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Richard G Boles - One of the best experts on this subject based on the ideXlab platform.
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reflex sympathetic dystrophy complex regional pain syndrome type i in children with Mitochondrial Disease and maternal inheritance
Archives of Disease in Childhood, 2008Co-Authors: Tomoyasu Higashimoto, Erin E Baldwin, Jeffrey I Gold, Richard G BolesAbstract:OBJECTIVE: Complex regional pain syndrome type I (CRPS-I), previously known as reflex sympathetic dystrophy (RSD), is an idiopathic condition characterised by localised, abnormally intense and prolonged pain, allodynia and autonomic nervous system changes (ie, swelling, skin colour and temperature changes and altered perspiration) that usually appear following a "noxious" trigger such as trauma or surgery. The objective of this report is to demonstrate that children with CRPS-I can have additional dysautonomic conditions secondary to an underlying maternally inherited Mitochondrial Disease, an association not previously published. METHODS: Medical records of about 500 patients seen by one paediatric metabolic geneticist were reviewed to identify children meeting established CRPS diagnostic criteria. RESULTS: CRPS-I was present in eight children in seven families, each of which also had additional functional/dysautonomic conditions, the most common (> or = 4 cases per condition) being gastrointestinal dysmotility, migraine, cyclic vomiting and chronic fatigue. All seven probands studied met Nijmegen (2002) diagnostic criteria for definite Mitochondrial Disease on the basis of the clinical signs and symptoms and biochemical analyses. Six of the seven families met our pedigree-based criteria for probable maternal inheritance. CONCLUSION: In one tertiary-care paediatric genetics practice, children meeting the CRPS-I diagnostic criteria frequently had additional autonomic-related conditions secondary to maternally inherited Mitochondrial Disease, suggesting that Mitochondrial DNA sequence variants can predispose children towards the development of CRPS-I and other dysautonomias. CRPS-I should be considered in patients with Mitochondrial Disease who complain of idiopathic pain. Maternally inherited Mitochondrial Disease may not be a rare cause of CRPS-I, especially in children who present with other manifestations of dysautonomia.
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reflex sympathetic dystrophy complex regional pain syndrome type i in children with Mitochondrial Disease and maternal inheritance
Archives of Disease in Childhood, 2008Co-Authors: Tomoyasu Higashimoto, Erin E Baldwin, Jeffrey I Gold, Richard G BolesAbstract:Objective: Complex regional pain syndrome type I (CRPS-I), previously known as reflex sympathetic dystrophy (RSD), is an idiopathic condition characterised by localised, abnormally intense and prolonged pain, allodynia and autonomic nervous system changes (ie, swelling, skin colour and temperature changes and altered perspiration) that usually appear following a “noxious” trigger such as trauma or surgery. The objective of this report is to demonstrate that children with CRPS-I can have additional dysautonomic conditions secondary to an underlying maternally inherited Mitochondrial Disease, an association not previously published. Methods: Medical records of about 500 patients seen by one paediatric metabolic geneticist were reviewed to identify children meeting established CRPS diagnostic criteria. Results: CRPS-I was present in eight children in seven families, each of which also had additional functional/dysautonomic conditions, the most common (⩾4 cases per condition) being gastrointestinal dysmotility, migraine, cyclic vomiting and chronic fatigue. All seven probands studied met Nijmegen (2002) diagnostic criteria for definite Mitochondrial Disease on the basis of the clinical signs and symptoms and biochemical analyses. Six of the seven families met our pedigree-based criteria for probable maternal inheritance. Conclusion: In one tertiary-care paediatric genetics practice, children meeting the CRPS-I diagnostic criteria frequently had additional autonomic-related conditions secondary to maternally inherited Mitochondrial Disease, suggesting that Mitochondrial DNA sequence variants can predispose children towards the development of CRPS-I and other dysautonomias. CRPS-I should be considered in patients with Mitochondrial Disease who complain of idiopathic pain. Maternally inherited Mitochondrial Disease may not be a rare cause of CRPS-I, especially in children who present with other manifestations of dysautonomia.
