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The Lancet. Neurology Jul 2021Mitochondrial diseases are some of the most common inherited neurometabolic disorders, and major progress has been made in our understanding, diagnosis, and treatment of... (Review)
Review
Mitochondrial diseases are some of the most common inherited neurometabolic disorders, and major progress has been made in our understanding, diagnosis, and treatment of these conditions in the past 5 years. Development of national mitochondrial disease cohorts and international collaborations has changed our knowledge of the spectrum of clinical phenotypes and natural history of mitochondrial diseases. Advances in high-throughput sequencing technologies have altered the diagnostic algorithm for mitochondrial diseases by increasingly using a genetics-first approach, with more than 350 disease-causing genes identified to date. While the current management strategy for mitochondrial disease focuses on surveillance for multisystem involvement and effective symptomatic treatment, new endeavours are underway to find better treatments, including repurposing current drugs, use of novel small molecules, and gene therapies. Developments made in reproductive technology offer women the opportunity to prevent transmission of DNA-related mitochondrial disease to their children.
Topics: DNA, Mitochondrial; Genetic Therapy; High-Throughput Nucleotide Sequencing; Humans; Mitochondrial Diseases; Mutation
PubMed: 34146515
DOI: 10.1016/S1474-4422(21)00098-3 -
Journal of Neurology Jan 2016Mitochondrial disease is one of the most common groups of genetic diseases with a minimum prevalence of greater than 1 in 5000 in adults. Whilst multi-system involvement... (Review)
Review
Mitochondrial disease is one of the most common groups of genetic diseases with a minimum prevalence of greater than 1 in 5000 in adults. Whilst multi-system involvement is often evident, neurological manifestation is the principal presentation in most cases. The multiple clinical phenotypes and the involvement of both the mitochondrial and nuclear genome make mitochondrial disease particularly challenging for the clinician. In this review article we cover mitochondrial genetics and common neurological presentations associated with adult mitochondrial disease. In addition, specific and supportive treatments are discussed.
Topics: Humans; Mitochondrial Diseases
PubMed: 26315846
DOI: 10.1007/s00415-015-7884-3 -
Journal of Internal Medicine Jun 2020Mitochondrial disease presenting in childhood is characterized by clinical, biochemical and genetic complexity. Some children are affected by canonical syndromes, but... (Review)
Review
Mitochondrial disease presenting in childhood is characterized by clinical, biochemical and genetic complexity. Some children are affected by canonical syndromes, but the majority have nonclassical multisystemic disease presentations involving virtually any organ in the body. Each child has a unique constellation of clinical features and disease trajectory, leading to enormous challenges in diagnosis and management of these heterogeneous disorders. This review discusses the classical mitochondrial syndromes presenting most frequently in childhood and then presents an organ-based perspective including systems less frequently linked to mitochondrial disease, such as skin and hair abnormalities and immune dysfunction. An approach to diagnosis is then presented, encompassing clinical evaluation and biochemical, neuroimaging and genetic investigations, and emphasizing the problem of phenocopies. The impact of next-generation sequencing is discussed, together with the importance of functional validation of novel genetic variants never previously linked to mitochondrial disease. The review concludes with a brief discussion of currently available and emerging therapies. The field of mitochondrial medicine has made enormous strides in the last 30 years, with approaching 400 different genes across two genomes now linked to primary mitochondrial disease. However, many important questions remain unanswered, including the reasons for tissue specificity and variability of clinical presentation of individuals sharing identical gene defects, and a lack of disease-modifying therapies and biomarkers to monitor disease progression and/or response to treatment.
Topics: Child; Humans; Mitochondria; Mitochondrial Diseases; Mutation; Phenotype
PubMed: 32176382
DOI: 10.1111/joim.13054 -
Genetics in Medicine : Official Journal... Sep 2015The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. This... (Review)
Review
PURPOSE
The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. This statement is intended for physicians who are engaged in diagnosing and treating these patients.
METHODS
The Writing Group members were appointed by the Mitochondrial Medicine Society. The panel included members with expertise in several different areas. The panel members utilized a comprehensive review of the literature, surveys, and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve.
RESULTS
Consensus-based recommendations are provided for the diagnosis and treatment of mitochondrial disease.
