Clinical and Genetic Analysis of Patients With TK2 Deficiency.

Fecha de publicación: 01/04/2024 Fecha Ahead of Print: 25/03/2024

Autores de IIS La Fe

Carmen Ayuso Garcia

Autor
Nuria Muelas Gómez

Autor
Teresa Jaijo Sanchís

Autor
Carmen Paradas Lopez

Autor
Rosa María Marti Trotonda

Autor

Participantes ajenos a IIS La Fe

Ceballos F
Serrano-Lorenzo P
Bermejo-Guerrero L
Blázquez A
Quesada-Espinosa JF
Amigo J
Minguez P
García-Arumí E
Nascimento A
Galán-Rodriguez B
Arenas J
Carracedo A
Martín MA
Domínguez-González C
for TK2d Spanish-Group

Grupos

Biomedicina Molecular, Celular y Genómica

Leader

José María Millán Salvador
Patología Neuromuscular y Ataxias

Investigador Principal

Teresa Sevilla Mantecón
Unidad mixta de investigación en enfermedades raras (CIPF)

Leader

José María Millán Salvador

Abstract

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.

Datos de la publicación

ISSN/ISSNe:: 2376-7839, 2376-7839
Tipo:: Article
Páginas:: 200138-200138
DOI:: 10.1212/NXG.0000000000200138
PubMed:: 38544965
Factor de Impacto:: 1,103 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

Ceballos F:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Serrano-Lorenzo P:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Bermejo-Guerrero L:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Blázquez A:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Quesada-Espinosa JF:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Amigo J:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Minguez P:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Ayuso C:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
García-Arumí E:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Muelas N:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Jaijo T:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Nascimento A:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Galán-Rodriguez B:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Paradas C:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Arenas J:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Carracedo A:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Martí R:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Martín MA:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain
Domínguez-González C:: Instituto de Investigación. Neuromuscular Unit (N.M.), Department of Neurology, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe

and Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (C.P.), Madrid, Spain