Grainne S Gorman - One of the best experts on this subject based on the ideXlab platform.
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safety of drug use in patients with a primary Mitochondrial Disease an international delphi based consensus
Journal of Inherited Metabolic Disease, 2020Co-Authors: Maaike De Vries, Amel Karaa, Grainne S Gorman, David Brown, Mitchell E Allen, Laurence A Bindoff, Nandaki KeshavanAbstract:Clinical guidance is often sought when prescribing drugs for patients with primary Mitochondrial Disease. Theoretical considerations concerning drug safety in patients with Mitochondrial Disease may lead to unnecessary withholding of a drug in a situation of clinical need. The aim of this study was to develop consensus on safe medication use in patients with a primary Mitochondrial Disease. A panel of 16 experts in Mitochondrial medicine, pharmacology, and basic science from six different countries was established. A modified Delphi technique was used to allow the panellists to consider draft recommendations anonymously in two Delphi rounds with predetermined levels of agreement. This process was supported by a review of the available literature and a consensus conference that included the panellists and representatives of patient advocacy groups. A high level of consensus was reached regarding the safety of all 46 reviewed drugs, with the knowledge that the risk of adverse events is influenced both by individual patient risk factors and choice of drug or drug class. This paper details the consensus guidelines of an expert panel and provides an important update of previously established guidelines in safe medication use in patients with primary Mitochondrial Disease. Specific drugs, drug groups, and clinical or genetic conditions are described separately as they require special attention. It is important to emphasise that consensus-based information is useful to provide guidance, but that decisions related to drug prescribing should always be tailored to the specific needs and risks of each individual patient. We aim to present what is current knowledge and plan to update this regularly both to include new drugs and to review those currently included.
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Pathogenic variants in MT-ATP6: A United Kingdom-based Mitochondrial Disease cohort study.
Annals of Neurology, 2019Co-Authors: Yi Shiau Ng, Mika H. Martikainen, Enrico Bugiardini, Alasdair P. Blain, Apphia Bunting, Andrew M. Schaefer, Emma L Blakely, Charlotte L Alston, Grainne S Gorman, Sunil SharmaAbstract:: Distinct clinical syndromes have been associated with pathogenic MT-ATP6 variants. In this cohort study, we identified 125 individuals (60 families) including 88 clinically affected individuals and 37 asymptomatic carriers. Thirty-one individuals presented with Leigh syndrome and 7 with neuropathy ataxia retinitis pigmentosa. The remaining 50 patients presented with variable nonsyndromic features including ataxia, neuropathy, and learning disability. We confirmed maternal inheritance in 39 families and demonstrated that tissue segregation patterns and phenotypic threshold are variant dependent. Our findings suggest that MT-ATP6-related Mitochondrial DNA Disease is best conceptualized as a Mitochondrial Disease spectrum disorder and should be routinely included in genetic ataxia and neuropathy gene panels. ANN NEUROL 2019;86:310-315.
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the adjunctive application of transcranial direct current stimulation in the management of de novo refractory epilepsia partialis continua in adolescent onset polg related Mitochondrial Disease
Epilepsia Open, 2018Co-Authors: Henriette Van Ruiten, Grainne S Gorman, Robert W Taylor, Ming H Lai, Rebecca Scott, Venkateswaran Ramesh, Karen Horridge, Douglass M Turnbull, Robert McfarlandAbstract:Focal status epilepticus in POLG-related Mitochondrial Disease is highly refractory to pharmacological agents, including general anesthesia. We report the challenges in managing a previously healthy teenager who presented with de novo epilepsia partialis continua and metabolic stroke resulting from the homozygous p.Ala467Thr POLG mutation, the most common pathogenic variant identified in the Caucasian population. We applied transcranial direct current stimulation (tDCS; 2 mA; 20 min) daily as an adjunctive therapy because her focal seizures failed to respond to five antiepileptic drugs at maximal doses. The electrical and clinical seizures stopped after 3 days of tDCS. The second course of tDCS was administered for 14 days when the focal seizures re-emerged a month later. The patient tolerated the procedure well. Following 4 months of hospitalization and prolonged community rehabilitation, our patient has now returned to full-time education with support, and there is no report of cognitive deficit. We have demonstrated the safety and efficacy of tDCS in treating refractory focal motor seizures caused by Mitochondrial Disease.
