Muscle MRI characteristic pattern for late-onset TK2 deficiency diagnosis

Domínguez‐González, Cristina; Fernández‐Torrón, Roberto; Moore, Ursula; Hoz, Carlos de Fuenmayor-Fernández de Pablo la; Vélez-Gómez, Beatriz; Cabezas, Juan Antonio; Alonso‐Pérez, Jorge; González-Mera, Laura; Olivé, Montse; García-García, Jorge; Morís, Germán; Hernández, Juan Carlos León; Muelas, Nuria; Servián‐Morilla, Emilia; Martín, Miguel; Díaz-Manera, Jordi; Paradas, Carmen

doi:10.1007/s00415-021-10957-0

Cited by 6 publications

(4 citation statements)

References 38 publications

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“…The less severe forms begin in childhood through adulthood and exhibit slower progression; bulbar, proximal limb, and respiratory weakness can be severe, causing the inability to walk or breathe independently. Early and accurate diagnosis is critical since a specific treatment is under development ( Dominguez-Gonzalez et al, 2019 ; Dominguez-Gonzalez et al, 2022 ). Two affected siblings from the late-onset group, patient 1, young adult, and patient 2, adolescent, with severe neuromuscular weakness, including diaphragmatic weakness, requiring respiratory support, have, with previously reported homozygous c.323C>T/p.…”

Section: Discussionmentioning

confidence: 99%

Clinical and bi-genomic DNA findings of patients suspected to have mitochondrial diseases

et al. 2023

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Background: Mitochondrial diseases are the most common group of inherited metabolic disorders, causing difficulties in definite diagnosis due to clinical and genetic heterogeneity. Clinical components are predominantly associated with pathogenic variants shown in nuclear or mitochondrial genomes that affect vital respiratory chain function. The development of high-throughput sequencing technologies has accelerated the elucidation of the genetic etiology of many genetic diseases that previously remained undiagnosed.Methods: Thirty affected patients from 24 unrelated families with clinical, radiological, biochemical, and histopathological evaluations considered for mitochondrial diseases were investigated. DNA isolated from the peripheral blood samples of probands was sequenced for nuclear exome and mitochondrial DNA (mtDNA) analyses. MtDNA sequencing was also performed from the muscle biopsy material in one patient. For segregation, Sanger sequencing is performed for pathogenic alterations in five other affected family members and healthy parents.Results: Exome sequencing revealed 14 different pathogenic variants in nine genes encoding mitochondrial function peptides (AARS2, EARS2, ECHS1, FBXL4, MICOS13, NDUFAF6, OXCT1, POLG, and TK2) in 12 patients from nine families and four variants in genes encoding important for muscle structure (CAPN3, DYSF, and TCAP) in six patients from four families. Three probands carried pathogenic mtDNA variations in two genes (MT-ATP6 and MT-TL1). Nine variants in five genes are reported for the first time with disease association: (AARS2: c.277C>T/p.(R93*), c.845C>G/p.(S282C); EARS2: c.319C>T/p.(R107C), c.1283delC/p.(P428Lfs*); ECHS1: c.161G>A/p.(R54His); c.202G>A/p.(E68Lys); NDUFAF6: c.479delA/p.(N162Ifs*27); and OXCT1: c.1370C>T/p.(T457I), c.1173-139G>T/p.(?).Conclusion: Bi-genomic DNA sequencing clarified genetic etiology in 67% (16/24) of the families. Diagnostic utility by mtDNA sequencing in 13% (3/24) and exome sequencing in 54% (13/24) of the families prioritized searching for nuclear genome pathologies for the first-tier test. Weakness and muscle wasting observed in 17% (4/24) of the families underlined that limb-girdle muscular dystrophy, similar to mitochondrial myopathy, is an essential point for differential diagnosis. The correct diagnosis is crucial for comprehensive genetic counseling of families. Also, it contributes to making treatment-helpful referrals, such as ensuring early access to medication for patients with mutations in the TK2 gene.

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Section: Discussionmentioning

confidence: 99%

Clinical and bi-genomic DNA findings of patients suspected to have mitochondrial diseases

et al. 2023

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“…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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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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“…A recent cohort by Domínguez-González et al demonstrated a characteristic lower limb muscle MRI pattern that can differentiate the condition from other myopathies with similar clinical features [77].…”

Section: Thymidine Kinase 2 (Tk2)mentioning

confidence: 99%

Mitochondrial Chronic Progressive External Ophthalmoplegia

Ali,

Esmaeil,

Behbehani

2024

Brain Sciences

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(1) Background: Chronic progressive external ophthalmoplegia (CPEO) is a rare disorder that can be at the forefront of several mitochondrial diseases. This review overviews mitochondrial CPEO encephalomyopathies to enhance accurate recognition and diagnosis for proper management. (2) Methods: This study is conducted based on publications and guidelines obtained by selective review in PubMed. Randomized, double-blind, placebo-controlled trials, Cochrane reviews, and literature meta-analyses were particularly sought. (3) Discussion: CPEO is a common presentation of mitochondrial encephalomyopathies, which can result from alterations in mitochondrial or nuclear DNA. Genetic sequencing is the gold standard for diagnosing mitochondrial encephalomyopathies, preceded by non-invasive tests such as fibroblast growth factor-21 and growth differentiation factor-15. More invasive options include a muscle biopsy, which can be carried out after uncertain diagnostic testing. No definitive treatment option is available for mitochondrial diseases, and management is mainly focused on lifestyle risk modification and supplementation to reduce mitochondrial load and symptomatic relief, such as ptosis repair in the case of CPEO. Nevertheless, various clinical trials and endeavors are still at large for achieving beneficial therapeutic outcomes for mitochondrial encephalomyopathies. (4) Key Messages: Understanding the varying presentations and genetic aspects of mitochondrial CPEO is crucial for accurate diagnosis and management.

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Muscle MRI characteristic pattern for late-onset TK2 deficiency diagnosis

Cited by 6 publications

References 38 publications

Clinical and bi-genomic DNA findings of patients suspected to have mitochondrial diseases

Clinical and bi-genomic DNA findings of patients suspected to have mitochondrial diseases

Clinical and Genetic Analysis of Patients With TK2 Deficiency

Mitochondrial Chronic Progressive External Ophthalmoplegia

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