<i>TK2</i>
            mutation presenting as indolent myopathy

Paradas, Carmen; Ríos, Purificación Gutiérrez; Rivas, Eloy; Carbonell, Pilar; Hirano, Michio; DiMauro, Salvatore

doi:10.1212/wnl.0b013e31827f0ff7

Cited by 28 publications

(24 citation statements)

References 6 publications

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“…1 Mutations in thymidine kinase 2 (TK2; GenBank accession number NM_004614.4) have been reported to cause an early fatal myopathic mtDNA depletion syndrome, 2 culminating in respiratory failure with or without encephalopathy, 3 adult-onset indolent myopathy, 4 or progressive external ophthalmoplegia (PEO) associated with multiple mtDNA deletions. 1 We describe a 74-year-old woman who presented with ptosis, a limbgirdle muscular dystrophy-like phenotype, and progressive respiratory failure due to recessive TK2 mutations and multiple mtDNA deletions in muscle.…”

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confidence: 99%

Late-onset respiratory failure due to TK2 mutations causing multiple mtDNA deletions

et al. 2013

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confidence: 99%

Late-onset respiratory failure due to TK2 mutations causing multiple mtDNA deletions

et al. 2013

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“…4,5,10,12 Five patients (P1-P5) had early onset severe myopathy defined by (1) onset before 24 months; and (2) inability to walk, use of MV, or both within 1 year of onset. [4][5][6][9][10][11][12][13][24][25][26][27][28][29][30] The other 11 patients showed slower progression. Two of these patients were never able to walk, and the other 3 had lost the ability to walk prior to treatment initiation.…”

Section: Patientsmentioning

confidence: 98%

“…5,6,[9][10][11][12][13][24][25][26][27][28][29][30] For other outcomes, 95% confidence intervals (CIs) and associated 2-sided p values were obtained for the mean values of each outcome at every visit and for the change between visits. 5,6,[9][10][11][12][13][24][25][26][27][28][29][30] For other outcomes, 95% confidence intervals (CIs) and associated 2-sided p values were obtained for the mean values of each outcome at every visit and for the change between visits.…”

Section: Statistical Analysesmentioning

confidence: 99%

“…TK2 phosphorylates the nucleosides deoxycytidine (dC) and deoxythymidine (dT) to generate deoxycytidine monophosphate (dCMP) and deoxythymidine monophosphate (dTMP). 3,4,[9][10][11][12][13] The infantile onset form manifests rapidly progressive myopathy weakness with motor regression and respiratory insufficiency occasionally accompanied by central nervous system involvement and virtually uniform early fatality with postonset survival of 1 year. 1,2 Autosomal recessive TK2 mutations cause mtDNA depletion, multiple deletions, or both.…”

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confidence: 99%

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Deoxynucleoside Therapy for Thymidine Kinase 2–Deficient Myopathy

Domínguez‐González

Madruga‐Garrido

Mavillard

et al. 2019

Annals of Neurology

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Objective: Thymidine kinase 2, encoded by the nuclear gene TK2, is required for mitochondrial DNA maintenance. Autosomal recessive TK2 mutations cause depletion and multiple deletions of mtDNA that manifest predominantly as a myopathy usually beginning in childhood and progressing relentlessly. We investigated the safety and efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies. Methods: We administered deoxynucleoside monophosphates and deoxynucleoside to 16 TK2-deficient patients under a compassionate use program. Results: In 5 patients with early onset and severe disease, survival and motor functions were better than historically untreated patients. In 11 childhood and adult onset patients, clinical measures stabilized or improved. Three of 8 patients who were nonambulatory at baseline gained the ability to walk on therapy; 4 of 5 patients who required enteric nutrition were able to discontinue feeding tube use; and 1 of 9 patients who required mechanical ventilation became able to breathe View this article online at wileyonlinelibrary.com.

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“…Rhabdomyolysis has been associated with mutations in CoQ2, mtDNA encoded CIV subunit genes (MT-CO1, MT-CO2, MT-CO3), and tRNA genes (MTT1, MT-TL1 m.3243 A > G MELAS mutation) [96][97][98][99][100][101][102][103][104][105][106][107] . Even late in the disease course, overtly dystrophic features with necrosis, fibrosis and fatty infiltration are not seen, with the exception of TK2-related myopathic form of mtDNA depletion syndrome 108,109 . Variable slow/type I fibre predominance and fast/type II atrophy may be present.…”

Section: Associated Pathological Featuresmentioning

confidence: 99%

Pathology of Adult and Paediatric Mitochondrial Myopathies

Phadke¹

2017

Preprint

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Mitochondria are dynamic organelles ubiquitously present in nucleated eukaryotic cells, subserving multiple metabolic functions, including cellular ATP generation by oxidative phosphorylation (OXPHOS). The OXPHOS machinery comprises five transmembrane respiratory chain enzyme complexes (RC). Defective OXPHOS gives rise to mitochondrial diseases (mtD). The incredible phenotypic and genetic diversity of mtD can be attributed at least in part to the RC dual genetic control (nuclear DNA [nDNA] and mitochondrial DNA [mtDNA]) and the complex interaction between the two genomes. Despite the increasing use of next-generation-sequencing (NGS) and various -omics platforms in unraveling novel mtD genes and pathomechanisms, current clinical practice for investigating mtD essentially involves a multipronged approach including clinical assessment, metabolic screening, imaging, pathological, biochemical and functional testing to guide molecular genetic analysis. This review addresses the broad muscle pathology landscape including genotype-phenotype correlations in adult and paediatric mtD, the role of immunodiagnostics in understanding some of the pathomechanisms underpinning the canonical features of mtD, and recent diagnostic advances in the field.

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TK2 mutation presenting as indolent myopathy

Cited by 28 publications

References 6 publications

Late-onset respiratory failure due to TK2 mutations causing multiple mtDNA deletions

Late-onset respiratory failure due to TK2 mutations causing multiple mtDNA deletions

Deoxynucleoside Therapy for Thymidine Kinase 2–Deficient Myopathy

Pathology of Adult and Paediatric Mitochondrial Myopathies

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