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solid organ transplantation in primary Mitochondrial Disease proceed with caution
Molecular Genetics and Metabolism, 2016Co-Authors: Sumit Parikh, Amel Karaa, Yi Shiau Ng, Grainne S Gorman, Annette Feigenbaum, John Christodoulou, Richard Haas, Mark A Tarnopolsky, Amy Goldstein, Bruce K CohenAbstract:Solid organ transplants are rarely performed in both adult and pediatric patients with primary Mitochondrial Disease. Poor outcomes have been described in case reports and small case series. It is unclear whether the underlying genetic Disease has a significant impact on post-transplant morbidity and mortality. Data were obtained for 35 patients from 17 Mitochondrial Disease Centers across North America, the United Kingdom and Australia. Patient outcomes were noted after liver, kidney or heart transplantation. Excluding patients with POLG-related Disease, post-transplant survival approached or met outcomes seen in non-Mitochondrial Disease transplant patients. The majority of Mitochondrial Disease patients did not have worsening of their Mitochondrial Disease within 90-days post-transplant. Post-transplant complications, including organ rejection, were not a common occurrence and were generally treatable. Many patients did not have a Mitochondrial Disease considered or diagnosed prior to transplantation. In conclusion, patients with Mitochondrial Disease in this cohort generally tolerated solid-organ transplantation. Such patients may not need to be excluded from transplant solely for their Mitochondrial diagnosis; additional caution may be needed for patients with POLG-related Disease. Transplant teams should be aware of Mitochondrial Disease as an etiology for organ-failure and consider appropriate consultation in patients without a known cause of their symptoms.
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adult onset leigh syndrome in the intensive care setting a novel presentation of a c12orf65 related Mitochondrial Disease
Journal of neuromuscular diseases, 2015Co-Authors: Maria Wesolowska, Charlotte L Alston, Grainne S Gorman, Patrick F Chinnery, Aleksandra Pajak, Angela Pyle, Helen Griffin, James Miller, Andrew M. SchaeferAbstract:BACKGROUND Mitochondrial Disease can present at any age, with dysfunction in almost any tissue making diagnosis a challenge. It can result from inherited or sporadic mutations in either the Mitochondrial or the nuclear genome, many of which affect intraorganellar gene expression. The estimated prevalence of 1/4300 indicates these to be amongst the commonest inherited neuromuscular disorders, emphasising the importance of recognition of the diagnostic clinical features. OBJECTIVE Despite major advances in our understanding of the molecular basis of Mitochondrial Diseases, accurate and early diagnoses are critically dependent on the fastidious clinical and biochemical characterisation of patients. Here we describe a patient harbouring a previously reported homozygous mutation in C12orf65, a Mitochondrial protein of unknown function, which does not adhere to the proposed distinct genotype-phenotype relationship. METHODS We performed clinical, biochemical and molecular analysis including whole exome sequencing on patient samples and cell lines. RESULTS We report an extremely rare case of an adult presenting with Leigh-like Disease, in intensive care, in the 5th decade of life, harbouring a recessively inherited mutation previously reported in children. A global reduction in intra-Mitochondrial protein synthesis was observed despite normal or elevated levels of mt-RNA, leading to an isolated complex IV deficiency. CONCLUSIONS All the reported C12orf65 mutations have shown an autosomal recessive pattern of inheritance. Mitochondrial Disease causing mutations inherited in this manner are usually of early onset and associated with a severe, often fatal clinical phenotype. Presentations in adulthood are usually less severe. This patient's late adulthood presentation is in sharp contrast emphasising the clinical variability that is characteristic of Mitochondrial Disease and illustrates why making a definitive diagnosis remains a formidable challenge.
