DOI: 10.1186/s13023-019-1071-zhttps://doi.org10.1186/s13023-019-1071-z
Recent research into the TK2 gene, which plays a critical role in the mitochondrial replication process, has shed light on a rare, late-onset form of mitochondrial myopathy. A team led by Cristina C. Domínguez-González has reported a comprehensive review of 18 clinical cases offering an extensive understanding of the disease’s natural history and prognosis, as well as insights into its therapeutic challenges and potential interventions.
Understanding Mitochondrial Myopathy and TK2 Deficiency
Mitochondrial myopathies are a group of neuromuscular diseases caused by defects in the mitochondria, which generate energy for the cell. The TK2 gene encodes for mitochondrial thymidine kinase, which is essential for the phosphorylation of pyrimidine nucleosides thymidine and deoxycytidine, both of which are needed for mitochondrial DNA (mtDNA) replication. Mutations in the TK2 gene lead to mitochondrial DNA depletion/multiple deletions syndrome. While commonly presenting in early life, there is a less known late-onset form that usually presents after the age of 12, with an average age of onset of 31 years.
The symptoms observed in the cases reviewed by Domínguez-González and colleagues included limb muscle weakness, eyelid ptosis, and respiratory insufficiency. These symptoms progressed to varying degrees of muscle weakness in all patients, with half of them experiencing swallowing difficulties. Respiratory muscle weakness was a universal feature among these patients, leading to the need for non-invasive mechanical ventilation. Notably, the most severely affected muscles, identified through radiological imaging, were the gluteus maximus, semitendinosus, and sartorius.
Muscle biopsies from these patients revealed typical signs of mitochondrial dysfunction alongside dystrophic changes. While multiple mtDNA deletions were observed across all cases, mtDNA depletion was only present in two.
Prognosis and Impact on Quality of Life
Patients with late-onset TK2 deficiency exhibit a distinct and recognizable clinical phenotype, albeit with a poor prognosis due to the high risk of progressive respiratory insufficiency, which was the cause of death in all four deceased patients from the study.
Progress in Therapy and Interventions
The complexities of mtDNA maintenance defects and the search for effective therapies have been a significant focus within the field of rare diseases. Studies have suggested potential treatment pathways, including the administration of deoxynucleosides or the inhibition of their catabolism, to counter the effects of TK2 deficiency.
Nevertheless, at the time of this review, there is no definitive cure for TK2 deficiency and related mitochondrial myopathies. Patients frequently require an interdisciplinary approach for managing symptoms and maintaining the quality of life, including regular monitoring of respiratory function and potential nutritional support for those with swallowing difficulties.
Competing Interests and Ethical Notes
It is important to note that two of the researchers involved in this study, Michio Hirano and Ramon Martí, are co-inventors on patent applications related to deoxynucleoside therapy for TK2 deficiency, with potential financial interests in the commercialization of such technologies. Their affiliations with Meves Pharmaceuticals, the licensee of these patents, are also disclosed.
Conclusions and Future Perspectives
This review significantly contributes to the understanding of late-onset TK2 deficiency, offering valuable insight into its clinical manifestations and the challenges faced in its management. The research lays the groundwork for ongoing efforts to find effective treatments and emphasizes the need for a better understanding of the disease’s natural history.
For healthcare professionals and researchers, this study highlights the importance of recognizing the symptoms and progression of late-onset TK2 deficiency to provide timely and appropriate interventions that could potentially improve the prognosis for affected individuals.
References
1. Domínguez-González, C., et al. (2019). Late-onset thymidine kinase 2 deficiency: a review of 18 cases. Orphanet J Rare Dis, 14(1), 100. doi: 10.1186/s13023-019-1071-z.
2. Viscomi, C., & Zeviani, M. (2017). MtDNA-maintenance defects: syndromes and genes. J Inherit Metab Dis, 40(4), 587–599. doi: 10.1007/s10545-017-0027-5.
3. El-Hattab, A.W., et al. (2017). Mitochondrial DNA maintenance defects. Biochim Biophys Acta, 1863(6), 1539–1555. doi: 10.1016/j.bbadis.2017.02.017.
4. Lopez-Gomez, C., et al. (2017). Deoxycytidine and Deoxythymidine treatment for thymidine kinase 2 deficiency. Ann Neurol, 81(5), 641–652. doi: 10.1002/ana.24922.
5. Saada, A., et al. (2001). Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet, 29(3), 342–344. doi: 10.1038/ng751.
Keywords
1. Late-Onset TK2 Deficiency
2. Mitochondrial Myopathy Treatment
3. TK2 Gene Mutations
4. mtDNA Depletion Syndrome
5. Respiratory Insufficiency Mitochondrial Disease
This comprehensive article not only provides in-depth understanding of this rare genetic disorder but also opens avenues for future research and potential therapeutic interventions targeting mitochondrial DNA maintenance defects.