Mitochondrial DNA depletion in single fibers in a patient with novel TK2 mutations |
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| Institution: | 1. Department of Pathology, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden;2. Department of Women’s and Children’s Health, Uppsala University Children’s Hospital, Uppsala, Sweden;1. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands;2. Department of Medical Sciences, University of Ferrara, Ferrara, Italy;3. United Parent Project Muscular Dystrophy, The Netherlands;1. Program in Rare and Genetic Diseases, Centro de Investigación Príncipe Felipe (CIPF), CIPF and IBV-CSIC Associated Unit at CIPF, Valencia, Spain;2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain;3. Neurology Department, Hospital Universitario La Paz, Madrid, Spain;4. Pediatric Neurology Department, Hospital Infantil Universitario Niño Jesús, Madrid, Spain;5. Program in Computational Medicine, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain;1. Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea;2. Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea;1. Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada;2. Division of Neurology, University Health Network, Toronto, Ontario, Canada;3. Division of Neurology, University of Toronto, Toronto, Ontario, Canada;1. Institute for Neuroscience and Muscle Research, The Children’s Hospital at Westmead, Sydney, Australia;2. Discipline of Paediatrics and Child Health, The University of Sydney, Sydney, Australia;3. Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA;4. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA;5. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA;6. Department of Medicine, Harvard Medical School, Boston, MA, USA |
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| Abstract: | 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. |
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| Keywords: | Mitochondrial DNA depletion syndrome Myopathy Thymidine kinase 2 TK2 Mitochondrial myopathy |
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