Tomoyasu Higashimoto - One of the best experts on this subject based on the ideXlab platform.
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reflex sympathetic dystrophy complex regional pain syndrome type i in children with Mitochondrial Disease and maternal inheritance
Archives of Disease in Childhood, 2008Co-Authors: Tomoyasu Higashimoto, Erin E Baldwin, Jeffrey I Gold, Richard G BolesAbstract:OBJECTIVE: Complex regional pain syndrome type I (CRPS-I), previously known as reflex sympathetic dystrophy (RSD), is an idiopathic condition characterised by localised, abnormally intense and prolonged pain, allodynia and autonomic nervous system changes (ie, swelling, skin colour and temperature changes and altered perspiration) that usually appear following a "noxious" trigger such as trauma or surgery. The objective of this report is to demonstrate that children with CRPS-I can have additional dysautonomic conditions secondary to an underlying maternally inherited Mitochondrial Disease, an association not previously published. METHODS: Medical records of about 500 patients seen by one paediatric metabolic geneticist were reviewed to identify children meeting established CRPS diagnostic criteria. RESULTS: CRPS-I was present in eight children in seven families, each of which also had additional functional/dysautonomic conditions, the most common (> or = 4 cases per condition) being gastrointestinal dysmotility, migraine, cyclic vomiting and chronic fatigue. All seven probands studied met Nijmegen (2002) diagnostic criteria for definite Mitochondrial Disease on the basis of the clinical signs and symptoms and biochemical analyses. Six of the seven families met our pedigree-based criteria for probable maternal inheritance. CONCLUSION: In one tertiary-care paediatric genetics practice, children meeting the CRPS-I diagnostic criteria frequently had additional autonomic-related conditions secondary to maternally inherited Mitochondrial Disease, suggesting that Mitochondrial DNA sequence variants can predispose children towards the development of CRPS-I and other dysautonomias. CRPS-I should be considered in patients with Mitochondrial Disease who complain of idiopathic pain. Maternally inherited Mitochondrial Disease may not be a rare cause of CRPS-I, especially in children who present with other manifestations of dysautonomia.
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reflex sympathetic dystrophy complex regional pain syndrome type i in children with Mitochondrial Disease and maternal inheritance
Archives of Disease in Childhood, 2008Co-Authors: Tomoyasu Higashimoto, Erin E Baldwin, Jeffrey I Gold, Richard G BolesAbstract:Objective: Complex regional pain syndrome type I (CRPS-I), previously known as reflex sympathetic dystrophy (RSD), is an idiopathic condition characterised by localised, abnormally intense and prolonged pain, allodynia and autonomic nervous system changes (ie, swelling, skin colour and temperature changes and altered perspiration) that usually appear following a “noxious” trigger such as trauma or surgery. The objective of this report is to demonstrate that children with CRPS-I can have additional dysautonomic conditions secondary to an underlying maternally inherited Mitochondrial Disease, an association not previously published. Methods: Medical records of about 500 patients seen by one paediatric metabolic geneticist were reviewed to identify children meeting established CRPS diagnostic criteria. Results: CRPS-I was present in eight children in seven families, each of which also had additional functional/dysautonomic conditions, the most common (⩾4 cases per condition) being gastrointestinal dysmotility, migraine, cyclic vomiting and chronic fatigue. All seven probands studied met Nijmegen (2002) diagnostic criteria for definite Mitochondrial Disease on the basis of the clinical signs and symptoms and biochemical analyses. Six of the seven families met our pedigree-based criteria for probable maternal inheritance. Conclusion: In one tertiary-care paediatric genetics practice, children meeting the CRPS-I diagnostic criteria frequently had additional autonomic-related conditions secondary to maternally inherited Mitochondrial Disease, suggesting that Mitochondrial DNA sequence variants can predispose children towards the development of CRPS-I and other dysautonomias. CRPS-I should be considered in patients with Mitochondrial Disease who complain of idiopathic pain. Maternally inherited Mitochondrial Disease may not be a rare cause of CRPS-I, especially in children who present with other manifestations of dysautonomia.
