Publication: Deoxynucleoside Therapy for Thymidine Kinase 2-Deficient Myopathy.
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Identifiers
Date
2019-07-11
Authors
Dominguez-Gonzalez, Cristina
Madruga-Garrido, Marcos
Mavillard, Fabiola
Garone, Caterina
Aguirre-Rodriguez, Francisco Javier
Donati, M Alice
Kleinsteuber, Karin
Marti, Itxaso
Martin-Hernandez, Elena
Morealejo-Aycinena, Juan P
Advisors
Journal Title
Journal ISSN
Volume Title
Publisher
John Wiley & Sons, Inc.
Abstract
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. We administered deoxynucleoside monophosphates and deoxynucleoside to 16 TK2-deficient patients under a compassionate use program. 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. 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.
Description
MeSH Terms
Adult
Child, Preschool
Compassionate Use Trials
Female
Humans
Muscular Diseases
Child, Preschool
Compassionate Use Trials
Female
Humans
Muscular Diseases
DeCS Terms
Pacientes
ADN Mitocondrial
Factor 15 de diferenciación de crecimiento
Respiración artificial
Enzimas
Dosificación
Mutación
Enfermedades musculares
Enfermedad
Diarrea
Timidina Quinasa
Hígado
ADN Mitocondrial
Factor 15 de diferenciación de crecimiento
Respiración artificial
Enzimas
Dosificación
Mutación
Enfermedades musculares
Enfermedad
Diarrea
Timidina Quinasa
Hígado
CIE Terms
Keywords
Child, Deoxyribonucleosides, Male, Thymidine Kinase, Walk Test
Citation
Domínguez-González C, Madruga-Garrido M, Mavillard F, Garone C, Aguirre-Rodríguez FJ, Donati MA, et al. Deoxynucleoside Therapy for Thymidine Kinase 2-Deficient Myopathy. Ann Neurol. 2019 Aug;86(2):293-303.