TY - JOUR T1 - Retrospective natural history of thymidine kinase 2 deficiency JF - Journal of Medical Genetics JO - J Med Genet SP - 515 LP - 521 DO - 10.1136/jmedgenet-2017-105012 VL - 55 IS - 8 AU - Caterina Garone AU - Robert W Taylor AU - Andrés Nascimento AU - Joanna Poulton AU - Carl Fratter AU - Cristina Domínguez-González AU - Julie C Evans AU - Mariana Loos AU - Pirjo Isohanni AU - Anu Suomalainen AU - Dipak Ram AU - M Imelda Hughes AU - Robert McFarland AU - Emanuele Barca AU - Carlos Lopez Gomez AU - Sandeep Jayawant AU - Neil D Thomas AU - Adnan Y Manzur AU - Karin Kleinsteuber AU - Miguel A Martin AU - Timothy Kerr AU - Grainne S Gorman AU - Ewen W Sommerville AU - Patrick F Chinnery AU - Monika Hofer AU - Christoph Karch AU - Jeffrey Ralph AU - Yolanda Cámara AU - Marcos Madruga-Garrido AU - Jana Domínguez-Carral AU - Carlos Ortez AU - Sonia Emperador AU - Julio Montoya AU - Anupam Chakrapani AU - Joshua F Kriger AU - Robert Schoenaker AU - Bruce Levin AU - John L P Thompson AU - Yuelin Long AU - Shamima Rahman AU - Maria Alice Donati AU - Salvatore DiMauro AU - Michio Hirano Y1 - 2018/08/01 UR - http://jmg.bmj.com/content/55/8/515.abstract N2 - 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. ER -