect of inotropic stimulation on LAA function in patients with chronic AF is unknown. LAA emptying velocity (LAAEV) and maximal LAA area at baseline and after dobutamine were measured by transesophageal echocardiography in 14 subjects in normal sinus rhythm (NSR) and 6 subjects in AF. SEC in the LA was assessed before and after dobutamine. LAAEV increased significantly in both groups. However, the LAAEV at peak dobutamine in patients with AF remained significantly lower than the baseline LAAEV in patients who were in NSR (P= 0.009). Maximal LAA area decreased significantly with dobutamine in both groups, but LAA area at peak dose of dobutamine inpatients with AF remained greater than baseline area in those in NSR (P= 0.01). Despite the increase in LAAEV, SEC improved in only two of five patients. We conclude that during AF, the LAA responds to inotropic stimulation with only a modest improvement in function. [source] Alcohol-Induced Disruption of Endocrine SignalingALCOHOLISM, Issue 8 2007Martin J. J. Ronis This article contains the proceedings of a symposium at the 2006 ISBRA Meeting in Sydney Australia, organized and cochaired by Martin J. Ronis and Thomas M. Badger. The presentations were (1) Effect of Long-Term Ethanol Consumption on Liver Injury and Repair, by Jack R. Wands; (2) Alcohol-Induced Insulin Resistance in Liver: Potential Roles in Regulation of ADH Expression, Ethanol Clearance, and Alcoholic Liver Disease, by Thomas M. Badger; (3) Chronic Gestational Exposure to Ethanol Causes Brain Insulin and Insulin-Like Growth Factor Resistance, by Suzanne M de la Monte; (4) Disruption of IGF-1 Signaling in Muscle: A Mechanism Underlying Alcoholic Myopathy, by Charles H. Lang; (5) The Role of Reduced Plasma Estradiol and Impaired Estrogen Signaling in Alcohol-Induced Bone Loss, by Martin J. Ronis; and (6) Short-Term Influence of Alcohol on Appetite-Regulating Hormones in Man, by Jan Calissendorff. [source] Molecular neuropathology of MELAS: level of heteroplasmy in individual neurones and evidence of extensive vascular involvementNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2006J. Betts Mitochondrial DNA (mtDNA) disease is an important genetic cause of neurological disability. A variety of different clinical features are observed and one of the most common phenotypes is MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes). The majority of patients with MELAS have the 3243A>G mtDNA mutation. The neuropathology is dominated by multifocal infarct-like lesions in the posterior cortex, thought to underlie the stroke-like episodes seen in patients. To investigate the relationship between mtDNA mutation load, mitochondrial dysfunction and neuropathological features in MELAS, we studied individual neurones from several brain regions of two individuals with the 3243A>G mutation using dual cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) histochemistry, and Polymerase Chain Reaction Restriction Fragment Lenght Polymorphism (PCR-RFLP) analysis. We found a low number of COX-deficient neurones in all brain regions. There appeared to be no correlation between the threshold level for the 3243A>G mutation to cause COX deficiency within single neurones and the degree of pathology in affected brain regions. The most severe COX deficiency associated with the highest proportion of mutated mtDNA was present in the walls of the leptomeningeal and cortical blood vessels in all brain regions. We conclude that vascular mitochondrial dysfunction is important in the pathogenesis of the stroke-like episodes in MELAS patients. As migraine is a commonly encountered feature in MELAS, we propose that coupling of the vascular mitochondrial dysfunction with cortical spreading depression (CSD) might underlie the selective distribution of ischaemic lesions in the posterior cortex in these patients. [source] Is Functional Capacity Related to Left Atrial Contractile Function in Nonobstructive Hypertrophic Cardiomyopathy?CONGESTIVE HEART FAILURE, Issue 5 2005Yukitaka Shizukuda MD The mechanisms underlying reduced exercise capacity in patients with nonobstructive hypertrophic cardiomyopathy (NHCM) could include perturbations of ventricular relaxation, diastolic compliance, or compensatory atrial systolic function. We hypothesized that a loss of atrial contractility in NHCM patients leads to reduced functional capacity. To test this hypothesis, we compared resting noninvasive left atrial ejection phase indices in 49 consecutive patients with NHCM (ages 36±10 years; 41% female) and normal left ventricular ejection fraction (mean, 68%±8%) with objective metabolic exercise parameters. Left atrial active emptying fraction, ejection force, and kinetic energy failed to predict exercise capacity. Only left atrial total and active emptying volumes correlated weakly with minute volume/CO2 production slope (r=0.31 and r=0.33; p<0.05 for both). Furthermore, when subjects were stratified by New York Heart Association symptomatology, exercise parameters,but not atrial contractility,differed between groups. These data, obtained at rest, fail to suggest that NHCM-related heart failure symptoms are due to an atrial myopathy. [source] The use of neuroimaging in the diagnosis of mitochondrial diseaseDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2010Seth D. Friedman Abstract Mutations in nuclear and mitochondrial DNA impacting mitochondrial function result in disease manifestations ranging from early death to abnormalities in all major organ systems and to symptoms that can be largely confined to muscle fatigue. The definitive diagnosis of a mitochondrial disorder can be difficult to establish. When the constellation of symptoms is suggestive of mitochondrial disease, neuroimaging features may be diagnostic and suggestive, can help direct further workup, and can help to further characterize the underlying brain abnormalities. Magnetic resonance imaging changes may be nonspecific, such as atrophy (both general and involving specific structures, such as cerebellum), more suggestive of particular disorders such as focal and often bilateral lesions confined to deep brain nuclei, or clearly characteristic of a given disorder such as stroke-like lesions that do not respect vascular boundaries in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS). White matter hyperintensities with or without associated gray matter involvement may also be observed. Across patients and discrete disease subtypes (e.g., MELAS, Leigh syndrome, etc.), patterns of these features are helpful for diagnosis. However, it is also true that marked variability in expression occurs in all mitochondrial disease subtypes, illustrative of the complexity of the disease process. The present review summarizes the role of neuroimaging in the diagnosis and characterization of patients with suspected mitochondrial disease. © 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:129,135. [source] Muscle biopsy without centrally located nuclei in a male child with mild X-linked myotubular myopathyDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 12 2005Christian G E L de Goede MRCP MRCPCH In children with a myopathy, muscle biopsy, together with the clinical presentation, can guide further investigations. The presence of centrally located nuclei suggests a myotubular myopathy, and gene testing may confirm this diagnosis. We describe a male child with a mild form of X-linked myotubular myopathy for which repeated muscle biopsy did not show the characteristic pattern of centrally located nuclei. Myotubular myopathy was not contemplated, therefore, until a maternally related relative was shown to have the disorder. Genetic testing showed that the index case carried the same mutation in his MTM1 gene as this relative. [source] Combination statin,fibrate therapy: safety aspectsDIABETES OBESITY & METABOLISM, Issue 2 2009R. Franssen Patients with type 2 diabetes or metabolic syndrome remain at high residual risk of cardiovascular events even after intensive statin therapy. While treatment guidelines recommend the addition of a fibrate to statin therapy in this setting, concerns about the potential for myopathy may limit the use of this combination in clinical practice. These concerns are certainly justified for gemfibrozil, which interferes with statin glucuronidation, leading to elevation in statin plasma concentrations and an increased risk of myotoxicity in combination with a range of commonly prescribed statins. However, the available evidence refutes suggestions that this is a class effect for fibrates. Fenofibrate does not adversely influence the metabolism or pharmacokinetics of any of the commonly prescribed statins. This in turn translates to a reduced potential for myotoxicity in combination with a statin. Data are awaited from the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study to evaluate the efficacy and safety of fenofibrate plus simvastatin combination therapy in type 2 diabetes patients. [source] Prevalence