Clinical and Genetic Analysis of Patients With TK2 Deficiency

Ceballos, Francisco C.; Serrano Lorenzo, Pablo; Bermejo-Guerrero, Laura; Blázquez, Alberto; Quesada-Espinosa, Juan F.; Amigo, Jorge; Mínguez, Pablo; Ayuso García, María del Carmen Tomasa; García Arumí, Elena; Muelas, Nuria; Jaijo, Teresa; Nascimento, Andrés; Galán-Rodriguez, Beatriz; Paradas, Carmen; Arenas, Joaquín; Carracedo, Ángel; Martí, Ramón; Martín, Miguel A.; Domínguez González, Cristina; TK2d Spanish-Group

Clinical and Genetic Analysis of Patients With TK2 Deficiency

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 myo...

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Autores:	Ceballos, Francisco C., Serrano Lorenzo, Pablo, Bermejo-Guerrero, Laura, Blázquez, Alberto, Quesada-Espinosa, Juan F., Amigo, Jorge, Mínguez, Pablo, Ayuso García, María del Carmen Tomasa, García Arumí, Elena, Muelas, Nuria, Jaijo, Teresa, Nascimento, Andrés, Galán-Rodriguez, Beatriz, Paradas, Carmen, Arenas, Joaquín, Carracedo, Ángel, Martí, Ramón, Martín, Miguel A., Domínguez González, Cristina, TK2d Spanish-Group
Tipo de recurso:	artículo
Fecha de publicación:	2025
País:	España
Institución:	Universidad Autónoma de Madrid
Repositorio:	Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:	inglés
OAI Identifier:	oai:dnet:biblosearchi::cb630241accdeb0660e03390785fdfc8
Acceso en línea:	https://hdl.handle.net/10486/761800 https://dx.doi.org/10.1212/NXG.0000000000200138
Access Level:	acceso abierto
Palabra clave:	Thymidine kinase 2 deficiency (TK2d) Mitochondrial DNA depletion Thymidine kinase 2 deficiency (TK2d) Mitochondrial DNA depletion Late-onset myopathy Genetic variants Nucleoside therapy Medicina

