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Oznur Bayraktar, Ozlem Oral, Nur Mehpare Kocaturk, Yunus Akkoc, Karin Eberhart, Ali Kosar, Devrim Gozuacik
The ubiquitin-proteasome system (UPS) degrades soluble proteins and small aggregates, whereas macroautophagy (autophagy herein) eliminates larger protein aggregates, tangles and even whole organelles in a lysosome-dependent manner. VCP/p97 was implicated in both pathways. VCP/p97 mutations cause a rare multisystem disease called IBMPFD (Inclusion Body Myopathy with Paget's Disease and Frontotemporal Dementia). Here, we studied the role IBMPFD-related mutants of VCP/p97 in autophagy. In contrast with the wild-type VCP/p97 protein or R155C or R191Q mutants, the P137L mutant was aggregate-prone...
2016: PloS One
Kavita J Rawat, Nilakshi H Sabnis, Udit Saraf, Gaurav Surana
Vitamin D functions as a vitamin as well as a hormone. Its major skeletal actions are complemented by varied extra-skeletal functions. During the past decade, association between Vitamin D and its role in various non-skeletal morbidities have been recognized. It plays a role in decreasing the risk of many chronic illnesses like allergies, asthma, autoimmune diseases, diabetes, cancers, infections and cardiovascular disease. We report the case of a middle aged female with chronic quadriparesis and new onset anemia associated with Vitamin D deficiency...
October 2016: Journal of the Association of Physicians of India
Matthias Boentert, Hélène Prigent, Katalin Várdi, Harrison N Jones, Uwe Mellies, Anita K Simonds, Stephan Wenninger, Emilia Barrot Cortés, Marco Confalonieri
Pompe disease is an autosomal-recessive lysosomal storage disorder characterized by progressive myopathy with proximal muscle weakness, respiratory muscle dysfunction, and cardiomyopathy (in infants only). In patients with juvenile or adult disease onset, respiratory muscle weakness may decline more rapidly than overall neurological disability. Sleep-disordered breathing, daytime hypercapnia, and the need for nocturnal ventilation eventually evolve in most patients. Additionally, respiratory muscle weakness leads to decreased cough and impaired airway clearance, increasing the risk of acute respiratory illness...
October 17, 2016: International Journal of Molecular Sciences
Angela Ceribelli, Natasa Isailovic, Maria De Santis, Elena Generali, Micaela Fredi, Ilaria Cavazzana, Franco Franceschini, Luca Cantarini, Minoru Satoh, Carlo Selmi
This study aims to characterize myositis-specific antibodies in a well-defined cohort of patients with idiopathic inflammatory myopathy and to determine their association with cancer. Sera from 40 patients with polymyositis, dermatomyositis, and controls were tested by protein and RNA immunoprecipitation to detect autoantibodies, and immunoprecipitation-Western blot was used for anti-MJ/NXP-2, anti-MDA5, and anti-TIF1γ/α identification. Medical records were re-evaluated with specific focus on cancer. Anti-MJ/NXP-2 and anti-TIF1γ/α were the most common antibodies in dermatomyositis...
October 20, 2016: Clinical Rheumatology
Masato Kadoya, Ayumi Hida, Meiko Hashimoto Maeda, Kenichiro Taira, Chiseko Ikenaga, Naohiro Uchio, Akatsuki Kubota, Kenichi Kaida, Yusuke Miwa, Kazuhiro Kurasawa, Hiroyuki Shimada, Masahiro Sonoo, Atsuro Chiba, Yasushi Shiio, Yoshikazu Uesaka, Yasuhisa Sakurai, Toru Izumi, Manami Inoue, Shin Kwak, Shoji Tsuji, Jun Shimizu
OBJECTIVE: To show cancer association is a risk factor other than statin exposure for anti-3-hydroxy-3-methylglutaryl coenzyme A reductase autoantibody-positive (anti-HMGCR Ab+) myopathy. METHODS: We analyzed the clinical features and courses of 33 patients (23 female and 10 male) with anti-HMGCR Ab+ myopathy among 621 consecutive patients with idiopathic inflammatory myopathies. RESULTS: Among the 33 patients, 7 (21%) were statin-exposed and 26 were statin-naive...
