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

ABSTRACT: Mutations in nuclear genes involved in the maintenance of mitochondrial DNA (mtDNA) are associated with an extensive spectrum of clinical phenotypes, manifesting as either mtDNA depletion syndromes or multiple mtDNA deletion disorders.(1.)

SUBMITTER: Alston CL

PROVIDER: S-EPMC3854830 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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

Alston Charlotte L CL Schaefer Andrew M AM Raman Pravrutha P Solaroli Nicola N Krishnan Kim J KJ Blakely Emma L EL He Langping L Craig Kate K Roberts Mark M Vyas Aashish A Nixon John J Horvath Rita R Turnbull Douglass M DM Karlsson Anna A Gorman Grainne S GS Taylor Robert W RW

Neurology 20131106 23

Mutations in nuclear genes involved in the maintenance of mitochondrial DNA (mtDNA) are associated with an extensive spectrum of clinical phenotypes, manifesting as either mtDNA depletion syndromes or multiple mtDNA deletion disorders.(1.) ...[more]

PMID: 24198295

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Muscle MRI characteristic pattern for late-onset TK2 deficiency diagnosis.

Project description:Background and objectiveTK2 deficiency (TK2d) is a rare mitochondrial disorder that manifests predominantly as a progressive myopathy with a broad spectrum of severity and age of onset. The rate of progression is variable, and the prognosis is poor due to early and severe respiratory involvement. Early and accurate diagnosis is particularly important since a specific treatment is under development. This study aims to evaluate the diagnostic value of lower limb muscle MRI in adult patients with TK2d.MethodsWe studied a cohort of 45 genetically confirmed patients with mitochondrial myopathy (16 with mutations in TK2, 9 with mutations in other nuclear genes involved in mitochondrial DNA [mtDNA] synthesis or maintenance, 10 with single mtDNA deletions, and 10 with point mtDNA mutations) to analyze the imaging pattern of fat replacement in lower limb muscles. We compared the identified pattern in patients with TK2d with the MRI pattern of other non-mitochondrial genetic myopathies that share similar clinical characteristics.ResultsWe found a consistent lower limb muscle MRI pattern in patients with TK2d characterized by involvement of the gluteus maximus, gastrocnemius medialis, and sartorius muscles. The identified pattern in TK2 patients differs from the known radiological involvement of other resembling muscle dystrophies that share clinical features.ConclusionsBy analyzing the largest cohort of muscle MRI from patients with mitochondrial myopathies studied to date, we identified a characteristic and specific radiological pattern of muscle involvement in patients with TK2d that could be useful to speed up its diagnosis.

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MPV17 Mutations Causing Adult-Onset Multisystemic Disorder With Multiple Mitochondrial DNA Deletions.

Project description:OBJECTIVE To identify the cause of an adult-onset multisystemic disease with multiple deletions of mitochondrial DNA (mtDNA). DESIGN Case report. SETTING University hospitals. PATIENT A 65-year-old man with axonal sensorimotor peripheral neuropathy, ptosis, ophthalmoparesis, diabetes mellitus, exercise intolerance, steatohepatopathy, depression, parkinsonism, and gastrointestinal dysmotility. RESULTS Skeletal muscle biopsy revealed ragged-red and cytochrome- c oxidase-deficient fibers, and Southern blot analysis showed multiple mtDNA deletions. No deletions were detected in fibroblasts, and the results of quantitative polymerase chain reaction showed that the amount of mtDNA was normal in both muscle and fibroblasts. Exome sequencing using a mitochondrial library revealed compound heterozygous MPV17 mutations (p.LysMet88-89MetLeu and p.Leu143*), a novel cause of mtDNA multiple deletions. CONCLUSIONS In addition to causing juvenile-onset disorders with mtDNA depletion, MPV17 mutations can cause adult-onset multisystemic disease with multiple mtDNA deletions.

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Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice.

Project description:Defects of mitochondrial DNA (mtDNA) maintenance have recently been associated with inherited neurodegenerative and muscle diseases and the aging process. Twinkle is a nuclear-encoded mtDNA helicase, dominant mutations of which cause adult-onset progressive external ophthalmoplegia (PEO) with multiple mtDNA deletions. We have generated transgenic mice expressing mouse Twinkle with PEO patient mutations. Multiple mtDNA deletions accumulate in the tissues of these mice, resulting in progressive respiratory dysfunction and chronic late-onset mitochondrial disease starting at 1 year of age. The muscles of the mice faithfully replicate all of the key histological, genetic, and biochemical features of PEO patients. Furthermore, the mice have progressive deficiency of cytochrome c oxidase in distinct neuronal populations. These "deletor" mice do not, however, show premature aging, indicating that subtle accumulation of mtDNA deletions and progressive respiratory chain dysfunction are not sufficient to accelerate aging. This model is a valuable tool for therapy development and testing for adult-onset mitochondrial disorders.

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Novel TK2 mutations as a cause of delayed muscle maturation in mtDNA depletion syndrome.

Project description:Recessive mutations in TK2 cause a severe mitochondrial DNA depletion syndrome (MDS),(1) characterized by severe myopathy from early infancy. Recent reports have suggested a wider clinical spectrum including encephalomyopathic form.(1,2) We report a patient with infantile-onset fatal encephalomyopathy presenting with extreme muscle fiber immaturity.

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Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions.

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Targeted transgenic overexpression of mitochondrial thymidine kinase (TK2) alters mitochondrial DNA (mtDNA) and mitochondrial polypeptide abundance: transgenic TK2, mtDNA, and antiretrovirals.

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Late-onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1.

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RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions.

Project description: Not available

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Childhood-Onset Generalized Dystonia Due to NDUFA9 Gene Mutation: An Expansion of Mutations Causing Leigh's Syndrome.

Project description: Not available

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Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice.

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