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Mitochondrial DNA depletion in single fibers in a patient with novel TK2 mutations

Journal article
Authors Sara Roos
U. Lindgren
C. Ehrstedt
Ali-Reza Moslemi
Anders Oldfors
Published in Neuromuscular Disorders
Volume 24
Issue 8
Pages 713-720
ISSN 0960-8966
Publication year 2014
Published at Institute of Biomedicine, Department of Pathology
Pages 713-720
Language en
Keywords Mitochondrial DNA depletion syndrome, Myopathy, Thymidine kinase 2, TK2, Mitochondrial, THYMIDINE KINASE-2 GENE, MTDNA DEPLETION, DEOXYRIBONUCLEOSIDE KINASES, HYPERTROPHIC CARDIOMYOPATHY, COENZYME Q(10), MYOPATHY, DELETIONS, MUSCLE, DEFICIENCY, SPECTRUM, Clinical Neurology, Neurosciences
Subject categories Neurology, Neuroscience


The mitochondrial DNA (mtDNA) depletion syndrome is a genetically heterogeneous group of diseases caused by nuclear gene mutations and secondary reduction in mtDNA copy number. We describe a patient with progressive muscle weakness and increased creatine kinase and lactate levels. Muscle weakness was first noted at age 1.5 years and he died of respiratory failure and bronchopneumonia at age 3.5 years. The muscle biopsy showed dystrophic features with ragged red fibers and numerous cytochrome c oxidase (COX)-negative fibers. qPCR analysis demonstrated depletion of mtDNA and sequence analysis of the mitochondrial thymidine kinase 2 (TK2) gene revealed two novel heterozygous variants, c.332C > T, p.(T111I) and c.156 + 5G > C. Quantitative analysis of mtDNA in single muscle fibers demonstrated that COX-deficient fibers showed more pronounced depletion of mtDNA when compared with fibers with residual COX activity (P < 0.01, n = 25). There was no evidence of manifestations from other organs than skeletal muscle although there was an apparent reduction of mtDNA copy number also in liver. The patient showed a pronounced, albeit transient, improvement in muscle strength after onset of treatment with coenzyme Q10, asparaginase, and increased energy intake, suggesting that nutritional modulation may be a therapeutic option in myopathic mtDNA depletion syndrome. (C) 2014 Elsevier B.V. All rights reserved.

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