Metrics of progression and prognosis in untreated adults with thymidine kinase 2 deficiency: An observational study

Domínguez‐González, Cristina; Hernández-Voth, Ana; Hoz, Carlos de Fuenmayor-Fernández de Pablo la; Bermejo-Guerrero, Laura; Morís, Germán; García-García, Jorge; Muelas, Nuria; Hernández, Juan Carlos León; Rabasa, M.; Lora, David; Blázquez, Alberto; Arenas, Joaquín; Martín, Miguel

doi:10.1016/j.nmd.2022.07.399

Cited by 3 publications

(4 citation statements)

References 49 publications

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“…Of note, the variants (p.Asp177Tyr), (p.Pro227Serfs*9), and (p.Leu14Argfs*41) had been previously first reported by Spanish research groups in patients included in this cohort. 19 , 21 …”

Section: Resultsmentioning

confidence: 99%

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Clinical and Genetic Analysis of Patients With TK2 Deficiency

Ceballos,

Serrano-Lorenzo,

Bermejo-Guerrero

et al. 2024

Neurol Genet

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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.

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“…Of note, the variants (p.Asp177Tyr), (p.Pro227Serfs*9), and (p.Leu14Argfs*41) had been previously first reported by Spanish research groups in patients included in this cohort. 19 , 21 …”

Section: Resultsmentioning

confidence: 99%

“…Partial clinical data from several patients were previously published elsewhere. 16 , 19 , 21 , 28 - 31 …”

Section: Methodsmentioning

confidence: 99%

Clinical and Genetic Analysis of Patients With TK2 Deficiency

Ceballos,

Serrano-Lorenzo,

Bermejo-Guerrero

et al. 2024

Neurol Genet

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“…However, normal CK levels do not exclude a muscle disorder, especially in the case of mitochondrial myopathies, which can present with normal or only slightly elevated CK levels. An exception are the mtDNA depletion/multiple deletions syndromes with muscle involvement, such as TK2 or POLG -related disorders where CK can be very high [ 15 ]. Conversely, mildly altered CK levels do not always indicate a primary muscle disease and may be present in patients with fatigue of another origin (e.g., sleep apnea-hypopnea syndrome [ 16 ], toxic myopathies, etc.)…”

Section: Discussionmentioning

confidence: 99%

“…Identifying the underlying genetic alteration in PMM sometimes requires the analysis of mtDNA extracted from the skeletal muscle to detect large-scale single deletions, somatic variants, or mtDNA variants with low mutation loads in other tissues, such as blood or uroepithelial cells [ 20 ]. On other occasions, the study of muscle mtDNA allows the detection of multiple deletions that guides the diagnosis towards disorders of mtDNA maintenance, which frequently present with muscle symptoms [ 15 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

Serum GDF-15 Levels Accurately Differentiate Patients with Primary Mitochondrial Myopathy, Manifesting with Exercise Intolerance and Fatigue, from Patients with Chronic Fatigue Syndrome

Bermejo-Guerrero

Hoz

Guerrero-Molina

et al. 2023

JCM

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Primary mitochondrial myopathies (PMM) are a clinically and genetically highly heterogeneous group that, in some cases, may manifest exclusively as fatigue and exercise intolerance, with minimal or no signs on examination. On these occasions, the symptoms can be confused with the much more common chronic fatigue syndrome (CFS). Nonetheless, other possibilities must be excluded for the final diagnosis of CFS, with PMM being one of the primary differential diagnoses. For this reason, many patients with CFS undergo extensive studies, including extensive genetic testing and muscle biopsies, to rule out this possibility. This study evaluated the diagnostic performance of growth differentiation factor-15 (GDF-15) as a potential biomarker to distinguish which patient with chronic fatigue has a mitochondrial disorder. We studied 34 adult patients with symptoms of fatigue and exercise intolerance with a definitive diagnosis of PMM (7), CFS (22), or other non-mitochondrial disorders (5). The results indicate that GDF-15 can accurately discriminate between patients with PMM and CFS (AUC = 0.95) and between PMM and patients with fatigue due to other non-mitochondrial disorders (AUC = 0.94). Therefore, GDF-15 emerges as a promising biomarker to select which patients with fatigue should undergo further studies to exclude mitochondrial disease.

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