December 2016: Neurology® Neuroimmunology & Neuroinflammation
Robyn T Rebbeck, Maram M Essawy, Florentin R Nitu, Benjamin D Grant, Gregory D Gillispie, David D Thomas, Donald M Bers, Razvan L Cornea
Using time-resolved fluorescence resonance energy transfer (FRET), we have developed and validated the first high-throughput screening (HTS) method to discover compounds that modulate an intracellular Ca(2+) channel, the ryanodine receptor (RyR), for therapeutic applications. Intracellular Ca(2+) regulation is critical for striated muscle function, and RyR is a central player. At resting [Ca(2+)], an increased propensity of channel opening due to RyR dysregulation is associated with severe cardiac and skeletal myopathies, diabetes, and neurological disorders...
October 19, 2016: Journal of Biomolecular Screening
Alan Pestronk, Richard Keeling, Rati Choksi
OBJECTIVE: We studied mitochondrial impairment as a factor in the pathologic equivalent of sarcopenia, muscle fiber atrophy associated with increased age. METHODS: Mitochondrial oxidative enzyme activities and coenzyme Q10 levels were measured in frozen human proximal limb muscles with combined age and atrophy, age alone, atrophy alone, denervation, immune myopathies, and mitochondrial disorders with ophthalmoplegia. RESULTS: Sarcopenia (age and atrophy) had reduced mean activities of mitochondrial Complexes I, II, and II+III, with severe reduction of Complex I activity in 54% of patients...
October 19, 2016: Muscle & Nerve
Joseph P Kitzmiller, Eduard B Mikulik, Anees M Dauki, Chandrama Murkherjee, Jasmine A Luzum
Statins are a cornerstone of the pharmacologic treatment and prevention of atherosclerotic cardiovascular disease. Atherosclerotic disease is a predominant cause of mortality and morbidity worldwide. Statins are among the most commonly prescribed classes of medications, and their prescribing indications and target patient populations have been significantly expanded in the official guidelines recently published by the American and European expert panels. Adverse effects of statin pharmacotherapy, however, result in significant cost and morbidity and can lead to nonadherence and discontinuation of therapy...
2016: Pharmacogenomics and Personalized Medicine
Chrisovalantis Papadopoulos, Philipp Kirchner, Monika Bug, Daniel Grum, Lisa Koerver, Nina Schulze, Robert Poehler, Alina Dressler, Sven Fengler, Khalid Arhzaouy, Vanda Lux, Michael Ehrmann, Conrad C Weihl, Hemmo Meyer
Rupture of endosomes and lysosomes is a major cellular stress condition leading to cell death and degeneration. Here, we identified an essential role for the ubiquitin-directed AAA-ATPase, p97, in the clearance of damaged lysosomes by autophagy. Upon damage, p97 translocates to lysosomes and there cooperates with a distinct set of cofactors including UBXD1, PLAA, and the deubiquitinating enzyme YOD1, which we term ELDR components for Endo-Lysosomal Damage Response. Together, they act downstream of K63-linked ubiquitination and p62 recruitment, and selectively remove K48-linked ubiquitin conjugates from a subpopulation of damaged lysosomes to promote autophagosome formation...
October 17, 2016: EMBO Journal
Laura C Cappelli, Ami A Shah, Clifton O Bingham
Immune checkpoint inhibitors (ICIs) are newly approved treatments for advanced malignancies that are increasing survival. The mechanism of these drugs, non-specifically activating T cells, also leads to immune-mediated damage of tissue or immune-related adverse events (IRAE). IRAEs with rheumatic phenotypes are increasingly being recognised. Inflammatory arthritis, sicca syndrome, inflammatory myopathy, vasculitis and lupus nephritis have been described as a result of ICIs. Use of ICIs will be expanding in the coming years for several reasons...