and Characteristics of Left Ventricular Noncompaction in a Community Hospital Cohort of Patients with Systolic DysfunctionECHOCARDIOGRAPHY, Issue 1 2008Roopinder Sandhu M.D. Background: Left ventricular noncompaction (LVNC) is felt to be a rare form of cardiomyopathy, although its prevalence in a nonreferred population is unknown. We examined the prevalence and clinical characteristics of LVNC in a community hospital cohort of adult patients with echocardiographic evidence of left ventricular (LV) systolic dysfunction. Methods: All adult echocardiograms with global LV dysfunction and an LVEF , 45% over a 1-year period were reviewed for signs of LV noncompaction. Its presence was confirmed by the consensus of at least 2/3 readers specifically searching for this using standard criteria for noncompaction. Results: A 3.7% prevalence of definite or probable LVNC was found in those with LVEF, 45% and a 0.26% prevalence for all patients referred for echocardiography during this period. This is appreciably higher than prior reports from tertiary centers. Conclusion: Noncompaction may not be a rare phenomenon and is comparable to other more widely recognized but less common causes of heart failure such as peripartum myopathy, connective tissue diseases, chronic substance abuse and HIV disease. [source] Effect of Inotropic Stimulation on Left Atrial Appendage Function in Atrial Myopathy of Chronic Atrial FibrillationECHOCARDIOGRAPHY, Issue 4 2000MASOOR KAMALESH M.D. Atrial fibrillation (AF) leads to remodeling of the left atrium (LA) and left atrial appendage (LAA), resulting in atrial myopathy. Reduced LA and LAA function in chronic AF leads to thrombus formation and spontaneous echo contrast (SEC). The effect of inotropic stimulation on LAA function in patients with chronic AF is unknown. LAA emptying velocity (LAAEV) and maximal LAA area at baseline and after dobutamine were measured by transesophageal echocardiography in 14 subjects in normal sinus rhythm (NSR) and 6 subjects in AF. SEC in the LA was assessed before and after dobutamine. LAAEV increased significantly in both groups. However, the LAAEV at peak dobutamine in patients with AF remained significantly lower than the baseline LAAEV in patients who were in NSR (P= 0.009). Maximal LAA area decreased significantly with dobutamine in both groups, but LAA area at peak dose of dobutamine inpatients with AF remained greater than baseline area in those in NSR (P= 0.01). Despite the increase in LAAEV, SEC improved in only two of five patients. We conclude that during AF, the LAA responds to inotropic stimulation with only a modest improvement in function. [source] Atypical myopathy: New insights into the pathophysiology, prevention and management of the conditionEQUINE VETERINARY EDUCATION, Issue 5 2008G. van Galen Summary Atypical myopathy (AM) is a frequently fatal seasonal pasture myopathy that has emerged in several European Countries in recent years. Currently, the aetiology of AM is unknown but recent surveys of confirmed cases have led to new insights into the pathophysiology, prevention and management of the condition. [source] Severe rhabdomyolysis due to polysaccharide storage myopathy in an Arabian mareEQUINE VETERINARY EDUCATION, Issue 3 2007C. T. Estill First page of article [source] Breed susceptibility in equine polysaccharide storage myopathyEQUINE VETERINARY EDUCATION, Issue 3 2007R. Stanley No abstract is available for this article. [source] An epidemiological study of myopathies in Warmblood horsesEQUINE VETERINARY JOURNAL, Issue 2 2008L. M. HUNT Summary Reasons for performing study: There are few detailed reports describing muscular disorders in Warmblood horses. Objectives: To determine the types of muscular disorders that occur in Warmblood horses, along with presenting clinical signs, associated risk factors and response to diet and exercise recommendations, and to compare these characteristics between horses diagnosed with polysaccharide storage myopathy (PSSM), those diagnosed with a neuromuscular disorder other than PSSM (non-PSSM) and control horses. Methods: Subject details, muscle biopsy diagnosis and clinical history were compiled for Warmblood horses identified from records of biopsy submissions to the University of Minnesota Neuromuscular Diagnostic Laboratory. A standardised questionnaire was answered by owners at least 6 months after receiving the muscle biopsy report for an affected and a control horse. Results: Polysaccharide storage myopathy (72/132 