Lishuang Shen - One of the best experts on this subject based on the ideXlab platform.
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mseqdr a centralized knowledge repository and bioinformatics web resource to facilitate genomic investigations in Mitochondrial Disease
Human Mutation, 2016Co-Authors: Maria Angela Diroma, Daniel Navarrogomez, Lishuang Shen, Marie T Lott, Mannis Van Oven, Jeremy Leipzig, Michael A Gonzalez, Douglas C Wallace, Colleen C MurareskuAbstract:textabstractMSeqDR is the Mitochondrial Disease Sequence Data Resource, a centralized and comprehensive genome and phenome bioinformatics resource built by the Mitochondrial Disease community to facilitate clinical diagnosis and research investigations of individual patient phenotypes, genomes, genes, and variants. A central Web portal (https://mseqdr.org) integrates community knowledge from expert-curated databases with genomic and phenotype data shared by clinicians and researchers. MSeqDR also functions as a centralized application server for Web-based tools to analyze data across both Mitochondrial and nuclear DNA, including investigator-driven whole exome or genome dataset analyses through MSeqDR-Genesis. MSeqDR-GBrowse genome browser supports interactive genomic data exploration and visualization with custom tracks relevant to mtDNA variation and Mitochondrial Disease. MSeqDR-LSDB is a locus-specific database that currently manages 178 Mitochondrial Diseases, 1,363 genes associated with Mitochondrial biology or Disease, and 3,711 pathogenic variants in those genes. MSeqDR Disease Portal allows hierarchical tree-style Disease exploration to evaluate their unique descriptions, phenotypes, and causative variants. Automated genomic data submission tools are provided that capture ClinVar compliant variant annotations. PhenoTips will be used for phenotypic data submission on deidentified patients using human phenotype ontology terminology. The development of a dynamic informed patient consent process to guide data access is underway to realize the full potential of these resources.
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mseqdr a centralized knowledge repository and bioinformatics web resource to facilitate genomic investigations in Mitochondrial Disease
Human Mutation, 2016Co-Authors: Maria Angela Diroma, Daniel Navarrogomez, Lishuang Shen, Marie T Lott, Jeremy Leipzig, Michael A Gonzalez, Douglas C Wallace, Mannis Van Oven, Colleen MurareskuAbstract:MSeqDR is the Mitochondrial Disease Sequence Data Resource, a centralized and comprehensive genome and phenome bioinformatics resource built by the Mitochondrial Disease community to facilitate clinical diagnosis and research investigations of individual patient phenotypes, genomes, genes, and variants. A central Web portal (https://mseqdr.org) integrates community knowledge from expert-curated databases with genomic and phenotype data shared by clinicians and researchers. MSeqDR also functions as a centralized application server for Web-based tools to analyze data across both Mitochondrial and nuclear DNA, including investigator-driven whole exome or genome dataset analyses through MSeqDR-Genesis. MSeqDR-GBrowse genome browser supports interactive genomic data exploration and visualization with custom tracks relevant to mtDNA variation and Mitochondrial Disease. MSeqDR-LSDB is a locus-specific database that currently manages 178 Mitochondrial Diseases, 1,363 genes associated with Mitochondrial biology or Disease, and 3,711 pathogenic variants in those genes. MSeqDR Disease Portal allows hierarchical tree-style Disease exploration to evaluate their unique descriptions, phenotypes, and causative variants. Automated genomic data submission tools are provided that capture ClinVar compliant variant annotations. PhenoTips will be used for phenotypic data submission on deidentified patients using human phenotype ontology terminology. The development of a dynamic informed patient consent process to guide data access is underway to realize the full potential of these resources.
