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 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 historical untreated patients. In 11 childhood‐ and adult‐onset patients, clinical measures stabilized or improved. Three of 8 patients who were non‐ambulatory at baseline gained 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 breath independently. In motor functional scales, improvements were observed in the: 6‐minute walk test performance in 7 of 8 subjects, Egen Klassification in 2 of 3, and North Star Ambulatory Assessment in all 5 tested. Baseline elevated GDF‐15 levels decreased with treatment in all 7 patients tested. A side‐effect observed in 8 of the 16 patients was dose‐dependent diarrhea, which did not require withdrawal of treatment. Among 12 other TK2 patients treated with deoxynucleoside, two adults developed elevated liver enzymes that normalized following discontinuation of therapy.
Interpretation
This open‐label study indicates favorable side‐effect profiles and clinical efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies for TK2 deficiency.
This article is protected by copyright. All rights reserved.
, admin,
No comments:
Post a Comment