horses) was the most common myopathy identified followed by recurrent exertional rhabdomyolysis (RER) (7/132), neurogenic or myogenic atrophy (7/132), and nonspecific myopathic changes (14/132). Thirty-two biopsies were normal. Gait abnormality, ,tying-up', Shivers, muscle fasciculations and atrophy were common presenting clinical signs. Forty-five owners completed questionnaires. There were no differences in sex, age, breed, history or management between control, PSSM and non-PSSM horses. Owners that provided the recommended low starch fat supplemented diet and regular daily exercise reported improvement in clinical signs in 68% (19/28) of horses with a biopsy submission and 71% of horses diagnosed with PSSM (15/21). Conclusions: Muscle biopsy evaluation was a valuable tool to identify a variety of myopathies in Warmblood breeds including PSSM and RER. These myopathies often presented as gait abnormalities or overt exertional rhabdomyolysis and both a low starch fat supplemented diet and regular exercise appeared to be important in their successful management. Potential relevance: Warmbloods are affected by a variety of muscle disorders, which, following muscle biopsy diagnosis can be improved through changes in diet and exercise regimes. [source] Concurrent conditions in single cases: The need to differentiate equine dysautonomia (grass sickness) and atypical myopathyEQUINE VETERINARY JOURNAL, Issue 5 2007D.-M. VOTION No abstract is available for this article. [source] The role of electromyography in clinical diagnosis of neuromuscular locomotor problems in the horseEQUINE VETERINARY JOURNAL, Issue 8 2004I. D. WIJNBERG Summary Reasons for performing study: Systematically performed EMG needle examination of muscles provides essential information about the functional aspects of the motor unit. However, clinical studies in which information is given on the diagnostic and discriminative values of electromyography (EMG) in the horse are scarce. Objectives: To determine to what extent inclusion of EMG analysis in clinical examination contributes to determination of type and localisation of abnormality. Methods: EMG analysis, complete clinical examination and diagnosis of 108 horses (mean ± s.d. age 7.5 ± 3.8 years; bodyweight 548 ± 86 kg; height 1.67 ± 0.07 m) were performed, and results without and with EMG analysis compared. Results: Without EMG, myopathy and neuropathy were diagnosed in 20 and 58 horses, respectively, and with EMG in 17 and 82 horses. EMG changed localisation in myopathy and neuropathy in 12 and 37% of cases, respectively. Lesions in the C1-T2, T2-L3 and L3-S3 segments were, respectively, diagnosed without EMG in 7, 11 and 30%, and with EMG in 27, 7 and 17% of cases. Where no clinical diagnosis could be made prior to EMG, many patients appeared to be suffering from localised cervical lesions (29%) or generalised neuropathy (54%). Conclusions and potential relevance: The assistance of EMG in discriminating between normal, neuropathy and myopathy, and in locating pathology, contributes to diagnosis of neuromuscular problems. [source] D-2-Hydroxyglutaric acid inhibits creatine kinase activity from cardiac and skeletal muscle of young ratsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 10 2003C. G. Da Silva Abstract Background, Tissue accumulation of high amounts of D-2-hydroxyglutaric acid (DGA) is the biochemical hallmark of the inherited neurometabolic disorder D-2-hydroxyglutaric aciduria (DHGA). Patients affected by this disease usually present hypotonia, muscular weakness, hypothrophy and cardiomyopathy, besides severe neurological findings. However, the underlying mechanisms of muscle injury in this disorder are virtually unknown. Materials and methods, In the present study we have evaluated the in vitro role of DGA, at concentrations ranging from 0·25 to 5·0 mm, on total, cytosolic and mitochondrial creatine kinase activities from skeletal and cardiac muscle of 30-day-old Wistar rats. We also tested the effects of various antioxidants on the effects elicited by DGA. Results, We first verified that total creatine kinase (CK) activity from homogenates was significantly inhibited by DGA (22,24% inhibition) in skeletal and cardiac muscle, and that this activity was approximately threefold higher in skeletal muscle than in cardiac muscle. We also observed that CK activities from mitochondrial (Mi-CK) and cytosolic (Cy-CK) preparations from skeletal muscle and cardiac muscle were also inhibited (12,35% inhibition) by