CONCLUSION
The Delphi process enabled the formation of consensus-based recommendations. We hope that these recommendations will help standardize the evaluation, diagnosis, and care of patients with suspected or demonstrated mitochondrial disease.
Topics: Consensus; Delphi Technique; Evidence-Based Medicine; Humans; Mitochondrial Diseases; Treatment Outcome
PubMed: 25503498
DOI: 10.1038/gim.2014.177 -
Handbook of Clinical Neurology 2023The anatomic complexity of the brain in combination with its high energy demands makes this organ specifically vulnerable to defects of mitochondrial oxidative... (Review)
Review
The anatomic complexity of the brain in combination with its high energy demands makes this organ specifically vulnerable to defects of mitochondrial oxidative phosphorylation. Therefore, neurodegeneration is a hallmark of mitochondrial diseases. The nervous system of affected individuals typically shows selective regional vulnerability leading to distinct patterns of tissue damage. A classic example is Leigh syndrome, which causes symmetric alterations of basal ganglia and brain stem. Leigh syndrome can be caused by different genetic defects (>75 known disease genes) with variable disease onset ranging from infancy to adulthood. Other mitochondrial diseases are characterized by focal brain lesions, which is a core feature of MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). Apart from gray matter, also white matter can be affected by mitochondrial dysfunction. White matter lesions vary depending on the underlying genetic defect and may progress into cystic cavities. In view of the recognizable patterns of brain damage in mitochondrial diseases, neuroimaging techniques play a key role in diagnostic work-up. In the clinical setting, magnetic resonance imaging (MRI) and MR spectroscopy (MRS) are the mainstay of diagnostic work-up. Apart from visualization of brain anatomy, MRS allows the detection of metabolites such as lactate, which is of specific interest in the context of mitochondrial dysfunction. However, it is important to note that findings like symmetric basal ganglia lesions on MRI or a lactate peak on MRS are not specific, and that there is a broad range of disorders that can mimic mitochondrial diseases on neuroimaging. In this chapter, we will review the spectrum of neuroimaging findings in mitochondrial diseases and discuss important differential diagnoses. Moreover, we will give an outlook on novel biomedical imaging tools that may provide interesting insights into mitochondrial disease pathophysiology.
Topics: Humans; Leigh Disease; Magnetic Resonance Imaging; Neuroimaging; Brain; Mitochondrial Diseases; MELAS Syndrome; Lactic Acid
PubMed: 36813312
DOI: 10.1016/B978-0-12-821751-1.00016-6 -
PloS One 2022Mitochondrial diseases are a large group of genetically heterogeneous and clinically diverse disorders. Diagnosis often takes many years for which treatment may not... (Review)
Review
BACKGROUND
Mitochondrial diseases are a large group of genetically heterogeneous and clinically diverse disorders. Diagnosis often takes many years for which treatment may not exist. Registries are often used to conduct research, establish natural disease progression, engage the patient community, and develop best disease management practices. In Canada, there are limited centralized registries for mitochondrial disease patients, presenting a challenge for patients and professionals.
OBJECTIVE
To support the creation of such a registry, a systematic scoping review was conducted to map the landscape of mitochondrial disease patient registries worldwide, with a focus on registry design and challenges. Furthermore, it addresses a knowledge gap by providing a narrative synthesis of published literature that describes these registries.
METHODS
Arksey and O'Malley's methodological framework was followed to systematically search English-language literature in PubMed and CINAHL describing the designs of mitochondrial disease patient registries, supplemented by a grey literature search. Data were extracted in Microsoft Excel. Stakeholder consultations were also performed with patient caregivers, advocates, and researchers to provide perspectives beyond those found in the literature. These data were thematically analyzed and were reported in accordance with the PRISMA-ScR reporting guidelines.
RESULTS
A total of 17 articles were identified describing 13 unique registries located in North America, Europe, Australia, and West Asia. These papers described the registries' designs, their strengths, and weaknesses, as well as their tangible outcomes such as facilitating recruitment for research and supporting epidemiological studies.
CONCLUSION
Based on our findings in this review, recommendations were formulated. These include establishing registry objectives, respecting patients and their roles in the registry, adopting international data standards, data evaluations, and considerations to privacy legislation, among others. These recommendations could be used to support designing a future Canadian mitochondrial disease patient registry, and to further research directly engaging these registries worldwide.
