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Nature Reviews. Drug Discovery Jun 2023
Topics: Humans; Mitochondrial Diseases; Mitochondria; Genetic Therapy
PubMed: 37106085
DOI: 10.1038/d41573-023-00067-z -
Handbook of Clinical Neurology 2023Mitochondrial dysfunction, especially perturbation of oxidative phosphorylation and adenosine triphosphate (ATP) generation, disrupts cellular homeostasis and is a... (Review)
Review
Mitochondrial dysfunction, especially perturbation of oxidative phosphorylation and adenosine triphosphate (ATP) generation, disrupts cellular homeostasis and is a surprisingly frequent cause of central and peripheral nervous system pathology. Mitochondrial disease is an umbrella term that encompasses a host of clinical syndromes and features caused by in excess of 300 different genetic defects affecting the mitochondrial and nuclear genomes. Patients with mitochondrial disease can present at any age, ranging from neonatal onset to late adult life, with variable organ involvement and neurological manifestations including neurodevelopmental delay, seizures, stroke-like episodes, movement disorders, optic neuropathy, myopathy, and neuropathy. Until relatively recently, analysis of skeletal muscle biopsy was the focus of diagnostic algorithms, but step-changes in the scope and availability of next-generation sequencing technology and multiomics analysis have revolutionized mitochondrial disease diagnosis. Currently, there is no specific therapy for most types of mitochondrial disease, although clinical trials research in the field is gathering momentum. In that context, active management of epilepsy, stroke-like episodes, dystonia, brainstem dysfunction, and Parkinsonism are all the more important in improving patient quality of life and reducing mortality.
Topics: Adult; Infant, Newborn; Humans; Mitochondrial Encephalomyopathies; DNA, Mitochondrial; Quality of Life; Mitochondrial Diseases; Stroke
PubMed: 37562887
DOI: 10.1016/B978-0-323-98818-6.00025-X -
Clinics in Laboratory Medicine Jun 2020Clinical bioinformatics system is well-established for diagnosing genetic disease based on next-generation sequencing, but requires special considerations when being... (Review)
Review
Clinical bioinformatics system is well-established for diagnosing genetic disease based on next-generation sequencing, but requires special considerations when being adapted for the next-generation sequencing-based genetic diagnosis of mitochondrial diseases. Challenges are caused by the involvement of mitochondrial DNA genome in disease etiology. Heteroplasmy and haplogroup are key factors in interpreting mitochondrial DNA variant effects. Data resources and tools for analyzing variant and sequencing data are available at MSeqDR, MitoMap, and HmtDB. Revised specifications of the American College of Medical Genetics/Association of Molecular Pathology standards and guidelines for mitochondrial DNA variant interpretation are proposed by the MSeqDr Consortium and community experts.
Topics: Computational Biology; Genome, Mitochondrial; High-Throughput Nucleotide Sequencing; Humans; Mitochondrial Diseases; Molecular Diagnostic Techniques; Pathology, Molecular; Sequence Analysis, DNA
PubMed: 32439066
DOI: 10.1016/j.cll.2020.02.002 -
EBioMedicine Jun 2020Mitochondrial diseases are amongst the most genetically and phenotypically diverse groups of inherited diseases. The vast phenotypic overlap with other disease entities... (Review)
Review
Mitochondrial diseases are amongst the most genetically and phenotypically diverse groups of inherited diseases. The vast phenotypic overlap with other disease entities together with the absence of reliable biomarkers act as driving forces for the integration of unbiased methodologies early in the diagnostic algorithm, such as whole exome sequencing (WES) and whole genome sequencing (WGS). Such approaches are used in variant discovery and in combination with high-throughput functional assays such as transcriptomics in simultaneous variant discovery and validation. By capturing all genes, they not only increase the diagnostic rate in heterogenous mitochondrial disease patients, but accelerate novel disease gene discovery, and are valuable in side-stepping the risk of overlooking unexpected or even treatable genetic disease diagnoses.
