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Mitochondrial myopathy

Md Fazlur Rahman, Radhika Raj, Rajgopal Govindarajan
Combination antiretroviral drug treatments depend on 3'-deoxy-nucleoside analogs such as AZT (3'-azido-3'-deoxythymidine) and DDI (2'3'-dideoxyinosine). Despite being effective in inhibiting HIV viral replication, these drugs produce a range of toxicities, including myopathy, pancreatitis, neuropathy and lactic acidosis, that are generally considered as sequelae to mitochondrial damage. While the cell surface localized nucleoside transporters (e.g., human equilibrative nucleoside transporter 2 (hENT2), human concentrative nucleoside transporter 1 (hCNT1)) are known to increase the carrier mediated uptake of 3'-deoxy-nucleoside analogs into cells, another ubiquitously expressed intracellular nucleoside transporter, namely, hENT3, has been implicated in the mitochondrial transport of 3'-deoxy-nucleoside analogs...
March 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Elisa Rubino, Ming Zhang, Tiziana Mongini, Silvia Boschi, Liliana Vercelli, Alessandro Vacca, Flora Govone, Annalisa Gai, Maria Teresa Giordana, Mark Grinberg, Ekaterina Rogaeva, Innocenzo Rainero
Mutations in CHCHD2 and CHCHD10 were recently reported in a broad spectrum of neurodegenerative diseases, for example, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, or mitochondrial myopathy (MM). The aim of the study was to evaluate the prevalence of CHCHD2 and CHCHD10 mutations in Italian MM patients without mitochondrial DNA mutations. The coding regions of CHCHD2 and CHCHD10 were sequenced in 62 MM patients. None of the patients showed CHCHD2 mutations, whereas 1 sporadic MM patient carried a homozygous Pro96Thr substitution in CHCHD10...
February 14, 2018: Neurobiology of Aging
Veronika Boczonadi, Martin S King, Anthony C Smith, Monika Olahova, Boglarka Bansagi, Andreas Roos, Filmon Eyassu, Christoph Borchers, Venkateswaran Ramesh, Hanns Lochmüller, Tuomo Polvikoski, Roger G Whittaker, Angela Pyle, Helen Griffin, Robert W Taylor, Patrick F Chinnery, Alan J Robinson, Edmund R S Kunji, Rita Horvath
PurposeTo understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease.MethodsWe identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons.ResultsThe patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy...
March 8, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Mark A Tarnopolsky, Arun N E Sundaram, John Provias, Lauren Brady, Bekim Sadikovic
Two patients with an m.8340G>A mitochondrial DNA variant have been reported with one patient showing ptosis, ophthalmoparesis and myopathy at 53% heteroplasmy and another with pigmentary retinopathy, cataracts and sensory neural deafness and slightly higher heteroplasmy (65%). Here we report that higher muscle mutant heteroplasmy (93%) for m.8340G>A is associated with ptosis, ophthalmoparesis and mitochondrial myopathy, thus confirming the initial phenotypic association and showing that heteroplasmy per se does not explain the phenotypic spectrum of disease associated with the m...
February 28, 2018: Mitochondrion
Amel Karaa, Richard Haas, Amy Goldstein, Jerry Vockley, W Douglas Weaver, Bruce H Cohen
OBJECTIVE: To assess the safety and efficacy of elamipretide, an aromatic-cationic tetrapeptide that readily penetrates cell membranes and transiently localizes to the inner mitochondrial membrane where it associates with cardiolipin, in adults with primary mitochondrial myopathy (PMM). METHODS: A Study Investigating the Safety, Tolerability, and Efficacy of MTP-131 for the Treatment of Mitochondrial Myopathy (MMPOWER) was a phase I/II multicenter, randomized, double-blind, placebo-controlled trial of elamipretide in 36 participants with genetically confirmed PMM...
March 2, 2018: Neurology
Vincent Lepori, Franziska Mühlhause, Adrian C Sewell, Vidhya Jagannathan, Nils Janzen, Marco Rosati, Filipe Miguel Maximiano Alves de Sousa, Aurélie Tschopp, Gertraud Schüpbach, Kaspar Matiasek, Andrea Tipold, Tosso Leeb, Marion Kornberg
Several enzymes are involved in fatty acid oxidation, which is a key process in mitochondrial energy production. Inherited defects affecting any step of fatty acid oxidation can result in clinical disease. We present here an extended family of German Hunting Terriers with 10 dogs affected by clinical signs of exercise induced weakness, muscle pain, and suspected rhabdomyolysis. The combination of clinical signs, muscle histopathology and acylcarnitine analysis with an elevated tetradecenoylcarnitine (C14:1) peak suggested a possible diagnosis of acyl-CoA dehydrogenase very long chain deficiency (ACADVLD)...
