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Deoxynucleoside Therapy for Thymidine Kinase 2-Deficient Myopathy
- Source :
- ANNALS OF NEUROLOGY, r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu, instname, Digital.CSIC. Repositorio Institucional del CSIC, r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu, Ann Neurol
- Publication Year :
- 2019
-
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 the safety and efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies.<br />[Methods] We administered deoxynucleoside monophosphates and deoxynucleoside to 16 TK2‐deficient patients under a compassionate use program.<br />[Results] In 5 patients with early onset and severe disease, survival and motor functions were better than historically untreated patients. In 11 childhood and adult onset patients, clinical measures stabilized or improved. Three of 8 patients who were nonambulatory at baseline gained the 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 breathe independently. In motor functional scales, improvements were observed in the 6‐minute walk test performance in 7 of 8 subjects, Egen Klassifikation in 2 of 3, and North Star Ambulatory Assessment in all 5 tested. Baseline elevated serum growth differentiation factor 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, 2 adults developed elevated liver enzymes that normalized following discontinuation of therapy.<br />[Interpretation] This open‐label study indicates favorable side effect profiles and clinical efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies for TK2 deficiency. ANN NEUROL 2019;86:293–303<br />This work was supported in part by grants from the Spanish Carlos III Health Institute (PMP15/00025 for C.P., F.Ma., and R.M.; PI16/00579 and CP09/00011 for C.J.‐M.), Muscular Dystrophy Association (577391), Arturo Estopinan TK2 Research Fund, Generalitat de Catalunya PERIS program (SLT002/16/00370 for J.T‐T.), and European Regional Development Fund.
- Subjects :
- 0301 basic medicine
Adult
Compassionate Use Trials
Male
medicine.medical_specialty
Neurology
Side effect
medicine.medical_treatment
Deoxyribonucleosides
Walk Test
Gastroenterology
Thymidine Kinase
Article
03 medical and health sciences
0302 clinical medicine
Muscular Diseases
Internal medicine
tk2, myopathy, nucleosides, therapy
medicine
Humans
Myopathy
Child
Feeding tube
Mechanical ventilation
business.industry
Discontinuation
Diarrhea
030104 developmental biology
Child, Preschool
Female
Neurology (clinical)
GDF15
medicine.symptom
business
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 03645134
- Database :
- OpenAIRE
- Journal :
- ANNALS OF NEUROLOGY, r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu, instname, Digital.CSIC. Repositorio Institucional del CSIC, r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu, Ann Neurol
- Accession number :
- edsair.doi.dedup.....cba628f1aa18bfad416c5dc37015aa45