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.
- metabolic disorders
- muscle disease
- neuromuscular disease
- clinical genetics
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Contributors CG and MIH designed the project, carried out systematic review analysis, collected the data, performed statistical analysis and drafted the manuscript. CG and MIH created a network for the study of TK2-deficient patients in the USA. EB, SDM and CLG contributed to the diagnosis with clinical and laboratory investigations. RWT created a network for the study of TK2 patients from UK and JP, CF, JCE, DR, MIH, RMcF, SJ, NDT, AYM, TK, AC, GSG, EWS, PFC, MH and SR contributed to the diagnosis with clinical and laboratory investigations. AN created a network for TK2-deficient patients in Spain and CD-G, CK, JR, YC, MM-G, JD-C, CO, SE, JM and CH contributed to the diagnosis with clinical and laboratory investigations. ML contributed to the diagnosis of TK2-deficient patients in Argentina. KK contributed to the diagnosis of the Chilean patient. AS and PI contributed to the diagnosis of patients in Finland. MAD contributed to diagnosis of the Italian patient. JFK, YL and JLPT contributed to the statistical analyses. All of the authors revised and approved the manuscript.
Funding This work was supported by research grants from NIH (P01 HD080642) and U54 NS078059 from NINDS, NICHD, ODS and the National Center for Advancing Translational Science (NCATS), the Muscular Dystrophy Association (MIH) and the Associazione Malattie Metaboliche Congenite eredit arie (AMMeC) (CG) as well as by the Arturo Estopinan TK2 Research Fund (MIH) and the Marriott Mitochondrial Disease Clinic Research Fund (MMDCRF) (MIH). RWT is funded by a Wellcome Trust Strategic Award (096919/Z/11/Z), the MRC Centre for Neuromuscular Diseases (G0601943), the Lily Foundation and the UK NHS Highly Specialised ‘Rare Mitochondrial Disorders of Adults and Children’ Service. JP is funded by a Medical Research Council Project Grant (MR/J010448/1), Wellcome Trust Project Grant (0948685/Z/10/Z), and UK NHS Highly Specialised ‘Rare Mitochondrial Disorders of Adults and Children’ Service. SR acknowledges support from a Great Ormond Street Hospital Children’s Charity Research Leadership award (V1260) and the Lily Foundation. PFC is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2), the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the Medical Research Council (UK) Centre for Translational Muscle Disease research (G0601943), EU FP7 TIRCON and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. During this study, AS has received support from Sigrid Jusélius Foundation, Jane and Aatos Erkko Foundation, Academy of Finland, European Research Council and University of Helsinki. MAM has received funding from the Spanish Instituto de Salud Carlos III (ISCIII) (FIS-PI12/01683). JM has received funding from the ISCIII (FIS-PI14/00005), Departamento de Ciencia, Tecnología y Universidad del Gobierno de Aragón (Grupos Consolidados B33), FEDER Funding Program from the European Union, and CIBERER, an initiative of the ISCIII. AN has received funding from ‘Biobanc de l’Hospital Infantil Sant Joan de Déu per a la Investigació’ integrated in the Spanish Biobank Network of ISCIII for the sample and data procurement. YC has received funding from the Spanish Ministry of Economy and Competitiveness (BFU2014-52618-R) and AFM-Téléthon (19965).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Columbia University Medical Center.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All of the data collected and used in this study are included in the manuscript.
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