2016: RMD Open
Thomas Schwartz, Louise Pyndt Diederichsen, Ingrid E Lundberg, Ivar Sjaastad, Helga Sanner
Idiopathic inflammatory myopathies (IIM) include the main subgroups polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM) and juvenile DM (JDM). The mentioned subgroups are characterised by inflammation of skeletal muscles leading to muscle weakness and other organs can also be affected as well. Even though clinically significant heart involvement is uncommon, heart disease is one of the major causes of death in IIM. Recent studies show an increased prevalence of traditional cardiovascular risk factors in JDM and DM/PM, which need attention...
2016: RMD Open
Jingzi Zhong, Tiantian Xu, Gang Chen, Haixia Liao, Jiapeng Zhang, Dan Lan
Introduction Duchenne and Becker muscular dystrophies (DMD and BMD) are X-linked myopathies caused by mutations of the dystrophin gene. Methods Multiplex ligation-dependent probe amplification (MLPA) combined with next-generation sequencing (NGS) of the exons of the dystrophin gene were performed in 92 suspected DMD/BMD patients. Patients with negative results were subjected to additional muscle diseases panel tests. Results DNA rearrangements were detected in 65(70.65%) patients using MLPA. The deletions primarily clustered at exons 45-55, followed by exons 2-19...
October 17, 2016: Muscle & Nerve
Jane Schröder, Lisa Goltz, Holger Knoth
The clinical relevance of the drug-drug interaction simvastatin and amlodipine is appraised controversially by german simvastatin Summary of Product Characteristics (SPCs) and different drug interaction databases. Results of clinical trials have shown that simultaneous administration of simvastatin and amlodipine can increase simvastatin bioavailability. However, it is unclear whether this increase is associated with a higher risk for adverse drug events. So far there is no evidence that the combination might increase cases of myopathy or rhabdomyolysis...
October 2016: Deutsche Medizinische Wochenschrift
Alessandra Ruggieri, Simona Saredi, Simona Zanotti, Maria Barbara Pasanisi, Lorenzo Maggi, Marina Mora
Mutations in the DNAJB6 gene have been associated with the autosomal dominant limb girdle muscular dystrophy type 1D (LGMD1D), a disorder characterized by abnormal protein aggregates and rimmed vacuoles in muscle fibers. DNAJB6 is a ubiquitously expressed Hsp40 co-chaperone characterized by a J domain that specifies Hsp70 functions in the cellular environment. DNAJB6 is also a potent inhibitor of expanded polyglutamine (polyQ) aggregation preventing aggregate toxicity in cells. In DNAJB6-mutated patients this anti-aggregation property is significantly reduced, albeit not completely lost...
2016: Frontiers in Molecular Biosciences
Subha Ghosh, Rahul Renapurkar, Subha V Raman
BACKGROUND: The objective of this study was to evaluate patients with known hereditary cardiac conduction and myocardial disease (HCCMD) caused by a lamin A/C gene mutation for skeletal muscle involvement using magnetic resonance imaging (MRI) computed tomography (CT). METHODS: Twenty-one patients with the diagnosis of HCCMD were available for study. Of these 21, 11 had MRI scans of the lower legs. The 11 that had an MRI were compared to a control group of 17 healthy controls...
