Journal
JOURNAL OF MEDICAL GENETICS
Volume 55, Issue 8, Pages 515-521Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jmedgenet-2017-105012
Keywords
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Categories
Funding
- NIH [P01 HD080642]
- NINDS, NICHD, ODS [U54 NS078059]
- National Center for Advancing Translational Science (NCATS)
- Muscular Dystrophy Association (MIH)
- Associarione Maalattie Metaboliche Congenite eredit arie (AMMeC)
- Arturo Estopinan TK2 Research Fund
- Marriott Mitochondrial Disease Clinic Research Fund (MMDCRF)
- Wellcome Trust Strategic Award [096919/Z/11/Z]
- MRC Centre for Nleuromuscular Diseases [G0601943]
- Lily Foundation
- UK NHS Highly Specialised 'Rare Mitochondrial Disorders of Adults and Children' Service
- Medical Research Council Project Grant [MR/101044811]
- Wellcome Trust Project Grant [0948685/Z/10/Z]
- Great Ormond Street Hospital Children's Charity Research Leadership award [V1260]
- Wellcome Trust Senior Fellow in Clinical Science [101876/Z/13/Z]
- K NIHR Senior Investigator
- Medical Research Council Mitochondrial Biology Unit [MC_UP_150112]
- Wellcome Trust Centre for Mitochondrial Research [096919Z/11/Z]
- Medical Research Council (UK) Centre for Translational Muscle Disease research [G0601943]
- EU FP7 TIRCON
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust
- University of Cambridge
- Sigrid Juselius Foundation
- Jane and Aatos Erkko Foundation
- Academy of Finland
- European Research Council
- University of Helsinki
- Spanish Instituto Salud Carlos III (ISCIII) [FIS-P112/01683]
- ISCIII [FIS-P114/00005]
- Departamento de Ciencia, Tecnologia y Universidad del Gobierno de Aragon (Grupos Consolidados B33)
- European Union
- European Union, and CIBERER
- ISCIII
- 'Biobanc de l'Hospital Infantil Sant Joan de Deu per a la Investigacia' integrated in the Spanish Biobank Network of ISCIII
- Spanish Ministry of Economy and Competitiveness [BFU2014-52618-R]
- AFM-Telethon [19965]
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [P01HD080642] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [U54NS078059] Funding Source: NIH RePORTER
- MRC [G0200335, G0800674] Funding Source: UKRI
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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.
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