Phenotypic spectrum and clinical course of single large-scale mitochondrial DNA deletion disease in the paediatric population: a multicentre study

BackgroundLarge-scale mitochondrial DNA deletions (LMD) are a common genetic cause of mitochondrial disease and give rise to a wide range of clinical features. Lack of longitudinal data means the natural history remains unclear. This study was undertaken to describe the clinical spectrum in a large cohort of patients with paediatric disease onset.MethodsA retrospective multicentre study was performed in patients with clinical onset <16 years of age, diagnosed and followed in seven European mitochondrial disease centres.ResultsA total of 80 patients were included. The average age at disease onset and at last examination was 10 and 31 years, respectively. The median time from disease onset to death was 11.5 years. Pearson syndrome was present in 21%, Kearns-Sayre syndrome spectrum disorder in 50% and progressive external ophthalmoplegia in 29% of patients. Haematological abnormalities were the hallmark of the disease in preschool children, while the most common presentations in older patients were ptosis and external ophthalmoplegia. Skeletal muscle involvement was found in 65% and exercise intolerance in 25% of the patients. Central nervous system involvement was frequent, with variable presence of ataxia (40%), cognitive involvement (36%) and stroke-like episodes (9%). Other common features were pigmentary retinopathy (46%), short stature (42%), hearing impairment (39%), cardiac disease (39%), diabetes mellitus (25%) and renal disease (19%).ConclusionOur study provides new insights into the phenotypic spectrum of childhood-onset, LMD-associated syndromes. We found a wider spectrum of more prevalent multisystem involvement compared with previous studies, most likely related to a longer time of follow-up.

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Multiple sclerosis and chronic progressive external ophthalmoplegia associated with a large scale mitochondrial DNA single deletion

Journal of Neurology ◽

10.1007/s00415-016-8120-5 ◽

2016 ◽

Vol 263 (7) ◽

pp. 1449-1451 ◽

Cited By ~ 2

Author(s):

Lorenzo Gaetani ◽

Andrea Mignarri ◽

Maria Di Gregorio ◽

Paola Sarchielli ◽

Alessandro Malandrini ◽

...

Keyword(s):

Multiple Sclerosis ◽

Mitochondrial Dna ◽

Large Scale ◽

Progressive External Ophthalmoplegia ◽

Chronic Progressive External Ophthalmoplegia ◽

Single Deletion

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Kearns-Sayre Syndrome: A Rare Mitochondrial Disorder

Journal of Medicine ◽

10.3329/jom.v19i1.34847 ◽

2017 ◽

Vol 19 (1) ◽

pp. 66-69

Author(s):

Quazi Tarikul Islam ◽

Homayra Tahseen Hossain ◽

Md Abul Kashem Khandaker ◽

HAM Nazmul Ahasan ◽

Maksudul Majumder ◽

...

Keyword(s):

Mitochondrial Disease ◽

Mitochondrial Disorder ◽

Progressive External Ophthalmoplegia ◽

Endocrine Disorders ◽

Chronic Progressive External Ophthalmoplegia ◽

Diagnostic Investigation ◽

Kearns Sayre Syndrome ◽

First Case ◽

Wide Range ◽

Clinical Background

Mitochondrial disease, once thought to be a rare clinical entity, is now recognized as an important cause of a wide range of neurologic, muscle, cardiac and endocrine disorders. Kearns Sayre syndrome is a rare mitochondrial disease, involving deletion of mitochondrial DNA. This syndrome ischaracterized by progressive external ophthalmoplegia (PEO), retinitis pigmentosa and an onset before the age of 20 years. First case was reported in 1958. We are reporting a case with chronic progressive external ophthalmoplegia, bilateral partial ptosis with onset at 10 years of age. He also had features of myopathy and neuropathy without any fatigable weakness. Our diagnosis is mostly based on clinical background and by exclusion of other common disorders, as definitive diagnostic investigation genetic testing due to unavailability so was not done.J MEDICINE Jan 2018; 19 (1) : 66-69

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The Phenotypic Spectrum of 47 Czech Patients with Single, Large-Scale Mitochondrial DNA Deletions

Brain Sciences ◽

10.3390/brainsci10110766 ◽

2020 ◽

Vol 10 (11) ◽

pp. 766 ◽

Cited By ~ 1

Author(s):

Nicole Anteneová ◽

Silvie Kelifová ◽

Hana Kolářová ◽

Alžběta Vondráčková ◽

Iveta Tóthová ◽

...