Topics: Humans; Canada; Registries; Research Personnel; Mitochondrial Diseases; Europe
PubMed: 36301904
DOI: 10.1371/journal.pone.0276883 -
Journal of Inherited Metabolic Disease Sep 2023Mitochondrial aminoacyl-tRNA synthetases (mtARS) are enzymes critical for the first step of mitochondrial protein synthesis by charging mitochondrial tRNAs with their... (Review)
Review
Mitochondrial aminoacyl-tRNA synthetases (mtARS) are enzymes critical for the first step of mitochondrial protein synthesis by charging mitochondrial tRNAs with their cognate amino acids. Pathogenic variants in all 19 nuclear mtARS genes are now recognized as causing recessive mitochondrial diseases. Most mtARS disorders affect the nervous system, but the phenotypes range from multisystem diseases to tissue-specific manifestations. However, the mechanisms behind the tissue specificities are poorly understood, and challenges remain in obtaining accurate disease models for developing and testing treatments. Here, some of the currently existing disease models that have increased our understanding of mtARS defects are discussed.
Topics: Humans; Amino Acyl-tRNA Synthetases; Mitochondria; Mitochondrial Diseases; RNA, Transfer; Phenotype
PubMed: 37410890
DOI: 10.1002/jimd.12652 -
Genetics in Medicine : Official Journal... Dec 2017The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This... (Review)
Review
The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease.
Topics: Disease Management; Humans; Mitochondrial Diseases; Standard of Care
PubMed: 28749475
DOI: 10.1038/gim.2017.107 -
Lancet (London, England) Jul 2006Defects of mitochondrial metabolism cause a wide range of human diseases that include examples from all medical subspecialties. This review updates the topic of... (Review)
Review
Defects of mitochondrial metabolism cause a wide range of human diseases that include examples from all medical subspecialties. This review updates the topic of mitochondrial diseases by reviewing the most important recent advances in this area. The factors influencing inheritance, maintenance and replication of mtDNA are reviewed and the genotype-phenotype of mtDNA disorders has been expanded, with new insights into epidemiology, pathogenesis and its role in ageing. Recently identified nuclear gene mutations of mitochondrial proteins include mutations of frataxin causing Friedreich's ataxia, PINK1, DJ1 causing Parkinson's disease and POLG causing infantile mtDNA depletion syndrome, ophthalmoplegia, parkinsonism, male subfertility and, in a transgenic mouse model, premature senescence. Mitochondrial defects in neurodegenerative diseases include Parkinson's, Alzheimer's and Huntington's disease. Improved understanding of mtDNA inheritance and mutation penetrance patterns, and novel techniques for mtDNA modification offer significant prospects for more accurate genetic counselling and effective future therapies.
Topics: Animals; Female; Genotype; Humans; Male; Mitochondria; Mitochondrial Diseases; Mutation; Phenotype; Ubiquinone
PubMed: 16815381
DOI: 10.1016/S0140-6736(06)68970-8 -
Open Biology Dec 2022Mitochondrial diseases are a broad, genetically heterogeneous class of metabolic disorders characterized by deficits in oxidative phosphorylation (OXPHOS). Primary... (Review)
Review
Mitochondrial diseases are a broad, genetically heterogeneous class of metabolic disorders characterized by deficits in oxidative phosphorylation (OXPHOS). Primary mitochondrial disease (PMD) defines pathologies resulting from mutation of mitochondrial DNA (mtDNA) or nuclear genes affecting either mtDNA expression or the biogenesis and function of the respiratory chain. Secondary mitochondrial disease (SMD) arises due to mutation of nuclear-encoded genes independent of, or indirectly influencing OXPHOS assembly and operation. Despite instances of novel SMD increasing year-on-year, PMD is much more widely discussed in the literature. Indeed, since the implementation of next generation sequencing (NGS) techniques in 2010, many novel mitochondrial disease genes have been identified, approximately half of which are linked to SMD. This review will consolidate existing knowledge of SMDs and outline discrete categories within which to better understand the diversity of SMD phenotypes. By providing context to the biochemical and molecular pathways perturbed in SMD, we hope to further demonstrate the intricacies of SMD pathologies outside of their indirect contribution to mitochondrial energy generation.
Topics: Humans; Mitochondrial Diseases
PubMed: 36475414
DOI: 10.1098/rsob.220274