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Mitochondrial Disease sequence data resource mseqdr a global grass roots consortium to facilitate deposition curation annotation and integrated analysis of genomic data for the Mitochondrial Disease clinical and research communities
Molecular Genetics and Metabolism, 2015Co-Authors: Marni J Falk, Maria Angela Diroma, Daniel Navarrogomez, Lishuang Shen, Marie T Lott, Jeremy Leipzig, Michael Gonzalez, Alphons P M Stassen, Philip E Yeske, Renkui BaiAbstract:Success rates for genomic analyses of highly heterogeneous disorders can be greatly improved if a large cohort of patient data is assembled to enhance collective capabilities for accurate sequence variant annotation, analysis, and interpretation. Indeed, molecular diagnostics requires the establishment of robust data resources to enable data sharing that informs accurate understanding of genes, variants, and phenotypes. The "Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium" is a grass-roots effort facilitated by the United Mitochondrial Disease Foundation to identify and prioritize specific genomic data analysis needs of the global Mitochondrial Disease clinical and research community. A central Web portal (https://mseqdr.org) facilitates the coherent compilation, organization, annotation, and analysis of sequence data from both nuclear and Mitochondrial genomes of individuals and families with suspected Mitochondrial Disease. This Web portal provides users with a flexible and expandable suite of resources to enable variant-, gene-, and exome-level sequence analysis in a secure, Web-based, and user-friendly fashion. Users can also elect to share data with other MSeqDR Consortium members, or even the general public, either by custom annotation tracks or through the use of a convenient distributed annotation system (DAS) mechanism. A range of data visualization and analysis tools are provided to facilitate user interrogation and understanding of genomic, and ultimately phenotypic, data of relevance to Mitochondrial biology and Disease. Currently available tools for nuclear and Mitochondrial gene analyses include an MSeqDR GBrowse instance that hosts optimized Mitochondrial Disease and Mitochondrial DNA (mtDNA) specific annotation tracks, as well as an MSeqDR locus-specific database (LSDB) that curates variant data on more than 1300 genes that have been implicated in Mitochondrial Disease and/or encode mitochondria-localized proteins. MSeqDR is integrated with a diverse array of mtDNA data analysis tools that are both freestanding and incorporated into an online exome-level dataset curation and analysis resource (GEM.app) that is being optimized to support needs of the MSeqDR community. In addition, MSeqDR supports Mitochondrial Disease phenotyping and ontology tools, and provides variant pathogenicity assessment features that enable community review, feedback, and integration with the public ClinVar variant annotation resource. A centralized Web-based informed consent process is being developed, with implementation of a Global Unique Identifier (GUID) system to integrate data deposited on a given individual from different sources. Community-based data deposition into MSeqDR has already begun. Future efforts will enhance capabilities to incorporate phenotypic data that enhance genomic data analyses. MSeqDR will fill the existing void in bioinformatics tools and centralized knowledge that are necessary to enable efficient nuclear and mtDNA genomic data interpretation by a range of shareholders across both clinical diagnostic and research settings. Ultimately, MSeqDR is focused on empowering the global Mitochondrial Disease community to better define and explore Mitochondrial Diseases.
Charlotte L Alston - One of the best experts on this subject based on the ideXlab platform.
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Pathogenic variants in MT-ATP6: A United Kingdom-based Mitochondrial Disease cohort study.