Topics: Early Diagnosis; Genetic Association Studies; High-Throughput Nucleotide Sequencing; Humans; Mitochondrial Diseases; Mutation; Exome Sequencing; Whole Genome Sequencing
PubMed: 32454403
DOI: 10.1016/j.ebiom.2020.102784 -
Archives of Disease in Childhood Nov 2017Mitochondria are dynamic organelles present in virtually all human cells that are needed for a multitude of cellular functions, including energy production, control of... (Review)
Review
Mitochondria are dynamic organelles present in virtually all human cells that are needed for a multitude of cellular functions, including energy production, control of cell apoptosis and numerous biochemical catabolic and synthetic pathways that are critical for cellular health. Primary mitochondrial disorders are a group of greater than 200 single gene defects arising from two genomes (nuclear and mitochondrial) leading to mitochondrial dysfunction, and are associated with extremely heterogeneous phenotypes. Neuromuscular features predominate, but often with multisystem involvement. Clinical suspicion of a mitochondrial disorder should prompt multipronged investigation with biochemical and molecular genetic studies. Recent wide-scale adoption of next-generation sequencing approaches has led to a rapid increase in the number of disease genes. The advances in unravelling the genetic landscape of mitochondrial diseases have not yet been matched by progress in developing effective therapies, and the mainstay of care remains supportive therapies in a multidisciplinary team setting.
Topics: Genetic Testing; Genetic Therapy; Humans; Mitochondria; Mitochondrial Diseases; Phenotype
PubMed: 28647693
DOI: 10.1136/archdischild-2016-311370 -
Biochimica Et Biophysica Acta Dec 2004The Drosophila mutant technical knockout (tko), affecting the mitochondrial protein synthetic apparatus, exhibits respiratory chain deficiency and a phenotype resembling... (Review)
Review
The Drosophila mutant technical knockout (tko), affecting the mitochondrial protein synthetic apparatus, exhibits respiratory chain deficiency and a phenotype resembling various features of mitochondrial disease in humans (paralytic seizures, deafness, developmental retardation). We are using this mutant to analyse the cellular and genomic targets of mitochondrial dysfunction, and to identify ways in which the phenotype can be alleviated. Transgenic expression of wild-type tko in different patterns in the mutant background reveals critical times and cell-types for production of components of the mitochondrial disease-like phenotype. Mitochondrial bioenergy deficit during the period of maximal growth, as well as in specific parts of the nervous system, appears to be most deleterious. Inbreeding of tko mutant lines results in a systematic improvement in all phenotypic parameters tested. The resulting sub-lines can be used for genetic mapping and transcriptomic analysis, revealing clues as to the genes and pathways that can modify mitochondrial disease-like phenotypes in a model metazoan.
Topics: Animals; Disease Models, Animal; Drosophila; Humans; Mitochondrial Diseases; Mutation; Phenotype; Transcription, Genetic
PubMed: 15576051
DOI: 10.1016/j.bbabio.2004.07.004 -
EMBO Molecular Medicine Dec 2015Ten years ago, there was an emerging view that the molecular basis for adult mitochondrial disorders was largely known and that the clinical phenotypes had been well... (Review)
Review
Ten years ago, there was an emerging view that the molecular basis for adult mitochondrial disorders was largely known and that the clinical phenotypes had been well described. Nothing could have been further from the truth. The establishment of large cohorts of patients has revealed new aspects of the clinical presentation that were not previously appreciated. Over time, this approach is starting to provide an accurate understanding of the natural history of mitochondrial disease in adults. Advances in molecular diagnostics, underpinned by next generation sequencing technology, have identified novel molecular mechanisms. Recently described mitochondrial disease phenotypes have disparate causes, and yet share common mechanistic themes. In particular, disorders of mtDNA maintenance have emerged as a major cause of mitochondrial disease in adults. Progressive mtDNA depletion and the accumulation of mtDNA mutations explain some of the clinical features, but the genetic and cellular processes responsible for the mtDNA abnormalities are not entirely clear in each instance. Unfortunately, apart from a few specific examples, treatments for adult mitochondrial disease have not been forthcoming. However, the establishment of international consortia, and the first multinational randomised controlled trial, have paved the way for major progress in the near future, underpinned by growing interest from the pharmaceutical industry. Adult mitochondrial medicine is, therefore, in its infancy, and the challenge is to harness the new understanding of its molecular and cellular basis to develop treatments of real benefit to patients.