Keyword(s):

Mitochondrial Dna ◽

Epithelial Cells ◽

Large Scale ◽

Childhood Mortality ◽

Progressive External Ophthalmoplegia ◽

Buccal Swab ◽

Pcr Screening ◽

Pearson Syndrome ◽

Significant Difference ◽

Dna Deletions

Background: In this retrospective study, we analysed clinical, biochemical and molecular genetic data of 47 Czech patients with Single, Large-Scale Mitochondrial DNA Deletions (SLSMD). Methods: The diagnosis was based on the long-range PCR (LX-PCR) screening of mtDNA isolated from muscle biopsy in 15 patients, and from the buccal swab, urinary epithelial cells and blood in 32 patients. Results: A total of 57% patients manifested before the age of 16. We did not find any significant difference between paediatric and adult manifestation in either the proportion of patients that would develop extraocular symptoms, or the timespan of its progression. The survival rate in patients with Pearson Syndrome reached 60%. Altogether, five patients manifested with atypical phenotype not fulfilling the latest criteria for SLSMD. No correlation was found between the disease severity and all heteroplasmy levels, lengths of the deletion and respiratory chain activities in muscle. Conclusions: Paediatric manifestation of Progressive External Ophthalmoplegia (PEO) is not associated with a higher risk of multisystemic involvement. Contrary to PEO and Kearns-Sayre Syndrome Spectrum, Pearson Syndrome still contributes to a significant childhood mortality. SLSMD should be considered even in cases with atypical presentation. To successfully identify carriers of SLSMD, a repeated combined analysis of buccal swab and urinary epithelial cells is needed.

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Mitochondrial DNA with a Large-Scale Deletion Causes Two Distinct Mitochondrial Disease Phenotypes in Mice

G3 Genes|Genome|Genetics ◽

10.1534/g3.113.007245 ◽

2013 ◽

Vol 3 (9) ◽

pp. 1545-1552 ◽

Cited By ~ 6

Author(s):

Shun Katada ◽

Takayuki Mito ◽

Emi Ogasawara ◽

Jun-Ichi Hayashi ◽

Kazuto Nakada

Keyword(s):

Mitochondrial Dna ◽

Mitochondrial Disease ◽

Large Scale ◽

Disease Phenotypes

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Deep sequencing of mitochondrial DNA and characterization of a novel POLG mutation in a patient with arPEO

Neurology Genetics ◽

10.1212/nxg.0000000000000391 ◽

2020 ◽

Vol 6 (1) ◽

pp. e391

Author(s):

Carola Hedberg-Oldfors ◽

Bertil Macao ◽

Swaraj Basu ◽

Christopher Lindberg ◽

Bradley Peter ◽

...

Keyword(s):

Mitochondrial Dna ◽

Muscle Biopsy ◽

Deep Sequencing ◽

Large Scale ◽

Biochemical Characterization ◽

Late Onset ◽

Novel Mutation ◽

Progressive External Ophthalmoplegia ◽

Oxidase Deficiency

ObjectiveTo determine the pathogenicity of a novel POLG mutation in a man with late-onset autosomal recessive progressive external ophthalmoplegia using clinical, molecular, and biochemical analyses.MethodsA multipronged approach with detailed neurologic examinations, muscle biopsy analyses, molecular genetic studies, and in vitro biochemical characterization.ResultsThe patient had slowly progressive bilateral ptosis and severely reduced horizontal and vertical gaze. Muscle biopsy showed slight variability in muscle fiber size, scattered ragged red fibers, and partial cytochrome c oxidase deficiency. Biallelic mutations were identified in the POLG gene encoding the catalytic A subunit of POLγ. One allele carried a novel mutation in the exonuclease domain (c.590T>C; p.F197S), and the other had a previously characterized null mutation in the polymerase domain (c.2740A>C; p.T914P). Biochemical characterization revealed that the novel F197S mutant protein had reduced exonuclease and DNA polymerase activities and confirmed that T914P was inactive. By deep sequencing of mitochondrial DNA (mtDNA) extracted from muscle, multiple large-scale rearrangements were mapped and quantified.ConclusionsThe patient's phenotype was caused by biallelic POLG mutations, resulting in one inactive POLγA protein (T914P) and one with decreased polymerase and exonuclease activity (F197S). The reduction in polymerase activity explains the presence of multiple pathogenic large-scale deletions in the patient's mtDNA.

