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Abstract
GDF-15 is a biomarker for mitochondrial diseases. We investigated the application of GDF-15 as biomarker of disease severity and response to deoxynucleoside treatment in patients with thymidine kinase 2 (TK2) deficiency and compared it to FGF-21. GDF-15 and FGF-21 were measured in serum from 24 patients with TK2 deficiency treated 1–49 months with oral deoxynucleosides. Patients were grouped according to age at treatment and biomarkers were analyzed at baseline and various time points after treatment initiation. GDF-15 was elevated on average 30-fold in children and 6-fold in adults before the start of treatment. There was a significant correlation between basal GDF-15 and severity based on pretreatment distance walked (6MWT) and weight (BMI). During treatment, GDF-15 significantly declined, and the decrease was accompanied by relevant clinical improvements. The decline was greater in the paediatric group, which included the most severe patients and showed the greatest clinical benefit, than in the adult patients. The decline of FGF-21 was less prominent and consistent. GDF-15 is a potential biomarker of severity and of therapeutic response for patients with TK2 deficiency. In addition, we show evidence of clinical benefit of deoxynucleoside treatment, especially when treatment is initiated at an early age.
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1 Neurology Department, Neuromuscular Disorders Unit, 12 de Octubre Hospital, Madrid, Spain (GRID:grid.144756.5) (ISNI:0000 0001 1945 5329); Research Institute i+12, 12 de Octubre Hospital, Madrid, Spain (GRID:grid.144756.5) (ISNI:0000 0001 1945 5329); Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427)
2 Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Neuromuscular Unit, Neuropediatrics Department, Barcelona, Spain (GRID:grid.411160.3) (ISNI:0000 0001 0663 8628)
3 University of Seville, Neuromuscular Disorders Unit, Neuropediatrics Department, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Consejo Superior de Investigaciones Científicas, Seville, Spain (GRID:grid.9224.d) (ISNI:0000 0001 2168 1229)
4 Hospital Universitario Donostia, Neuropediatrics Department, San Sebastian, Spain (GRID:grid.414651.3)
5 University of Seville, Neuromuscular Disorders Unit, Neurology Department, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Consejo Superior de Investigaciones Científicas, Seville, Spain (GRID:grid.9224.d) (ISNI:0000 0001 2168 1229); Biomedical Network Research Centre on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427)
6 Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Neuromuscular Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain (GRID:grid.413396.a) (ISNI:0000 0004 1768 8905)
7 Columbia University Medical Center, Department of Neurology, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675)
8 Neuromuscular Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain (GRID:grid.413396.a) (ISNI:0000 0004 1768 8905)
9 Statistics Unit, Fundación Sant Joan de Déu, Barcelona, Spain (GRID:grid.428876.7)
10 Moebius Research Ltd, Systems Biomedicine, London, UK (GRID:grid.428876.7)
11 Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Universitat Autònoma de Barcelona, Research group on Neuromuscular and Mitochondrial Diseases, Vall d’Hebron Institut de Recerca, Barcelona, Spain (GRID:grid.7080.f)
12 Research Institute i+12, 12 de Octubre Hospital, Madrid, Spain (GRID:grid.144756.5) (ISNI:0000 0001 1945 5329); Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427)
13 Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Universidad de Zaragoza, Instituto de Investigación Sanitaria de Aragón (IIS-Aragón), Departmento de Bioquímica y Biología Molecular, Zaragoza, Spain (GRID:grid.11205.37) (ISNI:0000 0001 2152 8769)
14 University of Barcelona, Biochemistry and Molecular Biology Department, Institute of Biomedicine (IBUB), Institut de Recerca Sant Joan de Déu, Barcelona, Spain (GRID:grid.5841.8) (ISNI:0000 0004 1937 0247); Biomedical Network Research Centre on Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427)
15 Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Clinical Biochemistry Department, Barcelona, Spain (GRID:grid.411160.3) (ISNI:0000 0001 0663 8628)
16 Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Neuromuscular Unit, Neuropediatrics Department, Barcelona, Spain (GRID:grid.411160.3) (ISNI:0000 0001 0663 8628)
17 Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Neuromuscular Unit, Neuropediatrics Department, Barcelona, Spain (GRID:grid.411160.3) (ISNI:0000 0001 0663 8628); University of Barcelona, Genetics Department, Faculty of Biology, Barcelona, Spain (GRID:grid.5841.8) (ISNI:0000 0004 1937 0247)