Topics: Adult; Biomarkers; DNA, Mitochondrial; Humans; Mitochondrial Diseases; Mutation Accumulation; Pathology, Molecular
PubMed: 26612854
DOI: 10.15252/emmm.201505079 -
Orphanet Journal of Rare Diseases Sep 2022Genetic mitochondrial diseases represent a significant challenge to human health. These diseases are extraordinarily heterogeneous in clinical presentation and genetic... (Review)
Review
BACKGROUND
Genetic mitochondrial diseases represent a significant challenge to human health. These diseases are extraordinarily heterogeneous in clinical presentation and genetic origin, and often involve multi-system disease with severe progressive symptoms. Mitochondrial diseases represent the most common cause of inherited metabolic disorders and one of the most common causes of inherited neurologic diseases, yet no proven therapeutic strategies yet exist. The basic cell and molecular mechanisms underlying the pathogenesis of mitochondrial diseases have not been resolved, hampering efforts to develop therapeutic agents.
MAIN BODY
In recent pre-clinical work, we have shown that pharmacologic agents targeting the immune system can prevent disease in the Ndufs4(KO) model of Leigh syndrome, indicating that the immune system plays a causal role in the pathogenesis of at least this form of mitochondrial disease. Intriguingly, a number of case reports have indicated that immune-targeting therapeutics may be beneficial in the setting of genetic mitochondrial disease. Here, we summarize clinical and pre-clinical evidence suggesting a key role for the immune system in mediating the pathogenesis of at least some forms of genetic mitochondrial disease.
CONCLUSIONS
Significant clinical and pre-clinical evidence indicates a key role for the immune system as a significant in the pathogenesis of at least some forms of genetic mitochondrial disease.
Topics: Humans; Immune System; Leigh Disease; Mitochondria; Mitochondrial Diseases; Nervous System Diseases
PubMed: 36056365
DOI: 10.1186/s13023-022-02495-3 -
Science (New York, N.Y.) Sep 2021Questions over mitochondrial replacement suggest a role for mitochondrial DNA editing.
Questions over mitochondrial replacement suggest a role for mitochondrial DNA editing.
Topics: Animals; DNA, Mitochondrial; Gene Editing; Genetic Therapy; Humans; Mitochondrial Diseases; Mitochondrial Replacement Therapy
PubMed: 34516801
DOI: 10.1126/science.abg0491 -
Biochemical Society Transactions Oct 2016Mitochondrial disorders are a group of genetic diseases affecting the energy-converting process of oxidative phosphorylation. The extreme variability of symptoms, organ... (Review)
Review
Mitochondrial disorders are a group of genetic diseases affecting the energy-converting process of oxidative phosphorylation. The extreme variability of symptoms, organ involvement, and clinical course represent a challenge to the development of effective therapeutic interventions. However, new possibilities have recently been emerging from studies in model organisms and awaiting verification in humans. I will discuss here the most promising experimental approaches and the challenges we face to translate them into the clinics. The current clinical trials will also be briefly reviewed.
Topics: Animals; Clinical Trials as Topic; DNA, Mitochondrial; Energy Metabolism; Humans; Mitochondria; Mitochondrial Diseases; Outcome Assessment, Health Care; Reactive Oxygen Species; Translational Research, Biomedical
PubMed: 27911730
DOI: 10.1042/BST20160085