Deoxynucleoside Therapy for Thymidine Kinase 2–Deficient Myopathy

Abstract

Objective: Thymidine kinase 2, encoded by the nuclear gene TK2, is required for mitochondrial DNA maintenance. Autosomal recessive TK2 mutations cause depletion and multiple deletions of mtDNA that manifest predominantly as a myopathy usually beginning in childhood and progressing relentlessly. We investigated the safety and efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies. Methods: We administered deoxynucleoside monophosphates and deoxynucleoside to 16 TK2-deficient patients under a compassionate use program. Results: In 5 patients with early onset and severe disease, survival and motor functions were better than historically untreated patients. In 11 childhood and adult onset patients, clinical measures stabilized or improved. Three of 8 patients who were nonambulatory at baseline gained the ability to walk on therapy; 4 of 5 patients who required enteric nutrition were able to discontinue feeding tube use; and 1 of 9 patients who required mechanical ventilation became able to breathe View this article online at wileyonlinelibrary.com.

Clinical, pathological and genetic spectrum in 89 cases of mitochondrial progressive external ophthalmoplegia

“…We suggest that reaching a definite genetic diagnosis is essential for patients with mitochondrial PEO since it allows proper genetic counselling and precision medicine in the near future; in this regard, patients with TK2 or POLG mutations could benefit from treatment with nucleosides 18 19…”

Mitochondrial disease in children

“…Some of these approaches are currently in clinical trial [150,151]. Targeted pharmacological approaches include the use of nucleosides to restore mtDNA synthesis in myopathic MDDS caused by TK2 deficiency [152]. Genetic therapies targeting the mtDNA include selective elimination of mutant mtDNA using restriction enzymes delivered as mitoTALENs [153] or zinc finger nucleases [154], or replacing a mitochondrial protein by expressing it from the nucleus, an approach that is currently in clinical trial for LHON [155].…”

Strategies for fighting mitochondrial diseases

“…Primary coenzyme Q deficiency, due to mutations in the genes encoding the enzymes of the CoQ biosynthetic pathway [94], is a striking example of the huge variability of mitochondrial diseases. The clinical outcomes include encephalomyopathy, multisystem disease, cerebellar ataxia, isolated myopathy and nephrotic syndrome [95].…”