Retrospective natural history of thymidine kinase 2 deficiency

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http://hdl.handle.net/10138/243584

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Garone , C , Taylor , R W , Nascimento , A , Poulton , J , Fratter , C , Dominguez-Gonzalez , C , Evans , J C , Loos , M , Isohanni , P , Suomalainen , A , Ram , D , Hughes , M I , McFarland , R , Barca , E , Gomez , C L , Jayawant , S , Thomas , N D , Manzur , A Y , Kleinsteuber , K , Martin , M A , Kerr , T , Gorman , G S , Sommerville , E W , Chinnery , P F , Hofer , M , Karch , C , Ralph , J , Camara , Y , Madruga-Garrido , M , Dominguez-Carral , J , Ortez , C , Emperador , S , Montoya , J , Chakrapani , A , Kriger , J F , Schoenaker , R , Levin , B , Thompson , J L P , Long , Y , Rahman , S , Donati , M A , DiMauro , S & Hirano , M 2018 , ' Retrospective natural history of thymidine kinase 2 deficiency ' , Journal of Medical Genetics , vol. 55 , no. 8 , pp. 515-521 . https://doi.org/10.1136/jmedgenet-2017-105012

Title: Retrospective natural history of thymidine kinase 2 deficiency
Author: Garone, Caterina; Taylor, Robert W.; Nascimento, Andres; Poulton, Joanna; Fratter, Carl; Dominguez-Gonzalez, Cristina; Evans, Julie C.; Loos, Mariana; Isohanni, Pirjo; Suomalainen, Anu; Ram, Dipak; Hughes, M. Imelda; McFarland, Robert; Barca, Emanuele; Gomez, Carlos Lopez; 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; Camara, Yolanda; Madruga-Garrido, Marcos; Dominguez-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
Contributor organization: Doctoral Programme in Clinical Research
Research Programs Unit
Anu Wartiovaara / Principal Investigator
Research Programme for Molecular Neurology
Children's Hospital
Clinicum
Lastenneurologian yksikkö
University of Helsinki
Doctoral Programme Brain & Mind
Neurologian yksikkö
Neuroscience Center
HUS Children and Adolescents
Date: 2018-08
Language: eng
Number of pages: 7
Belongs to series: Journal of Medical Genetics
ISSN: 0022-2593
DOI: https://doi.org/10.1136/jmedgenet-2017-105012
URI: http://hdl.handle.net/10138/243584
Abstract: 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.
Subject: MITOCHONDRIAL-DNA DEPLETION
SPINAL MUSCULAR-ATROPHY
TK2 GENE
MTDNA DEPLETION
MYOPATHIC FORM
MUTATIONS
PATIENT
DELETIONS
SPECTRUM
DEFECT
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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