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Suppression of Mitochondrial DNA Instability of Autosomal Dominant Forms of Progressive External Ophthalmoplegia-Associated ANT1 Mutations in Podospora anserina

Genetics ◽

10.1534/genetics.109.107813 ◽

2009 ◽

Vol 183 (3) ◽

pp. 861-871 ◽

Cited By ~ 9

Author(s):

Riyad El-Khoury ◽

Annie Sainsard-Chanet

Keyword(s):

Mitochondrial Dna ◽

Membrane Potential ◽

Large Scale ◽

Autosomal Dominant ◽

Adenine Nucleotide ◽

Podospora Anserina ◽

Progressive External Ophthalmoplegia ◽

Inner Membrane ◽

Mitochondrial Inner Membrane ◽

Mtdna Deletions

Maintenance and expression of mitochondrial DNA (mtDNA) are essential for the cell and the organism. In humans, several mutations in the adenine nucleotide translocase gene ANT1 are associated with multiple mtDNA deletions and autosomal dominant forms of progressive external ophthalmoplegia (adPEO). The mechanisms underlying the mtDNA instability are still obscure. A current hypothesis proposes that these pathogenic mutations primarily uncouple the mitochondrial inner membrane, which secondarily causes mtDNA instability. Here we show that the three adPEO-associated mutations equivalent to A114P, L98P, and V289M introduced into the Podospora anserina ANT1 ortholog dominantly cause severe growth defects, decreased reactive oxygen species production (ROS), decreased mitochondrial inner membrane potential (Δψ), and accumulation of large-scale mtDNA deletions leading to premature death. Interestingly, we show that, at least for the adPEO-type M106P and A121P mutant alleles, the associated mtDNA instability cannot be attributed only to a reduced membrane potential or to an increased ROS level since it can be suppressed without restoration of the Δψ or modification of the ROS production. Suppression of mtDNA instability due to the M106P and A121P mutations was obtained by an allele of the rmp1 gene involved in nucleo-mitochondrial cross- talk and also by an allele of the AS1 gene encoding a cytosolic ribosomal protein. In contrast, the mtDNA instability caused by the S296M mutation was not suppressed by these alleles.

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Generation of somatic mitochondrial DNA-replaced cells for mitochondrial dysfunction treatment

Scientific Reports ◽

10.1038/s41598-021-90316-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hideki Maeda ◽

Daisuke Kami ◽

Ryotaro Maeda ◽

Akira Shikuma ◽

Satoshi Gojo

Keyword(s):

Mitochondrial Dna ◽

Mitochondrial Dysfunction ◽

Mitochondrial Disease ◽

Respiratory Function ◽

Disease Patient ◽

Mitochondrial Diseases ◽

Wild Type ◽

Mutant Genotype ◽

Isolated Mitochondria ◽

Wide Range

AbstractMitochondrial diseases currently have no cure regardless of whether the cause is a nuclear or mitochondrial genome mutation. Mitochondrial dysfunction notably affects a wide range of disorders in aged individuals, including neurodegenerative diseases, cancers, and even senescence. Here, we present a procedure to generate mitochondrial DNA-replaced somatic cells with a combination of a temporal reduction in endogenous mitochondrial DNA and coincubation with exogeneous isolated mitochondria. Heteroplasmy in mitochondrial disease patient-derived fibroblasts in which the mutant genotype was dominant over the wild-type genotype was reversed. Mitochondrial disease patient-derived fibroblasts regained respiratory function and showed lifespan extension. Mitochondrial membranous components were utilized as a vehicle to deliver the genetic materials into endogenous mitochondria-like horizontal genetic transfer in prokaryotes. Mitochondrial DNA-replaced cells could be a resource for transplantation to treat maternal inherited mitochondrial diseases.

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Mitochondrial DNA Density Homeostasis Accounts for the Threshold Effect in Human Mitochondrial Disease

10.1101/078519 ◽

2016 ◽

Author(s):

Juvid Aryaman ◽

Iain G. Johnston ◽

Nick S. Jones

Keyword(s):