October 2016: Cardiovascular Diagnosis and Therapy
Gina L O'Grady, Heather A Best, Tamar E Sztal, Vanessa Schartner, Myriam Sanjuan-Vazquez, Sandra Donkervoort, Osorio Abath Neto, Roger Bryan Sutton, Biljana Ilkovski, Norma Beatriz Romero, Tanya Stojkovic, Jahannaz Dastgir, Leigh B Waddell, Anne Boland, Ying Hu, Caitlin Williams, Avnika A Ruparelia, Thierry Maisonobe, Anthony J Peduto, Stephen W Reddel, Monkol Lek, Taru Tukiainen, Beryl B Cummings, Himanshu Joshi, Juliette Nectoux, Susan Brammah, Jean-François Deleuze, Viola Oorschot Ing, Georg Ramm, Didem Ardicli, Kristen J Nowak, Beril Talim, Haluk Topaloglu, Nigel G Laing, Kathryn N North, Daniel G MacArthur, Sylvie Friant, Nigel F Clarke, Robert J Bryson-Richardson, Carsten G Bönnemann, Jocelyn Laporte, Sandra T Cooper
This study establishes PYROXD1 variants as a cause of early-onset myopathy and uses biospecimens and cell lines, yeast, and zebrafish models to elucidate the fundamental role of PYROXD1 in skeletal muscle. Exome sequencing identified recessive variants in PYROXD1 in nine probands from five families. Affected individuals presented in infancy or childhood with slowly progressive proximal and distal weakness, facial weakness, nasal speech, swallowing difficulties, and normal to moderately elevated creatine kinase...
September 28, 2016: American Journal of Human Genetics
Eman M Khedr, Gharib Fawi, Mohammed Abd-Allah Abbas, Noha Abo El-Fetoh, Ahmed F Zaki, Ayman Gamea, Ghada Al Attar
BACKGROUND: Few epidemiological studies of the prevalence of neuromuscular disorders have been undertaken. The aim of the study was to estimate the prevalence of the most common types of neuromuscular disorders in Qena governorate/Egypt. METHODS: A random sample was taken from 11 districts, involving 9303 inhabitants with 57.3% urban residents and 42.7% rural residence. Patients were diagnosed using a screening questionnaire for the diagnosis of neuromuscular disorders...
October 17, 2016: Neurological Research
Annika Strauch, Martin Haslbeck
All organisms rely on a conserved cellular machinery supporting and controlling the life cycle of proteins: the proteostasis network. Within this network, the main players that determine the fate of proteins are molecular chaperones, the ubiquitin-proteasome and the lysosome-autophagy systems. sHsps (small heat-shock proteins) represent one family of molecular chaperones found in all domains of life. They prevent irreversible aggregation of unfolded proteins and maintain proteostasis by stabilizing promiscuously a variety of non-native proteins in an ATP-independent manner...
October 15, 2016: Essays in Biochemistry
Isabelle Beaulieu-Boire, Camila C Aquino, Alfonso Fasano, Yu-Yan Poon, Melanie Fallis, Antony E Lang, Mojgan Hodaie, Suneil K Kalia, Andres Lozano, Elena Moro
BACKGROUND: Rare causes of inherited movement disorders often present with a debilitating phenotype of dystonia, sometimes combined with parkinsonism and other neurological signs. Since these disorders are often resistant to medications, DBS may be considered as a possible treatment. METHODS: Patients with identified genetic diseases (ataxia-telangiectasia, chorea-achantocytosis, dopa-responsive dystonia, congenital nemaline myopathy, methylmalonic aciduria, neuronal ceroid lipofuscinosis, spinocerebellar ataxia types 2 and 3, Wilson's disease, Woodhouse-Sakati syndrome, methylmalonic aciduria, and X trisomy) and disabling dystonia underwent bilateral GPi DBS (bilateral thalamic Vim nucleus in 1 case)...
October 4, 2016: Brain Stimulation
Mugundhan Krishnan, C Selvaraj, S Sivakumar
Centronuclear myopathy (CNM) is a rare congenital myopathy that is characterized by centrally placed nuclei in the muscle fibers. Three forms of the disease are clinically recognized. The severe neonatal form, the childhood onset form, and an adult-onset form. We report a 50 year old male patient with centronuclear myopathy (CNM) in whom the disease manifested itself in the fifth decade of life without any family history of such illness.
June 2016: Journal of the Association of Physicians of India
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