Late-onset TK2 deficiency in adults: Long-term clinical outcomes of deoxynucleoside therapy

Hacer Durmus; Asuman Gedikbaşı; Serdar Ceylaner; Arman Çakar; Sezan Mergen; Esen Kıyan; Yesim Gülşen Parman

doi:10.1016/j.mito.2026.102138

Late-onset TK2 deficiency in adults: Long-term clinical outcomes of deoxynucleoside therapy

Mitochondrion. 2026 Jul:89:102138. doi: 10.1016/j.mito.2026.102138. Epub 2026 Feb 28.

Authors

Hacer Durmus¹, Asuman Gedikbaşı², Serdar Ceylaner³, Arman Çakar⁴, Sezan Mergen⁴, Esen Kıyan⁵, Yesim Gülşen Parman⁴

Affiliations

¹ Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. Electronic address: hacer.durmus@istanbul.edu.tr.
² Institute of Child Health, Department of Pediatric Basic Sciences, Division of Medical Genetics, Istanbul University, Turkey.
³ Intergen Genetic Center, Ankara, Turkey.
⁴ Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
⁵ Department of Pulmonology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

PMID: 41771327
DOI: 10.1016/j.mito.2026.102138

Abstract

Objective: To evaluate the long-term efficacy and safety of deoxynucleoside therapy in adult patients with late-onset thymidine kinase 2 deficiency (TK2d).

Background: TK2d is a mitochondrial myopathy causing progressive weakness, respiratory insufficiency, and early mortality. While nucleoside supplementation benefits pediatric cases, evidence in adults remains limited.

Methods: Six genetically confirmed adults with TK2d were treated under compassionate-use protocols in Turkey, receiving escalating doses of oral or PEG-administered Doxecitine and Doxribtimine up to 800 mg/kg/day. Functional and clinical outcomes included the 6-minute walk test (6MWT), Hammersmith Functional Motor Scale Expanded (HFMSE), forced vital capacity (FVC), Fatigue Severity Scale (FSS), and body mass index (BMI).

Results: Over a median follow-up of 24 (range 6-36) months, therapy was associated with sustained functional and respiratory improvements. Mean 6MWT increased from 152 m at baseline to 468 m at 24 months and exceeded 600 m in patients with 36-month data. The mean HFMSE increased from 20.5 at baseline to 24.5 at 3 months, 29 at 6 months. Patients with the longest follow-up reached a mean HFMSE of 58 at 36 months. FVC, which had declined before treatment, stabilized or improved in all patients (mean increase from 36% to 55.6% at 36 months). The youngest patient achieved near-normal respiratory function. Fatigue severity decreased by ∼ 30%, and BMI improved notably in underweight individuals. Treatment was generally well tolerated; transient liver enzyme elevations and mild gastrointestinal side effects resolved spontaneously.

Conclusions: Deoxynucleoside therapy appears effective and well tolerated in adults with TK2d, producing sustained functional and respiratory gains. Early treatment initiation is crucial to maximize benefit; though partial improvements may occur even in advanced disease.

Keywords: Deoxynucleoside Therapy; Late-onset; TK2 deficiency.

MeSH terms

Adult
Compassionate Use Trials
Female
Humans
Male
Middle Aged
Mitochondrial Myopathies* / drug therapy
Thymidine Kinase* / deficiency
Thymidine Kinase* / genetics
Treatment Outcome

Substances

thymidine kinase 2
Thymidine Kinase