February 28, 2018: G3: Genes—Genomes—Genetics
Monique Fontaine, Isabelle Kim, Anne-Frédérique Dessein, Karine Mention-Mulliez, Dries Dobbelaere, Claire Douillard, Guilhem Sole, Manuel Schiff, Roland Jaussaud, Caroline Espil-Taris, Audrey Boutron, Wim Wuyts, Cécile Acquaviva, Christine Vianey-Saban, Dominique Roland, Marie Joncquel-Chevalier Curt, Joseph Vamecq
Carnitine palmitoyltransferase type 2 (CPT2) deficiency, a mitochondrial fatty acid oxidation disorder (MFAOD), is a cause of myopathy in its late clinical presentation. As for other MFAODs, its diagnosis may be evocated when blood acylcarnitine profile is abnormal. However, a lack of abnormalities or specificity in this profile is not exclusive of CPT2 deficiency. Our retrospective study reports clinical and biological data in a cohort of 11 patients with circulating acylcarnitine profile unconclusive enough for a specific diagnosis orientation...
February 12, 2018: Molecular Genetics and Metabolism
Karien Esterhuizen, J Zander Lindeque, Shayne Mason, Francois H van der Westhuizen, Anu Suomalainen, Anna H Hakonen, Christopher J Carroll, Richard J Rodenburg, Paul B de Laat, Mirian C H Janssen, Jan A M Smeitink, Roan Louw
We used a comprehensive metabolomics approach to study the altered urinary metabolome of two mitochondrial myopathy, encephalopathy lactic acidosis and stroke like episodes (MELAS) cohorts carrying the m.3243A>G mutation. The first cohort were used in an exploratory phase, identifying 36 metabolites that were significantly perturbed by the disease. During the second phase, the 36 selected metabolites were able to separate a validation cohort of MELAS patients completely from their respective control group, suggesting usefulness of these 36 markers as a diagnostic set...
February 19, 2018: Mitochondrion
Doris G Leung, Julie S Cohen, Elizabeth Harlan Michelle, Renkui Bai, Andrew L Mammen, Lisa Christopher-Stine
We report the cases of 2 patients who presented to our Myositis Center with myalgias and elevated creatine kinase levels. Muscle biopsy showed pathological features consistent with mitochondrial myopathy. In both cases, a single large deletion in mitochondrial DNA at low-level heteroplasmy was identified by next-generation sequencing in muscle tissue. In 1 case, the deletion was identified in muscle tissue but not blood. In both cases, the deletion was only identified on next-generation sequencing of muscle mitochondrial DNA and missed on array comparative genome hybridization testing...
March 2018: Journal of Clinical Neuromuscular Disease
Huan T Nguyen, Satoru Noguchi, Kazuma Sugie, Yoshiyuki Matsuo, Chuyen T H Nguyen, Hitoshi Koito, Ichiro Shiojima, Ichizo Nishino, Hiroyasu Tsukaguchi
Lysosomal associated membrane protein 2 (LAMP2) is physiologically implicated in autophagy. A genetic LAMP2 defect causes Danon disease, which consists of two major phenotypes of myopathy and cardiomyopathy. In addition, arteriopathy may manifest on rare occasions but the pathological basis remains unknown. We encountered two Danon families that developed small-vessel vasculopathy in the coronary or cerebral arteries. To investigate the underlying mechanisms, we characterized the biological features of LAMP-2-deficient mice and cultured cells...
February 20, 2018: Scientific Reports
B Debashree, Manish Kumar, T S Keshava Prasad, Archana Natarajan, Rita Christopher, A Nalini, P S Bindu, N Gayathri, M M Srinivas Bharath
Mitochondria regulate the balance between lipid metabolism and storage in the skeletal muscle. Altered lipid transport, metabolism and storage influence the bioenergetics, redox status and insulin signalling contributing to cardiac and neurological diseases. Lipid storage disorders (LSDs) are neurological disorders which entail intramuscular lipid accumulation and impaired mitochondrial bioenergetics in the skeletal muscle causing progressive myopathy with muscle weakness. However, the mitochondrial changes including molecular events associated with impaired lipid storage have not been completely understood in the human skeletal muscle...
February 9, 2018: Journal of Neurochemistry
Abdulmohsen Al Ghamdi
Kearns-Sayre syndrome (KSS), a rare form of mitochondrial myopathy, is a triad of chronic progressive external ophthalmoplegia, bilateral pigmentary retinopathy, and cardiac conduction abnormalities. In this report, we show how a combined spinal epidural anesthesia can be useful for cesarean delivery, as we illustrate in a dual-chamber and VVI implantable defibrillator pacemaker/defibrillator parturient with a KSS and preeclampsia.
January 2018: Saudi Journal of Anaesthesia
Juan Chen, Jingyang Wang, Jiyan Zhang, Chuanqiang Pu
Idiopathic inflammatory myopathies are a group of rare muscular diseases that are characterized by acute, subacute or chronic proximal and symmetric muscle weakness, muscle fiber necrosis and infiltration of inflammatory cells, particularly activated CD8+ cytotoxic T cells and phagocytes. 3-n-butylphthalide (NBP) protects mitochondria and reduces the inflammatory response in multiple disease models. In myositis, it has remained elusive whether NBP can protect muscle cells from muscle fiber injury. Experimental autoimmune myositis (EAM) was induced in a total of 40 guinea pigs by myosin immunization...