DGA at concentrations as low as 0·25 mm, with the effect being more pronounced in cardiac muscle preparations. Finally, we verified that the DGA-inhibitory effect was fully prevented by preincubation of the homogenates with reduced glutathione and cysteine, suggesting that this effect is possibly mediated by modification of essential thiol groups of the enzyme. Furthermore, ,-tocopherol, melatonin and the inhibitor of nitric oxide synthase L-NAME were unable to prevent this effect, indicating that the most common reactive oxygen and nitrogen species were not involved in the inhibition of CK provoked by DGA. Conclusion, Considering the importance of creatine kinase activity for cellular energy homeostasis, our results suggest that inhibition of this enzyme by increased levels of DGA might be an important mechanism involved in the myopathy and cardiomyopathy of patients affected by DHGA. [source] Novel RYR1 missense mutation causes core rod myopathyEUROPEAN JOURNAL OF NEUROLOGY, Issue 4 2008M. Von Der Hagen No abstract is available for this article. [source] Dysferlin mutation analysis in a group of Italian patients with limb-girdle muscular dystrophy and Miyoshi myopathyEUROPEAN JOURNAL OF NEUROLOGY, Issue 10 2004K. Kawabe Mutations in the dysferlin gene (DYSF) on chromosome 2p13 cause distinct phenotypes of muscular dystrophy: limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM), and distal anterior compartment myopathy, which are known by the term ,dysferlinopathy'. We performed mutation analyses of DYSF in 14 Italian patients from 10 unrelated families with a deficiency of dysferlin protein below 20% of the value in normal controls by immunoblotting analysis. We identified 11 different mutations, including eight missense and three deletion mutations. Nine of them were novel mutations. We also identified a unique 6-bp insertion polymorphism within the coding region of DYSF in 15% of Italian population, which was not observed in East Asian populations. The correlation between clinical phenotype and the gene mutations was unclear, which suggested the role of additional genetic and epigenetic factors in modifying clinical symptoms. [source] Pure quadriceps myopathy in two sistersEUROPEAN JOURNAL OF NEUROLOGY, Issue 4 2003I. Mahjneh The authors carried out a clinical, laboratory and muscle computed tomographgy CT follow-up study of 18,21 years on two sisters affected by quadriceps myopathy (QM). The onset in the fourth decade was a weakness in the thighs. During the follow-up study, the patients showed only vasti muscles involvement, normal creatine kinase (CK) levels, myopathic muscle biopsy and electromyography (EMG) and normal membrane protein expression on immunocytochemical analysis. Therefore, all muscle pathologies known to have quadriceps involvement as a leading feature have been ruled out. We conclude that our patients have pure QM with probable autosomal recessive inheritance. [source] Myotonic dystrophy type 2EUROPEAN JOURNAL OF NEUROLOGY, Issue 5 2002J. Finsterer Myotonic dystrophy type 2 (DM2) is a clinically but not genetically heterogeneous, multisystem disorder, that is clinically similar to, but distinct from myotonic dystrophy type 1 (DM1). Initially, different phenotypes of DM2 were described by Ricker (proximal myotonic myopathy, PROMM), Ranum (myotonic dystrophy 2, DM2) and Udd (proximal myotonic dystrophy, PDM). Clinical features these three phenotypes had in common were diffuse, proximal or distal weakness, wasting, myotonia, cataract, cerebral, endocrine and cardiac abnormalities. Initially, the clinical differences between DM1 and PROMM seemed unmistakable, but meanwhile it has become apparent that the clinical differences between these entities are blurring. In 1999, Day et al., Meola et al. and Ricker et al. mapped the mutated gene of all three phenotypes to chromosome 3q. In 2001, the three different phenotypes were found to rely on the same mutation in the ZNF9 gene on chromosome 3q21.3. Although DM2 may be clinically heterogeneous, it is by result of a mutation in a single gene. The mutation responsible for DM2 is a CCTG-repeat expansion of 75,11 000 repeats in intron 1 of the ZNF9 gene on chromosome 3q21.3. Because of the clinical heterogeneity, the diagnosis of DM2 should rely on DNA analysis alone. [source] Alcoholic skeletal muscle myopathy: definitions, features, contribution of neuropathy, impact and diagnosisEUROPEAN JOURNAL OF NEUROLOGY, Issue 6 2001V. R. Preedy Alcohol misusers frequently