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

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.

SUBMITTER: Hernandez-Voth A

PROVIDER: S-EPMC7703425 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

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

BMJ open respiratory research 20201101 1

<h4>Background</h4>Recessive mutations in the thymidine kinase 2 (<i>TK2)</i> gene cause a rare mitochondrial myopathy, frequently with severe respiratory involvement. Deoxynucleoside therapy is currently under investigation.<h4>Research question</h4>What is the impact of nucleosides in respiratory function in patients with TK2-deficient myopathy?<h4>Study design and methods</h4>Retrospective observational study of patients treated with deoxycytidine and deoxythymidine. Evaluations were performe ...[more]

PMID: 33246973

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Project description:BackgroundThymidine kinase 2 (TK2) catalyses the phosphorylation of deoxythymidine (dThd) and deoxycytidine (dCtd) within mitochondria. TK2 deficiency leads to mtDNA depletion or accumulation of multiple deletions. In patients, TK2 mutations typically manifest as a rapidly progressive myopathy with infantile onset, leading to respiratory insufficiency and encephalopathy in the most severe clinical presentations. TK2-deficient mice develop the most severe form of the disease and die at average postnatal day 16. dThd+dCtd administration delayed disease progression and expanded lifespan of a knockin murine model of the disease.MethodsWe daily administered TK2 knockout mice (Tk2KO) from postnatal day 4 with equimolar doses of dThd+dCtd, dTMP+dCMP, dThd alone or dCtd alone. We monitored body weight and survival and studied different variables at 12 or 29 days of age. We determined metabolite levels in plasma and target tissues, mtDNA copy number in tissues, and the expression and activities of enzymes with a relevant role in mitochondrial dNTP anabolism or catabolism.FindingsdThd+dCtd treatment extended average lifespan of Tk2KO mice from 16 to 34 days, attenuated growth retardation, and rescued mtDNA depletion in skeletal muscle and other target tissues of 12-day-old mice, except in brain. However, the treatment was ineffective in 29-day-old mice that still died prematurely. Bioavailability of dThd and dCtd markedly decreased during mouse development. Activity of enzymes catabolizing dThd and dCtd increased with age in small intestine. Conversely, the activity of the anabolic enzymes decreased in target tissues during mouse development. We also found that administration of dThd alone had the same impact on survival to that of dThd+dCtd, whereas dCtd alone had no influence on lifespan.InterpretationdThd+dCtd treatment recruits alternative cytosolic salvage pathways for dNTP synthesis, suggesting that this therapy would be of benefit for any Tk2 mutation. dThd accounts for the therapeutic effect of the combined treatment in mice. During the first weeks after birth, mice experience marked tissue-specific metabolic regulations and ontogenetic changes in dNTP metabolism-related enzymes that limit therapeutic efficacy to early developmental stages. FUND: This study was funded by grants from the Spanish Ministry of Industry, Economy and Competitiveness, the Spanish Instituto de Salud Carlos III, the Fundación Inocente, Inocente, AFM Téléthon and the Generalitat de Catalunya. The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Dataset Information

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

Publications

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

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