January 2018: Experimental and Therapeutic Medicine
Marina Bartsakoulia, Angela Pyle, Diego Troncosco, Josefa Vial, Marysol V Paz-Fiblas, Jennifer Duff, Helen Griffin, Veronika Boczonadi, Hanns Lochmüller, Stephanie Kleinle, Patrick F Chinnery, Sarah Grünert, Janbernd Kirschner, Veronica Eisner, Rita Horvath
Mitochondrial dynamics play an important role in cellular homeostasis and a variety of human diseases are linked to its dysregulated function. Here we describe a 15-year-old boy with a novel disease caused by altered mitochondrial dynamics. The patient was the second child of consanguineous Jewish parents. He developed progressive muscle weakness and exercise intolerance at 6 years of age. His muscle biopsy revealed mitochondrial myopathy with numerous ragged red and cytochrome c oxidase (COX) negative fibers and combined respiratory chain complex I and IV deficiency...
January 19, 2018: Human Molecular Genetics
Pirjo Isohanni, Christopher J Carroll, Christopher B Jackson, Max Pohjanpelto, Tuula Lönnqvist, Anu Suomalainen
Mutations in mitochondrial ATP synthase 6 (MT-ATP6) are a frequent cause of NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) or Leigh syndromes, especially a point mutation at nucleotide position 8993. M.8969G>A is a rare MT-ATP6 mutation, previously reported only in three individuals, causing multisystem disorders with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia or IgA nephropathy. We present two siblings with the m.8969G>A mutation and a novel, substantially milder phenotype with lactic acidosis, poor growth, and intellectual disability...
January 2018: Neurogenetics
A Schänzer, S Rupp, S Gräf, D Zengeler, C Jux, H Akintürk, L Gulatz, N Mazhari, T Acker, R Van Coster, B K Garvalov, A Hahn
Myofibrillary myopathies (MFM) are hereditary myopathies histologically characterized by degeneration of myofibrils and aggregation of proteins in striated muscle. Cardiomyopathy is common in MFM but the pathophysiological mechanisms are not well understood. The BAG3-Pro209Leu mutation is associated with early onset MFM and severe restrictive cardiomyopathy (RCM), often necessitating heart transplantation during childhood. We report on a young male patient with a BAG3-Pro209Leu mutation who underwent heart transplantation at eight years of age...
January 6, 2018: Molecular Genetics and Metabolism
M Almannai, A Alsamri, A Alqasmi, E Faqeih, F AlMutairi, M Alotaibi, M M Samman, W Eyaid, Y I Aljadhai, H E Shamseldin, W Craigen, F S Alkuraya
SLC25A42 gene encodes an inner mitochondrial membrane protein that imports Co-enzyme A (CoA) into the mitochondrial matrix. A mutation in this gene was recently reported in a subject born to consanguineous parents who presented with mitochondrial myopathy with muscle weakness and lactic acidosis. In this report, we present 12 additional individuals with the same founder mutation who presented with variable manifestations ranging from asymptomatic lactic acidosis to a severe phenotype characterized by developmental regression and epilepsy...
January 12, 2018: Clinical Genetics
Laura Kytövuori, Maria Gardberg, Kari Majamaa, Mika H Martikainen
Objectives: Mutations in mitochondrial DNA cause a variety of clinical phenotypes ranging from a mild hearing impairment (HI) to severe encephalomyopathy. The MT-TS1 gene is a hotspot for mutations causing HI. The m.7510T>C mutation in MT-TS1 has been previously associated with non-syndromic HI in four families from different ethnic backgrounds. Materials and Methods: We describe the clinical, genetic, and histopathological findings in a Finnish family with the heteroplasmic m...
December 2017: Brain and Behavior
Yu-Ting Wu, Yu-Hung Hsu, Ching-Ying Huang, Ming-Ching Ho, Yu-Che Cheng, Cheng-Hao Wen, Hui-Wen Ko, Huai-En Lu, Yen-Chun Chen, Chia-Ling Tsai, Yi-Chao Hsu, Yau-Huei Wei, Patrick C H Hsieh
Mitochondrial defects are associated with clinical manifestations from common diseases to rare genetic disorders. Myoclonus epilepsy associated with ragged-red fibers (MERRF) syndrome results from an A to G transition at nucleotide position 8344 in the tRNALys gene of mitochondrial DNA (mtDNA) and is characterized by myoclonus, myopathy and severe neurological symptoms. In this study, Sendai reprogramming method was used to generate an iPS cell line carrying the A8344G mutation of mtDNA from a MERRF patient...
December 19, 2017: Stem Cell Research
Ayman W El-Hattab, Julia Wang, Hongzheng Dai, Mohammed Almannai, Christian Staufner, Majid Alfadhel, Michael J Gambello, Pankaj Prasun, Saleem Raza, Hernando J Lyons, Manal Afqi, Mohammed A M Saleh, Eissa A Faqeih, Hamad I Alzaidan, Abduljabbar Alshenqiti, Leigh Anne Flore, Jozef Hertecant, Stephanie Sacharow, Deborah S Barbouth, Kei Murayama, Amit A Shah, Henry C Lin, Lee-Jun C Wong
Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile-onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17-related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants...
December 27, 2017: Human Mutation
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