have difficulties in gait, and various muscle symptoms such as cramps, local pain and reduced muscle mass. These symptoms are common in alcoholic patients and have previously been ascribed as neuropathological in origin. However, biochemical lesions and/or the presence of a defined myopathy occur in alcoholics as a direct consequence of alcohol misuse. The myopathy occurs independently of peripheral neuropathy, malnutrition and overt liver disease. Chronic alcoholic myopathy is characterized by selective atrophy of Type II fibres and the entire muscle mass may be reduced by up to 30%. This myopathy is arguably the most prevalent skeletal muscle disorder in the Western Hemisphere and occurs in approximately 50% of alcohol misusers. Alcohol and acetaldehyde are potent inhibitors of muscle protein synthesis, and both contractile and non-contractile proteins are affected by acute and chronic alcohol dosage. Muscle RNA is also reduced by mechanisms involving increased RNase activities. In general, muscle protease activities are either reduced or unaltered, although markers of muscle membrane damage are increased which may be related to injury by reactive oxygen species. This supposition is supported by the observation that in the UK, , -tocopherol status is poor in myopathic alcoholics. Reduced , -tocopherol may pre-dispose the muscle to metabolic injury. However, experimental , -tocopherol supplementation is ineffective in preventing ethanol-induced lesions in muscle as defined by reduced rates of protein synthesis and in Spanish alcoholics with myopathy, there is no evidence of impaired , -tocopherol status. In conclusion, by a complex series of mechanisms, alcohol adversely affects skeletal muscle. In addition to the mechanical changes to muscle, there are important metabolic consequences, by virtue of the fact that skeletal muscle is 40% of body mass and an important contributor to whole-body protein turnover. [source] The mammalian exercise pressor reflex in health and diseaseEXPERIMENTAL PHYSIOLOGY, Issue 1 2006Scott A. Smith The exercise pressor reflex (a peripheral neural reflex originating in skeletal muscle) contributes significantly to the regulation of the cardiovascular system during exercise. Exercise-induced signals that comprise the afferent arm of the reflex are generated by activation of mechanically (muscle mechanoreflex) and chemically sensitive (muscle metaboreflex) skeletal muscle receptors. Activation of these receptors and their associated afferent fibres reflexively adjusts sympathetic and parasympathetic nerve activity during exercise. In heart failure, the cardiovascular response to exercise is augmented. Owing to the peripheral skeletal myopathy that develops in heart failure (e.g. muscle atrophy, decreased peripheral blood flow, fibre-type transformation and reduced oxidative capacity), the exercise pressor reflex has been implicated as a possible mechanism by which the cardiovascular response to physical activity is exaggerated in this disease. Accumulating evidence supports this conclusion. This review therefore focuses on the role of the exercise pressor reflex in regulating the cardiovascular system during exercise in both health and disease. Updates on our current understanding of the exercise pressor reflex neural pathway as well as experimental models used to study this reflex are presented. In addition, special emphasis is placed on the changes in exercise pressor reflex activity that develop in heart failure, including the contributions of the muscle mechanoreflex and metaboreflex to this pressor reflex dysfunction. [source] R120G ,B-crystallin promotes the unfolding of reduced ,-lactalbumin and is inherently unstableFEBS JOURNAL, Issue 3 2005Teresa M. Treweek ,-Crystallin is the principal lens protein which, in addition to its structural role, also acts as a molecular chaperone, to prevent aggregation and precipitation of other lens proteins. One of its two subunits, ,B-crystallin, is also expressed in many nonlenticular tissues, and a natural missense mutation, R120G, has been associated with cataract and desmin-related myopathy, a disorder of skeletal muscles [Vicart P, Caron A, Guicheney P, Li Z, Prevost MC, Faure A, Chateau D, Chapon F, Tome F, Dupret JM, Paulin D & Fardeau M (1998) Nat Genet20, 92,95]. In the present study, real-time 1H-NMR spectroscopy showed that the ability of R120G ,B-crystallin to stabilize the partially folded, molten globule state of ,-lactalbumin was significantly reduced