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spelling	Clinical and Genetic Analysis of Patients With TK2 DeficiencyCeballos, Francisco C.Serrano Lorenzo, PabloBermejo-Guerrero, LauraBlázquez, AlbertoQuesada-Espinosa, Juan F.Amigo, JorgeMínguez, PabloAyuso García, María del Carmen TomasaGarcía Arumí, ElenaMuelas, NuriaJaijo, TeresaNascimento, AndrésGalán-Rodriguez, BeatrizParadas, CarmenArenas, JoaquínCarracedo, ÁngelMartí, RamónMartín, Miguel A.Domínguez González, CristinaTK2d Spanish-GroupThymidine kinase 2 deficiency (TK2d)Mitochondrial DNA depletionThymidine kinase 2 deficiency (TK2d) Mitochondrial DNA depletion Late-onset myopathyGenetic variantsNucleoside therapyMedicinaObjectives 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 variantThis 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.MLippincott, Williams & WilkinsFacultad de MedicinaDepartamento de MedicinaGobierno de EspañaInstituto de Salud Carlos III20252025-03-25research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10486/761800https://dx.doi.org/10.1212/NXG.000000000020013838544965reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:dnet:biblosearchi::cb630241accdeb0660e03390785fdfc82026-06-23T12:46:27Z
dc.title.none.fl_str_mv	Clinical and Genetic Analysis of Patients With TK2 Deficiency
title	Clinical and Genetic Analysis of Patients With TK2 Deficiency
spellingShingle	Clinical and Genetic Analysis of Patients With TK2 Deficiency Ceballos, Francisco C. Thymidine kinase 2 deficiency (TK2d) Mitochondrial DNA depletion Thymidine kinase 2 deficiency (TK2d) Mitochondrial DNA depletion Late-onset myopathy Genetic variants Nucleoside therapy Medicina
title_short	Clinical and Genetic Analysis of Patients With TK2 Deficiency
title_full	Clinical and Genetic Analysis of Patients With TK2 Deficiency
title_fullStr	Clinical and Genetic Analysis of Patients With TK2 Deficiency
title_full_unstemmed	Clinical and Genetic Analysis of Patients With TK2 Deficiency
title_sort	Clinical and Genetic Analysis of Patients With TK2 Deficiency
dc.creator.none.fl_str_mv	Ceballos, Francisco C. Serrano Lorenzo, Pablo Bermejo-Guerrero, Laura Blázquez, Alberto Quesada-Espinosa, Juan F. Amigo, Jorge Mínguez, Pablo Ayuso García, María del Carmen Tomasa García Arumí, Elena Muelas, Nuria Jaijo, Teresa Nascimento, Andrés Galán-Rodriguez, Beatriz Paradas, Carmen Arenas, Joaquín Carracedo, Ángel Martí, Ramón Martín, Miguel A. Domínguez González, Cristina TK2d Spanish-Group
author	Ceballos, Francisco C.
author_facet	Ceballos, Francisco C. Serrano Lorenzo, Pablo Bermejo-Guerrero, Laura Blázquez, Alberto Quesada-Espinosa, Juan F. Amigo, Jorge Mínguez, Pablo Ayuso García, María del Carmen Tomasa García Arumí, Elena Muelas, Nuria Jaijo, Teresa Nascimento, Andrés Galán-Rodriguez, Beatriz Paradas, Carmen Arenas, Joaquín Carracedo, Ángel Martí, Ramón Martín, Miguel A. Domínguez González, Cristina TK2d Spanish-Group
author_role	author
author2	Serrano Lorenzo, Pablo Bermejo-Guerrero, Laura Blázquez, Alberto Quesada-Espinosa, Juan F. Amigo, Jorge Mínguez, Pablo Ayuso García, María del Carmen Tomasa García Arumí, Elena Muelas, Nuria Jaijo, Teresa Nascimento, Andrés Galán-Rodriguez, Beatriz Paradas, Carmen Arenas, Joaquín Carracedo, Ángel Martí, Ramón Martín, Miguel A. Domínguez González, Cristina TK2d Spanish-Group
author2_role	author author author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Facultad de Medicina Departamento de Medicina Gobierno de España Instituto de Salud Carlos III
dc.subject.none.fl_str_mv	Thymidine kinase 2 deficiency (TK2d) Mitochondrial DNA depletion Thymidine kinase 2 deficiency (TK2d) Mitochondrial DNA depletion Late-onset myopathy Genetic variants Nucleoside therapy Medicina
topic	Thymidine kinase 2 deficiency (TK2d) Mitochondrial DNA depletion Thymidine kinase 2 deficiency (TK2d) Mitochondrial DNA depletion Late-onset myopathy Genetic variants Nucleoside therapy Medicina
description	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
publishDate	2025
dc.date.none.fl_str_mv	2025 2025-03-25
dc.type.none.fl_str_mv	research article http://purl.org/coar/resource_type/c_2df8fbb1 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	https://hdl.handle.net/10486/761800 https://dx.doi.org/10.1212/NXG.0000000000200138 38544965
url	https://hdl.handle.net/10486/761800 https://dx.doi.org/10.1212/NXG.0000000000200138
identifier_str_mv	38544965
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	Lippincott, Williams & Wilkins
publisher.none.fl_str_mv	Lippincott, Williams & Wilkins
dc.source.none.fl_str_mv	reponame:Biblos-e Archivo. Repositorio Institucional de la UAM instname:Universidad Autónoma de Madrid
instname_str	Universidad Autónoma de Madrid
reponame_str	Biblos-e Archivo. Repositorio Institucional de la UAM
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Clinical and Genetic Analysis of Patients With TK2 Deficiency

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