Deoxynucleoside therapy for respiratory involvement in adult patients with thymidine kinase 2-deficient myopathy

Ana Hernandez-Voth, Javier Sayas Catalan, Marta Corral Blanco, Alba Castaño Mendez, Miguel Angel Martin, Carlos De Fuenmayor Fernandez de la Hoz, Victoria Villena Garrido, Cristina Dominguez-Gonzalez, Ana Hernandez-Voth, Javier Sayas Catalan, Marta Corral Blanco, Alba Castaño Mendez, Miguel Angel Martin, Carlos De Fuenmayor Fernandez de la Hoz, Victoria Villena Garrido, Cristina Dominguez-Gonzalez

Abstract

Background: Recessive mutations in the thymidine kinase 2 (TK2) gene cause a rare mitochondrial myopathy, frequently with severe respiratory involvement. Deoxynucleoside therapy is currently under investigation.

Research question: What is the impact of nucleosides in respiratory function in patients with TK2-deficient myopathy?

Study design and methods: Retrospective observational study of patients treated with deoxycytidine and deoxythymidine. Evaluations were performed every 3 to 4 months after treatment during approximately 30 months. Forced vital capacity (FVC), maximuminspiratory and expiratory pressures (MIP/MEP), sniff nasal inspiratory pressure (SNIP), cough peak flow (CPF), arterial blood gas and nocturnal pulse oximeter (SpO2) were collected.

Results: We studied six patients, five of which were women, with a median age at onset of symptoms was 35.8 (range 5 to 60) years old. Patients presented a restrictive ventilatory pattern (median FVC of 50 (26 to 71)%) and severe neuromuscular respiratory weakness (MIP 38 (12 to 47)% and SNIP 14 (8 to 19) cmH2O). Four patients required ventilatory support before starting the treatment. FVC improved by 6%, proportion of sleep time with SpO2 <90% diminished from 14% to 0%, CPF increased by 23%, MEP increased by 73%, production and management of bronchial secretions improved and respiratory infections diminished.

Interpretation: Early detection of respiratory involvement requires an active search, even in asymptomatic patients. The nucleosides therapy may improve respiratory function, and stabilise the loss of respiratory capacity.

Trial registration: ClinicalTrials.gov NCT03845712.

Keywords: non invasive ventilation; rare lung diseases; respiratory muscles.

Conflict of interest statement

Competing interests: AH-V and CD-G are currently involved in a clinical trial (NCT03845712) designed to evaluate safety and efficacy of deoxythymidine/deoxythymidine substrate enhancement therapy in TK2-deficient myopathy patients (Sponsor: Modis Therapeutics, Inc). Nevertheless, we here present retrospective data of our experimentally treated patients, prior to the start of funded research.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Evolution of principal lung function test at baseline and after treatment. FVC, forced vital capacity; MEP, maximumexpiratory pressure; MIP, maximum inspiratory pressure.

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