in comparison with wild-type ,B-crystallin. The mutant showed enhanced interaction with, and promoted unfolding of, reduced ,-lactalbumin, but showed limited chaperone activity for other target proteins. Using NMR spectroscopy, gel electrophoresis, and MS, we observed that, unlike the wild-type protein, R120G ,B-crystallin is intrinsically unstable in solution, with unfolding of the protein over time leading to aggregation and progressive truncation from the C-terminus. Light scattering, MS, and size-exclusion chromatography data indicated that R120G ,B-crystallin exists as a larger oligomer than wild-type ,B-crystallin, and its size increases with time. It is likely that removal of the positive charge from R120 of ,B-crystallin causes partial unfolding, increased exposure of hydrophobic regions, and enhances its susceptibility to proteolysis, thus reducing its solubility and promoting its aggregation and complexation with other proteins. These characteristics may explain the involvement of R120G ,B-crystallin with human disease states. [source] MBSJ MCC Young Scientist Award 2009 REVIEW: Selective autophagy regulates various cellular functionsGENES TO CELLS, Issue 9 2010Masaaki Komatsu Autophagy is a self-eating system conserved among eukaryotes, in which cellular components including organelles are entrapped into a double membrane structure called the autophagosome and then degraded by lysosomal hydrolases. In addition to its role in supplying amino acids in response to nutrient starvation, autophagy is involved in quality control to maintain cell health. Thus, inactivation of autophagy causes the formation of cytoplasmic protein inclusions, which comprise misfolded proteins and the accumulation of many degenerated organelles, resulting in liver injury, diabetes, myopathy and neurodegeneration. Furthermore, although autophagy has been considered nonselective, increasing evidence points to the selectivity of autophagy in sorting vacuolar enzymes and removal of aggregate-prone proteins and unwanted organelles. Such selectivity allows diverse cellular regulation, similar to the ubiquitin proteasome pathway. In this review, we discuss the physiological roles of selective autophagy and their molecular mechanisms. [source] Inflammatory myopathy and hepatitis C in a pediatric patient: Role of liver biopsy in evaluating the severity of liver diseaseHEPATOLOGY, Issue 4 2001Parvathi Mohan M.D. No abstract is available for this article. [source] Alcohol-induced myopathy: What is the role of mitochondria?HEPATOLOGY, Issue 1 2001Ph.D., Stephan Krähenbühl M.D. No abstract is available for this article. [source] Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency,HUMAN MUTATION, Issue 8 2010Fang-Yuan Li Abstract Systemic primary carnitine deficiency (CDSP) is caused by recessive mutations in the SLC22A5 (OCTN2) gene encoding the plasmalemmal carnitine transporter and characterized by hypoketotic hypoglycemia, and skeletal and cardiac myopathy. The entire coding regions of the OCTN2 gene were sequenced in 143 unrelated subjects suspected of having CDSP. In 70 unrelated infants evaluated because of abnormal newborn screening (NBS) results, 48 were found to have at least 1 mutation/unclassified missense variant. Twenty-eight of 33 mothers whose infants had abnormal NBS results were found to carry at least 1 mutation/unclassified missense variant, including 11 asymptomatic mothers who had 2 mutations. Therefore, sequencing of the OCTN2 gene is recommended for infants with abnormal NBS results and for their mothers. Conversely, 52 unrelated subjects were tested due to clinical indications other than abnormal NBS and only 14 of them were found to have at least one mutation/unclassified variant. Custom designed oligonucleotide array CGH analysis revealed a heterozygous ,1.6 Mb deletion encompassing the entire OCTN2 gene in one subject who was apparently homozygous for the c.680G>A (p.R227H) mutation. Thus, copy number abnormalities at the OCTN2 locus should be considered if by sequencing, an apparently homozygous mutation or only one mutant allele is identified. ©2010 Wiley-Liss, Inc. [source] Dynamin 2 mutations associated with human diseases impair clathrin-mediated receptor endocytosis,HUMAN MUTATION, Issue 10 2009Marc Bitoun Abstract Dynamin 2 (DNM2) is a large GTPase involved in the release of nascent vesicles during endocytosis and intracellular membrane trafficking. Distinct DNM2 mutations, affecting the middle domain (MD) and the Pleckstrin