Pyrimidine nucleos(t)ide therapy was linked to a statistically significant reduction in the risk of death and meaningful improvements in daily function for people with Thymidine Kinase 2 deficiency (TK2d), an ultra-rare and life-threatening muscle disease, according to a review published recently in Neurology.
In this global review of patient records, none of the 38 treated patients died, compared with 58 percent of 69 untreated patients drawn from published reports. Statistical analyses showed an estimated 85 percent to 95 percent reduction in the risk of death with treatment, results that remained consistent across multiple methods of comparison.
TK2d is caused by harmful changes in a gene needed for healthy mitochondria, the parts of cells that make energy. The disease often begins in infancy or early childhood and can lead to loss of walking, swallowing and independent breathing. No approved therapies for TK2d exist.
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Researchers reviewed medical records from children and adults who received oral pyrimidine nucleosides or nucleotides at doses up to 800 mg per kilogram per day and compared outcomes with those of untreated patients described in the medical literature.
The treated group included 38 patients, about 55 percent male, with a median symptom onset age of 2.46 years. Most began treatment during childhood, though many started years after symptoms first appeared. The median treatment duration was about 1.6 years with a total exposure of 74.3 patient-years. Baseline features such as age at onset and sex were similar between treated and untreated groups, supporting fair comparisons.
Beyond survival, treatment appeared to change the course of the disease. Before therapy, 71 percent of treated patients had lost at least one motor milestone such as sitting, standing or walking. During treatment, no patients lost additional milestones and about 65 percent regained at least one lost ability.
Improvements were most common in head control, sitting and assisted standing. Among patients who needed breathing support, nearly one-quarter used fewer hours after treatment and none needed more. Three of eight patients using feeding tubes were able to stop using them.
“Although these results were overwhelmingly positive and strongly suggest that pyrimidine nucleos(t)ide therapy has a beneficial effect on the survival of patients with TK2d, further studies are needed to delineate the effects of this treatment in different disease presentations,” explained the authors of this study.
Side effects were common but usually mild. About 63 percent of reported treatment-related events were mild, most often diarrhea. Some patients had temporary increases in liver enzymes or muscle enzymes, but these changes were generally small, did not cause symptoms and resolved with dose adjustments or monitoring. Only two patients stopped treatment because of side effects. No serious side effects affecting more than one patient were judged to be caused by the therapy.
For patients and families facing TK2d, these findings suggest a potential option that may extend life, preserve abilities and improve daily care needs. While the study was retrospective and classified as Class III evidence, the size of the survival difference and the functional gains highlight the importance of continued research and access to carefully monitored treatment for this devastating disease.