Annals of Neurology, 2019Co-Authors: Yi Shiau Ng, Mika H. Martikainen, Enrico Bugiardini, Alasdair P. Blain, Apphia Bunting, Andrew M. Schaefer, Emma L Blakely, Charlotte L Alston, Grainne S Gorman, Sunil SharmaAbstract:: Distinct clinical syndromes have been associated with pathogenic MT-ATP6 variants. In this cohort study, we identified 125 individuals (60 families) including 88 clinically affected individuals and 37 asymptomatic carriers. Thirty-one individuals presented with Leigh syndrome and 7 with neuropathy ataxia retinitis pigmentosa. The remaining 50 patients presented with variable nonsyndromic features including ataxia, neuropathy, and learning disability. We confirmed maternal inheritance in 39 families and demonstrated that tissue segregation patterns and phenotypic threshold are variant dependent. Our findings suggest that MT-ATP6-related Mitochondrial DNA Disease is best conceptualized as a Mitochondrial Disease spectrum disorder and should be routinely included in genetic ataxia and neuropathy gene panels. ANN NEUROL 2019;86:310-315.
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mtdna heteroplasmy level and copy number indicate Disease burden in m 3243a g Mitochondrial Disease
Embo Molecular Medicine, 2018Co-Authors: John P Grady, Emma L Blakely, Charlotte L Alston, Sarah J Pickett, Steven A Hardy, Catherine Feeney, Alexandra BrightAbstract:Abstract Mitochondrial Disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and linear mixed modelling, we evaluated which commonly assayed tissue (blood N = 231, urine N = 235, skeletal muscle N = 77) represents the m.3243A>G mutation load and Mitochondrial DNA (mtDNA) copy number most strongly associated with Disease burden and progression. m.3243A>G levels are correlated in blood, muscle and urine ( R 2 = 0.61–0.73). Blood heteroplasmy declines by ~2.3%/year; we have extended previously published methodology to adjust for age. In urine, males have higher mtDNA copy number and ~20% higher m.3243A>G mutation load; we present formulas to adjust for this. Blood is the most highly correlated mutation measure for Disease burden and progression in m.3243A>G‐harbouring individuals; increasing age and heteroplasmy contribute ( R 2 = 0.27, P R 2 = 0.40, P G heteroplasmy is the most convenient and reliable measure for routine clinical assessment, additional factors such as mtDNA copy number may also influence Disease severity.
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the genetics and pathology of Mitochondrial Disease
The Journal of Pathology, 2017Co-Authors: Charlotte L Alston, D M Turnbull, Mariana C Rocha, Nichola Z Lax, Robert W TaylorAbstract:Mitochondria are double-membrane-bound organelles that are present in all nucleated eukaryotic cells and are responsible for the production of cellular energy in the form of ATP. Mitochondrial function is under dual genetic control - the 16.6-kb Mitochondrial genome, with only 37 genes, and the nuclear genome, which encodes the remaining ∼1300 proteins of the mitoproteome. Mitochondrial dysfunction can arise because of defects in either Mitochondrial DNA or nuclear Mitochondrial genes, and can present in childhood or adulthood in association with vast clinical heterogeneity, with symptoms affecting a single organ or tissue, or multisystem involvement. There is no cure for Mitochondrial Disease for the vast majority of Mitochondrial Disease patients, and a genetic diagnosis is therefore crucial for genetic counselling and recurrence risk calculation, and can impact on the clinical management of affected patients. Next-generation sequencing strategies are proving pivotal in the discovery of new Disease genes and the diagnosis of clinically affected patients; mutations in >250 genes have now been shown to cause Mitochondrial Disease, and the biochemical, histochemical, immunocytochemical and neuropathological characterization of these patients has led to improved diagnostic testing strategies and novel diagnostic techniques. This review focuses on the current genetic landscape associated with Mitochondrial Disease, before focusing on advances in studying associated Mitochondrial pathology in two, clinically relevant organs - skeletal muscle and brain. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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recurrent de novo dominant mutations in slc25a4 cause severe early onset Mitochondrial Disease and loss of Mitochondrial dna copy number
