UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Retrospective natural history of thymidine kinase 2 deficiency

Garone, C; Taylor, RW; Nascimento, A; Poulton, J; Fratter, C; Dominguez-Gonzalez, C; Evans, JC; ... Hirano, M; + view all (2018) Retrospective natural history of thymidine kinase 2 deficiency. Journal of Medical Genetics , 55 (8) pp. 515-521. 10.1136/jmedgenet-2017-105012. Green open access

[thumbnail of Rahman_Retrospective natural history of thymidine kinase 2 deficiency_VoR2.pdf]
Preview
Text
Rahman_Retrospective natural history of thymidine kinase 2 deficiency_VoR2.pdf - Published Version

Download (1MB) | Preview

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.

Type: Article
Title: Retrospective natural history of thymidine kinase 2 deficiency
Open access status: An open access version is available from UCL Discovery
DOI: 10.1136/jmedgenet-2017-105012
Publisher version: http://dx.doi.org/10.1136/jmedgenet-2017-105012
Language: English
Additional information: © 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 (https://creativecommons.org/licenses/by/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10049663
Downloads since deposit
78Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item