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oai:recercat.cat:11351/112662025-10-24T10:39:19Zcom_2072_378070com_2072_378040col_2072_378092

Clinical and Genetic Analysis of Patients With TK2 Deficiency Ceballos, Francisco Serrano-Lorenzo, Pablo Bermejo-Guerrero, Laura Blázquez, Alberto Quesada-Espinosa, Juan Francisco Amigo, Jorge Marti, Ramon Garcia-Arumi, Elena Institut Català de la Salut [Ceballos F] Spanish Network for Biomedical Research in Rare Diseases (CIBERER), Madrid, Spain. [Serrano-Lorenzo P, Blázque A] Spanish Network for Biomedical Research in Rare Diseases (CIBERER), Madrid, Spain. Mitochondrial and Neuromuscular Research Group ‘12 de Octubre’, Hospital Research Institute (imas12), Madrid, Spain. [Bermejo-Guerrero L] Neurology Department, Neuromuscular Disorders Unit, Hospital 12 de Octubre, Madrid, Spain. [Quesada-Espinosa JF] Genetics Department, Hospital Universitario 12 de Octubre, Madrid, Spain. [Amigo J] Spanish Network for Biomedical Research in Rare Diseases (CIBERER), Madrid, Spain. Fundación Pública Galega de Medicina Xenomica (FPGMX), Spain. Genetic’s Group, Santiago de Compostela Research Institute (IDIS), Spain. Medicine Xenómica’s Group, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), Santiago de Compostela University (USC), Spain. [García-Arumí E] Spanish Network for Biomedical Research in Rare Diseases (CIBERER), Madrid, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Grup de Recerca de Patologia Neuromuscular i Mitocondrial, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Martí R] Spanish Network for Biomedical Research in Rare Diseases (CIBERER), Madrid, Spain. Grup de Recerca de Patologia Neuromuscular i Mitocondrial, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain Vall d'Hebron Barcelona Hospital Campus Mitocondris - Malalties - Aspectes genètics Músculs - Malalties - Aspectes genètics Timidina ADN mitocondrial CHEMICALS AND DRUGS::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::DNA::DNA, Circular::DNA, Mitochondrial DISEASES::Musculoskeletal Diseases::Muscular Diseases::Mitochondrial Myopathies CHEMICALS AND DRUGS::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Thymidine Kinase Other subheadings::Other subheadings::Other subheadings::Other subheadings::/deficiency COMPUESTOS QUÍMICOS Y DROGAS::nucleótidos y nucleósidos de ácidos nucleicos::ácidos nucleicos::ADN::ADN circular::ADN mitocondrial ENFERMEDADES::enfermedades musculoesqueléticas::enfermedades musculares::miopatías mitocondriales COMPUESTOS QUÍMICOS Y DROGAS::enzimas y coenzimas::enzimas::transferasas::fosfotransferasas::fosfotransferasas (grupo alcohol aceptor)::timidina cinasa Otros calificadores::Otros calificadores::Otros calificadores::Otros calificadores::/deficiencia Thymidine kinase 2 deficiency; Mitochondrial DNA; Underdiagnosis Deficiència de timidina cinasa 2; ADN mitocondrial; Infradiagnòstic Deficiencia de timidina quinasa 2; ADN mitocondrial; Infradiagnóstico Objectives Thymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive disorder that stems from a perturbation of the mitochondrial DNA maintenance. Nucleoside treatment has recently shown promise as a disease-modifying therapy. TK2d was initially associated with rapidly progressive fatal myopathy in children featuring mitochondrial DNA depletion. Subsequently, less severe variants of the disease were described, with onset of symptoms during adolescence or adulthood and associated with the presence of multiple mtDNA deletions. These less severe phenotypes have been reported in only 15% of the approximately 120 patients described worldwide. However, some reports suggest that these juvenile and adult-onset presentations may be more common. The objective of this study was to describe the clinical phenotype in a sample of patients from Spain. Methods This study includes 53 patients harboring biallelic TK2 pathogenic variants, compiling data retrospectively from 7 Spanish centers. We analyzed allele frequency, investigated the most recent common ancestor of core haplotypes, and used the Runs of Homozygosity approach to investigate variant coalescence. Results Symptom onset distribution revealed that 32 patients (60%) experienced symptoms beyond 12 years of age. Approximately 30% of patients died of respiratory insufficiency, while 56% of surviving patients needed mechanical ventilation. Genetic analysis identified 16 distinct variants in TK2. Two variants, p.Lys202del and p.Thr108Met, exhibited significantly higher prevalence in the Spanish population than that reported in gnomAD database (86-fold and 13-fold, respectively). These variants are estimated to have originated approximately 16.8 generations ago for p.Thr108Met and 95.2 generations ago for p.Lys202del within the Spanish population, with the increase in frequency attributed to various forms of inbreeding. In late-onset cases, 46.9% carried the p.Lys202del variant. Discussion The higher frequency of TK2d in Spain can be partially attributed to the increased prevalence of 2 variants and consanguinity. Notably, in 60% of the cohort, the disease was late-onset, emphasizing the potential underdiagnosis of this subgroup of patients in other regions. Raising awareness of this potentially treatable disorder is of utmost importance because early interventions can significantly affect the quality of life and survival of affected individuals. This research was funded by the Instituto de Salud Carlos III, (ISCIII) and the Ministerio de Ciencia e Innovación (Madrid, Spain; cofunded by European Regional Development Fund “A way to make Europe”), grant number PI22/01587, to C.D.-G., PI19/01772 to E.G.-A. and PI21/00381 to M.A.M. 2024-04-02T10:28:13Z 2024-04-02T10:28:13Z 2024-03-25 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Ceballos F, Serrano-Lorenzo P, Bermejo-Guerrero L, Blázquez A, Quesada-Espinosa JF, Amigo J, et al. Clinical and Genetic Analysis of Patients With TK2 Deficiency. Neurol Genet. 2024 Mar 25;10(2):e200138. 2376-7839 https://hdl.handle.net/11351/11266 10.1212/NXG.0000000000200138 38544965 http://hdl.handle.net/11351/11266 eng Neurology Genetics;10(2) https://doi.org/10.1212/NXG.0000000000200138 info:eu-repo/grantAgreement/ES/PE2017-2020/PI19%2F01772 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess application/pdf Wolters Kluwer Health Scientia