American Journal of Human Genetics, 2016Co-Authors: Kyle Thompson, Charlotte L Alston, Homa Majd, Christina Dallabona, Karit Reinson, Martin S King, Tiziana Lodi, Simon Jones, Aviva FattalvalevskiAbstract:Mutations in SLC25A4 encoding the Mitochondrial ADP/ATP carrier AAC1 are well-recognized causes of Mitochondrial Disease. Several heterozygous SLC25A4 mutations cause adult-onset autosomal-dominant progressive external ophthalmoplegia associated with multiple Mitochondrial DNA deletions, whereas recessive SLC25A4 mutations cause childhood-onset Mitochondrial myopathy and cardiomyopathy. Here, we describe the identification by whole-exome sequencing of seven probands harboring dominant, de novo SLC25A4 mutations. All affected individuals presented at birth, were ventilator dependent and, where tested, revealed severe combined Mitochondrial respiratory chain deficiencies associated with a marked loss of Mitochondrial DNA copy number in skeletal muscle. Strikingly, an identical c.239G>A (p.Arg80His) mutation was present in four of the seven subjects, and the other three case subjects harbored the same c.703C>G (p.Arg235Gly) mutation. Analysis of skeletal muscle revealed a marked decrease of AAC1 protein levels and loss of respiratory chain complexes containing Mitochondrial DNA-encoded subunits. We show that both recombinant AAC1 mutant proteins are severely impaired in ADP/ATP transport, affecting most likely the substrate binding and mechanics of the carrier, respectively. This highly reduced capacity for transport probably affects Mitochondrial DNA maintenance and in turn respiration, causing a severe energy crisis. The confirmation of the pathogenicity of these de novo SLC25A4 mutations highlights a third distinct clinical phenotype associated with mutation of this gene and demonstrates that early-onset Mitochondrial Disease can be caused by recurrent de novo mutations, which has significant implications for the application and analysis of whole-exome sequencing data in Mitochondrial Disease.
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adult onset leigh syndrome in the intensive care setting a novel presentation of a c12orf65 related Mitochondrial Disease
Journal of neuromuscular diseases, 2015Co-Authors: Maria Wesolowska, Charlotte L Alston, Grainne S Gorman, Patrick F Chinnery, Aleksandra Pajak, Angela Pyle, Helen Griffin, James Miller, Andrew M. SchaeferAbstract:BACKGROUND Mitochondrial Disease can present at any age, with dysfunction in almost any tissue making diagnosis a challenge. It can result from inherited or sporadic mutations in either the Mitochondrial or the nuclear genome, many of which affect intraorganellar gene expression. The estimated prevalence of 1/4300 indicates these to be amongst the commonest inherited neuromuscular disorders, emphasising the importance of recognition of the diagnostic clinical features. OBJECTIVE Despite major advances in our understanding of the molecular basis of Mitochondrial Diseases, accurate and early diagnoses are critically dependent on the fastidious clinical and biochemical characterisation of patients. Here we describe a patient harbouring a previously reported homozygous mutation in C12orf65, a Mitochondrial protein of unknown function, which does not adhere to the proposed distinct genotype-phenotype relationship. METHODS We performed clinical, biochemical and molecular analysis including whole exome sequencing on patient samples and cell lines. RESULTS We report an extremely rare case of an adult presenting with Leigh-like Disease, in intensive care, in the 5th decade of life, harbouring a recessively inherited mutation previously reported in children. A global reduction in intra-Mitochondrial protein synthesis was observed despite normal or elevated levels of mt-RNA, leading to an isolated complex IV deficiency. CONCLUSIONS All the reported C12orf65 mutations have shown an autosomal recessive pattern of inheritance. Mitochondrial Disease causing mutations inherited in this manner are usually of early onset and associated with a severe, often fatal clinical phenotype. Presentations in adulthood are usually less severe. This patient's late adulthood presentation is in sharp contrast emphasising the clinical variability that is characteristic of Mitochondrial Disease and illustrates why making a definitive diagnosis remains a formidable challenge.