Cristina Domínguez-González1,2,3, Marcos Madruga-Garrido4, Fabiola Mavillard5,6, Caterina Garone7, Francisco Javier Aguirre-Rodríguez8, M Alice Donati9, Karin Kleinsteuber10, Itxaso Martí11, Elena Martín-Hernández2,3,12, Juan P Morealejo-Aycinena13, Francina Munell14, Andrés Nascimento3,15, Susana G Kalko3,15, M Dolores Sardina16, Concepcion Álvarez Del Vayo6,17, Olga Serrano18, Yuelin Long19, Yuqi Tu19, Bruce Levin19, John L P Thompson19, Kristen Engelstad20, Jasim Uddin20, Javier Torres-Torronteras3,21, Cecilia Jimenez-Mallebrera3,15, Ramon Martí3,21, Carmen Paradas5,6, Michio Hirano20. 1. Neuromuscular Disorders Unit, Neurology Department, Hospital 12 de Octubre, Madrid, Spain. 2. Instituto de Investigación i + 12, Hospital 12 de Octubre, Madrid, Spain. 3. Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. 4. Neuromuscular Disorders Unit, Pediatric Neurology Department, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío, Consejo Superior de Investigaciones Científicas, University of Seville, Seville, Spain. 5. Neuromuscular Disorders Unit, Neurology Department, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío, Consejo Superior de Investigaciones Científicas, University of Seville, Seville, Spain. 6. Center for Biomedical Network Research on Neurodegenerative Diseases, Instituto de Salud Carlos III, Madrid, Spain. 7. Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, UK. 8. Department of Pediatric Neurology, Torrecardenas Hospital Complex, Almeria, Spain. 9. Metabolic and Neuromuscular Unit, Meyer Hospital, Florence, Italy. 10. Pediatric Neurology Department, Faculty of Medicine, University of Chile, Las Condes Clinic, Santiago, Chile. 11. Pediatric Neurology Department, Donostia University Hospital, San Sebastian, Spain. 12. Hereditary Metabolic and Mitochondrial Disorders Unit, Pediatric Department, October 12 Hospital, Madrid, Spain. 13. Hospital of Guatemala, Guatemala City, Guatemala. 14. Pediatric Department, Vall d'Hebron Hospital, Barcelona, Spain. 15. Neuromuscular Unit, Neurology Department, Sant Joan de Déu Research Institute, Sant Joan de Déu Hospital, Barcelona, Spain. 16. Pediatric Neurology Department, Badajoz Hospital Complex, Badajoz, Spain. 17. Pharmacy Department, Virgin of el Rocío University Hospital, Seville, Spain. 18. Pharmacy Department, October 12 Hospital, Madrid, Spain. 19. Department of Biostatistics, Mailman School of Public Health, Columbia University Medical Center, New York, NY. 20. Neurology Department, H. Houston Merritt Center, Columbia University Medical Center, New York, NY. 21. Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain.
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. 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 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. 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.
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. METHODS: We administered deoxynucleoside monophosphates and deoxynucleoside to 16 TK2-deficientpatients under a compassionate use program. 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 TK2patients treated with deoxynucleoside, 2 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. ANN NEUROL 2019;86:293-303.
Authors: Cristina Domínguez-González; Roberto Fernández-Torrón; Ursula Moore; Carlos Pablo de Fuenmayor-Fernández de la Hoz; Beatriz Vélez-Gómez; Juan Antonio Cabezas; Jorge Alonso-Pérez; Laura González-Mera; Montse Olivé; Jorge García-García; Germán Moris; Juan Carlos León Hernández; Nuria Muelas; Emilia Servian-Morilla; Miguel A Martin; Jordi Díaz-Manera; Carmen Paradas Journal: J Neurol Date: 2022-03-14 Impact factor: 6.682
Authors: Carlos Lopez-Gomez; Henly Hewan; Carlos Sierra; Hasan O Akman; Maria J Sanchez-Quintero; Marti Juanola-Falgarona; Saba Tadesse; Kurenai Tanji; Elisa E Konofagou; Michio Hirano Journal: EBioMedicine Date: 2019-08-02 Impact factor: 11.205
Authors: Sara Laine-Menéndez; Cristina Domínguez-González; Alberto Blázquez; Aitor Delmiro; Inés García-Consuegra; Miguel Fernández-de la Torre; Aurelio Hernández-Laín; Javier Sayas; Miguel Ángel Martín; María Morán Journal: Int J Mol Sci Date: 2021-05-25 Impact factor: 5.923
Authors: Carlos Lopez-Gomez; Maria J Sanchez-Quintero; Eung Jeon Lee; Giulio Kleiner; Saba Tadesse; Jun Xie; Hasan Orhan Akman; Guangping Gao; Michio Hirano Journal: Ann Neurol Date: 2021-08-13 Impact factor: 11.274