homology domain (PH), have been identified in autosomal dominant centronuclear myopathy (CNM) and in the intermediate and axonal forms of the Charcot-Marie-Tooth peripheral neuropathy (CMT). We report here the first CNM mutation (c.1948G>A, p.E650,K) in the DNM2 GTPase effector domain (GED), leading to a slowly progressive moderate myopathy. COS7 cells transfected with DNM2 constructs harboring a disease-associated mutation in MD, PH, or GED show a reduced uptake of transferrin and low-density lipoprotein (LDL) complex, two markers of clathrin-mediated receptor endocytosis. A decrease in clathrin-mediated endocytosis was also identified in skin fibroblasts from one CNM patient. We studied the impact of DNM2 mutant overexpression on epidermal growth factor (EGF)-induced extracellular signal-regulated kinase 1 (ERK1) and ERK2 activation, known to be an endocytosis- and DNM2-dependent process. Activation of ERK1/2 was impaired for all the transfected mutants in COS7 cells, but not in CNM fibroblasts. Our results indicate that impairment of clathrin-mediated endocytosis may play a role in the pathophysiological mechanisms leading to DNM2-related diseases, but the tissue-specific impact of DNM2 mutations in both diseases remains unclear. Hum Mutat 30:1,9, 2009. © 2009 Wiley-Liss, Inc. [source] Identifying sequence variants in the human mitochondrial genome using high-resolution melt (HRM) profiling,HUMAN MUTATION, Issue 6 2009Steven F. Dobrowolski Abstract Identifying mitochondrial DNA (mtDNA) sequence variants in human diseases is complicated. Many pathological mutations are heteroplasmic, with the mutant allele represented at highly variable percentages. High-resolution melt (HRM or HRMA) profiling was applied to comprehensive assessment of the mitochondrial genome and targeted assessment of recognized pathological mutations. The assay panel providing comprehensive coverage of the mitochondrial genome utilizes 36 overlapping fragments (301,658,bp) that employ a common PCR protocol. The comprehensive assay identified heteroplasmic mutation in 33 out of 33 patient specimens tested. Allele fraction among the specimens ranged from 1 to 100%. The comprehensive assay panel was also used to assess 125 mtDNA specimens from healthy donors, which identified 431 unique sequence variants. Utilizing the comprehensive mtDNA panel, the mitochondrial genome of a patient specimen may be assessed in less than 1 day using a single 384-well plate or two 96-well plates. Specific assays were used to identify the myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) mutation m.3243A>G, myoclonus epilepsy, ragged red fibers (MERRF) mutation m.8344A>G, and m.1555A>G associated with aminoglycoside hearing loss. These assays employ a calibrated, amplicon-based strategy that is exceedingly simple in design, utilization, and interpretation, yet provides sensitivity to detect variants at and below 10% heteroplasmy. Turnaround time for the genotyping tests is about 1,hr. Hum Mutat 30,1,8, 2009. © 2009 Wiley-Liss, Inc. [source] Mutations in RYR1 in malignant hyperthermia and central core disease,HUMAN MUTATION, Issue 10 2006Rachel Robinson Abstract The RYR1 gene encodes the skeletal muscle isoform ryanodine receptor and is fundamental to the process of excitation,contraction coupling and skeletal muscle calcium homeostasis. Mapping to chromosome 19q13.2, the gene comprises 106 exons and encodes a protein of 5,038 amino acids. Mutations in the gene have been found in association with several diseases: the pharmacogenetic disorder, malignant hyperthermia (MH); and three congenital myopathies, including central core disease (CCD), multiminicore disease (MmD), and in an isolated case of a congenital myopathy characterized on histology by cores and rods. The majority of gene mutations reported are missense changes identified in cases of MH and CCD. In vitro analysis has confirmed that alteration of normal calcium homeostasis is a functional consequence of some of these changes. Genotype,phenotype correlation studies performed using data from MH and CCD patients have also suggested that mutations may be associated with a range of disease severity phenotypes. This review aims to summarize the current understanding of RYR1 mutations reported in association with MH and CCD and the present viewpoint on the use of mutation data to aid clinical diagnosis of these conditions. Hum Mutat 27(10), 977,989, 2006. © 2006 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||||||||