Mathematical Model ◽

Mitochondrial Dna ◽

Mitochondrial Dysfunction ◽

Cell Volume ◽

Mitochondrial Disease ◽

Large Scale ◽

Threshold Effect ◽

Progressive Increase ◽

Theoretical Understanding ◽

Demand Reduction

AbstractMitochondrial dysfunction is involved in a wide array of devastating diseases but the heterogeneity and complexity of these diseases’ symptoms challenges theoretical understanding of their causation. With the explosion of -omics data, we have the unprecedented ability to gain deep understanding of the biochemical mechanisms of mitochondrial dysfunction. However, there is also a need to make such datasets interpretable, and quantitative modelling allows us to translate such datasets into intuition and suggest rational biomedical treatments. Working towards this interdisciplinary goal, we use a recently published large-scale dataset, and develop a mathematical model of progressive increase in mutant load of the MELAS 3243A>G mtDNA mutation to develop a descriptive and predictive biophysical model. The experimentally observed behaviour is surprisingly rich, but we find that a simple, biophysically-motivated model intuitively accounts for this heterogeneity and yields a wealth of biological predictions. Our findings suggest that cells attempt to maintain wild-type mtDNA density through cell volume reduction, and thus energy demand reduction, until a minimum cell volume is reached. Thereafter, cells toggle from demand reduction to supply increase, upregulating energy production pathways. Our analysis provides further evidence for the physiological significance of mtDNA density, and emphasizes the need for performing single-cell volume measurements jointly with mtDNA quantification. We propose novel experiments to verify the hypotheses made here, to further develop our understanding of the threshold effect, and connect with rational choices for mtDNA disease therapies.Author SummaryMitochondria are organelles which produce the major energy currency of the cell: ATP. Mitochondrial dysfunction is associated with a multitude of devastating diseases, from Parkinson’s disease to cancer. Large volumes of data related to these diseases are being produced, but translation of these data into rational biomedical treatment is challenged by a lack of theoretical understanding. We develop a mathematical model of progressive increase of mutant load in mitochondrial DNA, for the mutation associated with MELAS (the most common mitochondrial disease), to address this. We predict that cells attempt to maintain the ratio of healthy mtDNA to cell volume by reducing their cell volume until they reach a minimum cell volume. As mutant load continues to increase, cells switch strategy by increasing their energy supply pathways. Our work accounts for large-scale experimental data and makes testable predictions about mitochondrial dysfunction. It also provides support for increasing mitochondrial content, as well as reduction in dependence upon mitochondrial metabolism via the ketogenic diet, as relevant treatments for mitochondrial disease.

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Generation of Somatic Mitochondrial DNA-Replaced Cells for Mitochondrial Dysfunction Treatment

10.1101/2020.10.01.321851 ◽

2020 ◽

Author(s):

Hideki Maeda ◽

Daisuke Kami ◽

Ryotaro Maeda ◽

Akira Shikuma ◽

Satoshi Gojo

Keyword(s):

Mitochondrial Dna ◽

Mitochondrial Dysfunction ◽

Mitochondrial Disease ◽

Pluripotent Stem Cells ◽

Disease Patient ◽

Mitochondrial Diseases ◽

Wild Type ◽

Mutant Genotype ◽

Wide Range

AbstractMitochondrial diseases currently have no cure regardless of whether the cause is a nuclear or mitochondrial genome mutation. Mitochondrial dysfunction notably affects a wide range of disorders in aged individuals, including neurodegenerative diseases, cancers, and even senescence. Here, we present a procedure to generate mitochondrial DNA-replaced somatic cells with a combination of a temporal reduction in endogenous mitochondrial DNA and coincubation with exogeneous isolated mitochondria. Heteroplasmy in mitochondrial disease patient-derived fibroblasts in which the mutant genotype was dominant over the wild-type genotype was reversed over the long term, even inducing the production of pluripotent stem cells from the mitochondrial DNA-replaced cells to maintain the genotype without a reversion to the original. Both mitochondrial disease patient-derived and aged fibroblasts could regain respiratory function and showed lifespan extension. Mitochondrial membranous components were utilized as a vehicle to deliver the genetic materials into endogenous mitochondria-like horizontal genetic transfer in prokaryotes. The mitochondrial DNA-replaced cells could be a resource for transplantation to treat not only mitochondrial diseases, but also senescence-related diseases.

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A study of mitochondrial DNA mutations in peripheral lymphocytes in an aging cohort

Biochemical Society Transactions ◽

10.1042/bst0310444 ◽

2003 ◽

Vol 31 (2) ◽

pp. 444-446 ◽

Cited By ~ 4

Author(s):

B. Zhang ◽

S. Ye ◽

A.A. Sayer ◽

S.R. Hammans ◽

S. Adio ◽

...

Keyword(s):

Mitochondrial Dna ◽

Mitochondrial Genome ◽

Somatic Mutation ◽

Large Scale ◽

Nuclear Genome ◽

Epidemiological Studies ◽

Elderly Subjects ◽

Long Pcr ◽

Peripheral Lymphocytes ◽

Wide Range

Somatic mutation in the mitochondrial genome occurs much more rapidly than in the nuclear genome and is a feature, possibly contributory, of the aging of cells and tissues. Identifying mitochondrial sequence changes in blood DNA of elderly subjects may provide a maker for the epigenetic changes of mitochondrial DNA known to occur in tissues with lower cellular turnover, and would also have implications for immunosenescence. No large-scale epidemiological studies have been reported previously. In this study we have established long-PCR banks of the mitochondrial genome from peripheral lymphocytes for an elderly cohort of 716 individuals with a range of measured aging phenotypes, and we have established assays for three widely reported mutations: the 4977 bp and 8048 bp deletions and point mutation A3243G. No individuals were identified with detectable heteroplasmy for these changes. Implications for tissue and population prevalence are discussed. The mitochondrial long-PCR DNA banks established will be useful for a wide range of studies of somatic mutation and of germline haplotypes in relation to aging.

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