Introduction
Late-onset thymidine kinase 2 (TK2)-deficient myopathy is a rare and only recently recognised disorder1 (MIM #609560) that is caused by recessive mutations in the TK2 gene.
TK2 deficiency predominantly manifests as a mitochondrial myopathy, with a broad spectrum of severity. It includes both extremely severe and rapidly progressive early-onset forms, with a survival of less than 2 years, and less severe forms with a childhood, late or very late onset, and a slower rate of progression, but with frequent respiratory involvement that shortens the patient’s life expectancy.2–4
A detailed description of the late onset form of the disease has only been reported in a recently published series of 18 cases.3 This review suggests preferential effects on the diaphragm and other respiratory muscles. Indeed, respiratory insufficiency is the most common cause of death. Diaphragmatic weakness was identified in all cases reported in this series, as 66.6% of the patients required mechanical ventilation during the course of the disease. Diaphragmatic weakness was the cause of the first medical consultation in approximately half of the patients. Other symptoms included progressive proximal and distal limb muscle weakness, facial weakness, neck flexor weakness and axial weakness, that was often associated with isolated ptosis or ptosis with chronic external ophthalmoplegia. Neck flexor weakness was more severe than limb weakness.
The respiratory involvement of patients with neuromuscular disorders has generally been evaluated with standard spirometry, using forced vital capacity (FVC) as the main prognostic value. Nevertheless, since FVC can be preserved even with severe respiratory muscle weakness,5 additional respiratory tests may be necessary to improve accuracy and early detection of respiratory insufficiency. In addition, more sensitive tests are needed to detect minor positive changes during treatment, such as maximum inspiratory and expiratory pressures (MIP and MEP), sniff nasal inspiratory pressure (SNIP), cough peak flow (CPF) and nocturnal blood oxygenation (CT90).6–8
A new treatment for TK2 deficiency, based on the administration of oral deoxynucleosides, is currently under investigation. Its efficacy was reported in preclinical studies9–11 and recently in patients treated under a compassionate use/expanded access programme. Without any major side effects, the therapy exerted striking effects on patients with early-onset severe myopathy, produced considerable functional improvements in childhood-onset cases and at least stabilised late-onset cases.12
Here, we describe a series of six adult patients with TK2-deficient myopathy who were treated under a compassionate use protocol with oral deoxythymidine (dT) and deoxycytidine (dC) and evaluated the response to treatment by focussing on the respiratory impairment. We analysed respiratory functional tests and non-invasive mechanical ventilation parameters by comparing the basal records with post-treatment evaluations.