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Retrospective natural history of thymidine kinase 2 deficiency
BACKGROUND: Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy....
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073909/ https://www.ncbi.nlm.nih.gov/pubmed/29602790 http://dx.doi.org/10.1136/jmedgenet-2017-105012 |
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author | Garone, Caterina Taylor, Robert W Nascimento, Andrés Poulton, Joanna Fratter, Carl Domínguez-González, Cristina Evans, Julie C Loos, Mariana Isohanni, Pirjo Suomalainen, Anu Ram, Dipak Hughes, M Imelda McFarland, Robert Barca, Emanuele Lopez Gomez, Carlos Jayawant, Sandeep Thomas, Neil D Manzur, Adnan Y Kleinsteuber, Karin Martin, Miguel A Kerr, Timothy Gorman, Grainne S Sommerville, Ewen W Chinnery, Patrick F Hofer, Monika Karch, Christoph Ralph, Jeffrey Cámara, Yolanda Madruga-Garrido, Marcos Domínguez-Carral, Jana Ortez, Carlos Emperador, Sonia Montoya, Julio Chakrapani, Anupam Kriger, Joshua F Schoenaker, Robert Levin, Bruce Thompson, John L P Long, Yuelin Rahman, Shamima Donati, Maria Alice DiMauro, Salvatore Hirano, Michio |
author_facet | Garone, Caterina Taylor, Robert W Nascimento, Andrés Poulton, Joanna Fratter, Carl Domínguez-González, Cristina Evans, Julie C Loos, Mariana Isohanni, Pirjo Suomalainen, Anu Ram, Dipak Hughes, M Imelda McFarland, Robert Barca, Emanuele Lopez Gomez, Carlos Jayawant, Sandeep Thomas, Neil D Manzur, Adnan Y Kleinsteuber, Karin Martin, Miguel A Kerr, Timothy Gorman, Grainne S Sommerville, Ewen W Chinnery, Patrick F Hofer, Monika Karch, Christoph Ralph, Jeffrey Cámara, Yolanda Madruga-Garrido, Marcos Domínguez-Carral, Jana Ortez, Carlos Emperador, Sonia Montoya, Julio Chakrapani, Anupam Kriger, Joshua F Schoenaker, Robert Levin, Bruce Thompson, John L P Long, Yuelin Rahman, Shamima Donati, Maria Alice DiMauro, Salvatore Hirano, Michio |
author_sort | Garone, Caterina |
collection | PubMed |
description | BACKGROUND: Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy. OBJECTIVE: To perform a retrospective natural history study of a large cohort of patients with TK2 deficiency. METHODS: The study was conducted by 42 investigators across 31 academic medical centres. RESULTS: We identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion. CONCLUSIONS: In TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder. |
format | Online Article Text |
id | pubmed-6073909 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-60739092018-08-09 Retrospective natural history of thymidine kinase 2 deficiency Garone, Caterina Taylor, Robert W Nascimento, Andrés Poulton, Joanna Fratter, Carl Domínguez-González, Cristina Evans, Julie C Loos, Mariana Isohanni, Pirjo Suomalainen, Anu Ram, Dipak Hughes, M Imelda McFarland, Robert Barca, Emanuele Lopez Gomez, Carlos Jayawant, Sandeep Thomas, Neil D Manzur, Adnan Y Kleinsteuber, Karin Martin, Miguel A Kerr, Timothy Gorman, Grainne S Sommerville, Ewen W Chinnery, Patrick F Hofer, Monika Karch, Christoph Ralph, Jeffrey Cámara, Yolanda Madruga-Garrido, Marcos Domínguez-Carral, Jana Ortez, Carlos Emperador, Sonia Montoya, Julio Chakrapani, Anupam Kriger, Joshua F Schoenaker, Robert Levin, Bruce Thompson, John L P Long, Yuelin Rahman, Shamima Donati, Maria Alice DiMauro, Salvatore Hirano, Michio J Med Genet Phenotypes BACKGROUND: Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy. OBJECTIVE: To perform a retrospective natural history study of a large cohort of patients with TK2 deficiency. METHODS: The study was conducted by 42 investigators across 31 academic medical centres. RESULTS: We identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion. CONCLUSIONS: In TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder. BMJ Publishing Group 2018-08 2018-03-30 /pmc/articles/PMC6073909/ /pubmed/29602790 http://dx.doi.org/10.1136/jmedgenet-2017-105012 Text en © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Phenotypes Garone, Caterina Taylor, Robert W Nascimento, Andrés Poulton, Joanna Fratter, Carl Domínguez-González, Cristina Evans, Julie C Loos, Mariana Isohanni, Pirjo Suomalainen, Anu Ram, Dipak Hughes, M Imelda McFarland, Robert Barca, Emanuele Lopez Gomez, Carlos Jayawant, Sandeep Thomas, Neil D Manzur, Adnan Y Kleinsteuber, Karin Martin, Miguel A Kerr, Timothy Gorman, Grainne S Sommerville, Ewen W Chinnery, Patrick F Hofer, Monika Karch, Christoph Ralph, Jeffrey Cámara, Yolanda Madruga-Garrido, Marcos Domínguez-Carral, Jana Ortez, Carlos Emperador, Sonia Montoya, Julio Chakrapani, Anupam Kriger, Joshua F Schoenaker, Robert Levin, Bruce Thompson, John L P Long, Yuelin Rahman, Shamima Donati, Maria Alice DiMauro, Salvatore Hirano, Michio Retrospective natural history of thymidine kinase 2 deficiency |
title | Retrospective natural history of thymidine kinase 2 deficiency |
title_full | Retrospective natural history of thymidine kinase 2 deficiency |
title_fullStr | Retrospective natural history of thymidine kinase 2 deficiency |
title_full_unstemmed | Retrospective natural history of thymidine kinase 2 deficiency |
title_short | Retrospective natural history of thymidine kinase 2 deficiency |
title_sort | retrospective natural history of thymidine kinase 2 deficiency |
topic | Phenotypes |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073909/ https://www.ncbi.nlm.nih.gov/pubmed/29602790 http://dx.doi.org/10.1136/jmedgenet-2017-105012 |
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