Deoxynucleoside therapy appears to provide meaningful and sustained benefits for adults with late-onset thymidine kinase 2 deficiency (TK2d), improving mobility, muscle function and breathing while remaining generally well tolerated.
Researchers reported in a study published recently in Mitochondrion that patients experienced lasting functional gains during up to 36 months of follow-up, with the largest improvements seen in those who began treatment earlier in the course of the disease.
Although nucleoside therapy has previously shown benefit in children with TK2d, evidence in adults has been limited. This new report evaluated long-term outcomes in adults with genetically confirmed late-onset TK2d treated under compassionate-use protocols in Turkey.
The cohort included six adults, three of whom were women. The average age at symptom onset was 16.5 years, and the average age at treatment initiation was 32.5 years. All patients had symptoms typical of the condition, including drooping eyelids, nasal speech, tongue weakness and progressive weakness affecting the neck and proximal limb muscles. Five patients carried the same pathogenic genetic variant, while one had two different disease-causing variants.
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“Our findings clearly indicate that treatment is effective beyond pediatric-early-onset cases, inducing sustained improvements in ambulation, motor function, respiratory capacity, fatigue, and nutritional status, even when initiated in severely affected adult patients,” stated the study’s authors.
Patients received escalating doses of oral or PEG-administered deoxynucleoside therapy using doxecitine and doxribtimine, eventually reaching up to 800 mg/kg/day. Over a median follow-up of 24 months, functional improvements were substantial. The average distance patients could walk during the 6-minute walk test increased from 152 meters at baseline to 468 meters at 24 months among those with longer follow-up. By 36 months, some patients exceeded 600 meters, reflecting sustained gains in walking ability.
Motor function scores also improved. Researchers measured these changes using the Hammersmith Functional Motor Scale Expanded, a standardized test that evaluates muscle strength and the ability to perform everyday movements such as sitting, standing and walking. The average score rose from 20.5 at baseline to 24.5 after three months and 29 after six months. Among patients followed for three years, the average score reached 58. Improvements were greatest in patients who began treatment earlier.
Respiratory health also stabilized or improved. Forced vital capacity increased from an average of 36% of predicted lung function at baseline to 55.6% at 36 months in patients with complete follow-up. One younger patient was able to stop using nighttime ventilatory support after nearly restoring normal breathing capacity. Fatigue scores decreased by about 30%, and body mass index increased, especially among patients who were underweight.
“Even in advanced stages, therapy can provide stabilization of decline, improvements in fatigue, and potentially meaningful enhancements in quality of life,” explained the authors.
For patients with TK2d, these results suggest that starting therapy as early as possible may slow disease progression and improve daily function, while even people with advanced disease may still experience stabilization or partial improvement.
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