Outcome Measures Capture Progression in Late-Onset TK2d

Late-onset thymidine kinase 2 deficiency (TK2d) can progress for decades, and that relatively slow course creates a challenge for clinical trials: which measures can reliably capture meaningful change over a practical study period? A prospective natural history study published in the Journal of Inherited Metabolic Disease offers new evidence that motor speed, respiratory function, and selected biomarkers may provide a clearer picture than some conventional assessments.

Investigators at Hospital 12 de Octubre in Madrid followed 11 untreated adults with TK2d for up to 24 months. The cohort had a mean age of 50.1 years, with disease onset beginning at a mean age of 27.2 years. Seven patients had progressive myopathy, 2 had chronic progressive external ophthalmoplegia plus, and 2 presented predominantly with exercise intolerance.

The study combined clinic-based motor and respiratory assessments with serum biomarkers, quantitative muscle MRI, and, in 9 patients, remote monitoring through patient-reported outcomes and wearable devices.

Progression Emerges Across Motor and Respiratory Measures
Despite its late onset, TK2d carried substantial respiratory involvement. Mean forced vital capacity (FVC) was 70.4% predicted at baseline, and 9 of 11 patients required noninvasive ventilation. Neurophysiologic testing also identified axonal polyneuropathy in 7 of 10 tested patients, despite an absence of reported sensory symptoms.

Over 24 months, several measures captured deterioration. FVC declined by 9.11% (95% CI, −15.0 to −2.66; p=0.006), while sniff nasal inspiratory pressure declined by 7.55 cmH₂O (95% CI, −13.05 to −2.04; p=0.007).

Motor measures did not perform uniformly. Patients took an average of 6 seconds longer to complete the 100-m run test (100MRT) at 24 months (95% CI, 3.38-8.63; p<0.001). North Star Ambulatory Assessment (NSAA) scores declined by 2.65 points overall, although they were not statistically significant. In patients with progressive myopathy, however, NSAA declined by 12 points (95% CI, −23.0 to −0.7; p=0.037).

By contrast, the 6-minute walk test did not change significantly. The divergence suggests that commonly used functional measures may differ considerably in their sensitivity to progression in TK2d. The investigators identified the 100MRT as particularly promising because it captured longitudinal change across phenotypes, including among patients without overt limb weakness.

Biomarkers Reflect Disease Severity
Growth differentiation factor 15 (GDF15) provided another potential window into disease burden. Levels exceeded the age-adjusted 95th percentile in every patient and correlated with poorer motor and respiratory performance. Higher GDF15 was associated with lower NSAA scores, slower 100MRT performance, and lower FVC.

MRI findings pointed in the same direction. Fatty replacement preferentially affected muscles including the gluteus maximus, sartorius, gracilis, tensor fascia latae, and semitendinosus. Greater gluteus maximus fat fraction correlated strongly with slower 100MRT performance (r=0.883; p=0.0135), supporting quantitative MRI as a potential objective marker, although MRI did not show significant progression during the 1-year imaging follow-up.

Muscle mitochondrial DNA (mtDNA) copy number was also substantially reduced compared with pseudo-controls and correlated with age at initiation of mechanical ventilation.

None of the circulating biomarkers, including GDF15, changed significantly over 24 months. Notably, GDF15 remained persistently elevated in untreated patients despite some fluctuations. The investigators suggest that this pattern may help interpret treatment response, because a reduction following treatment would be more consistent with genuine improvement in oxidative phosphorylation.

Building Endpoints for Future TK2d Trials
The findings come with important constraints. This was a single-center study of only 11 patients, and the heterogeneous phenotypes limit broad conclusions about individual outcome measures. The investigators also acknowledge that remote monitoring was brief and relied on patient-initiated symptom reporting, which was intermittent. They note that the digital measures need validation over a longer period before they can serve as formal outcome measures.

Still, the study provides prospective evidence that late-onset TK2d is measurably progressive over 2 years, particularly in patients with progressive myopathy. Rather than relying on a single functional test, future therapeutic trials may benefit from combining sensitive motor measures such as the 100MRT with respiratory assessments, GDF15 as a marker of disease burden and potential treatment response, and possibly quantitative muscle imaging. Continuous digital monitoring could eventually add a real-world dimension, but longer validation will be needed before it can serve as a formal trial endpoint.

Reference:
Martín-Jimenez P, Bermejo-Guerrero L, Ochoa LE, et al. Exploring outcome measures for mitochondrial myopathies: insights from a longitudinal study on TK2 deficiency. J Inherit Metab Dis. 2026;49:e70147. doi:10.1002/jimd.70147.