title: Mitochondrial DNA depletion in single fibers in a patient with novel TK2 mutations.
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.
authors: Department of Pathology, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. Electronic address: sara.roos@gu.se.
authors: S
authors: S
authors: Roos
authors: Department of Pathology, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors: U
authors: U
authors: Lindgren
authors: Department of Women's and Children's Health, Uppsala University Children's Hospital, Uppsala, Sweden.
authors: C
authors: C
authors: Ehrstedt
authors: Department of Pathology, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors: A R
authors: AR
authors: Moslemi
authors: Department of Pathology, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors: A
authors: A
authors: Oldfors
mesh_terms: D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000378:metabolism*; D017809:Fatal Outcome; D006801:Humans; D008099:Liver / Q000473:pathology; D008297:Male; D008931:Mitochondria, Muscle / Q000235:genetics / Q000378:metabolism; D017240:Mitochondrial Myopathies / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D018908:Muscle Weakness / Q000235:genetics; D009154:Mutation; D013937:Thymidine Kinase / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; C105339:thymidine kinase 2; D013937:Thymidine Kinase
keywords: Mitochondrial DNA depletion syndrome; Mitochondrial myopathy; Myopathy; TK2; Thymidine kinase 2