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J Med Genet. 2018 Aug;55(8):515-521. doi: 10.1136/jmedgenet-2017-105012. Epub 2018 Mar 30.

Retrospective natural history of thymidine kinase 2 deficiency.

Author information

1
Department of Neurology, Columbia University Medical Center, New York City, New York, USA.
2
MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, UK.
3
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
4
Neuromuscular Unit, Hospital Universitario 12 de Octubre, Madrid, Spain.
5
Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK.
6
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
7
Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
8
Instituto de Investigación, Hospital Universitario 12 de Octubre, Madrid, Spain.
9
Neurology Department, Hospital de Pediatría 'Prof. Dr JP Garrahan', Buenos Aires, Argentina.
10
Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
11
Department of Child Neurology, Children's Hospital, University of Helsinki, Helsinki University Hospital, Helsinki, Finland.
12
Neuroscience Center, University of Helsinki, Helsinki, Finland.
13
Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
14
Department of Paediatric Neurology, Royal Manchester Children's Hospital, Manchester, UK.
15
UOC Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
16
Paediatric Neurology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
17
Paediatric Neurology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
18
Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
19
Pediatric Neurology, Faculty of Medicine, Universidad de Chile, Clínica Las Condes, Santiago, Chile.
20
Paediatric Neurology, St George's University Hospitals NHS Foundation Trust, London, UK.
21
Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
22
Department of Neuropathology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
23
Department of Neurology, University of California San Francisco, San Francisco, California, USA.
24
Research Group on Neuromuscular and Mitochondrial Disorders, Vall d'Hebron Institut de Recerca, Barcelona, Spain.
25
Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain.
26
Sección de Neuropediatría, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, Seville, Spain.
27
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, CIBERER, ISCIII, Universitat de Barcelona, Barcelona, Spain.
28
Department of Biochemistry and Molecular Biology, University of Zaragoza-CIBERER-Instituto de investigaciones Sanitarias de Aragón, Zaragoza, Spain.
29
Metabolic Unit, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
30
Department of Biostatistics, Mailman School of Public Health, Columbia University Medical Center, New York City, New York, USA.
31
Mitochondrial Research Group, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK.
32
Metabolic and Neuromuscular Unit, Meyer Hospital, Florence, Italy.

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.

KEYWORDS:

clinical genetics; metabolic disorders; muscle disease; neuromuscular disease

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