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Annual Review of Genomics and Human... Aug 2017Mitochondrial disease is a challenging area of genetics because two distinct genomes can contribute to disease pathogenesis. It is also challenging clinically because of... (Review)
Review
Mitochondrial disease is a challenging area of genetics because two distinct genomes can contribute to disease pathogenesis. It is also challenging clinically because of the myriad of different symptoms and, until recently, a lack of a genetic diagnosis in many patients. The last five years has brought remarkable progress in this area. We provide a brief overview of mitochondrial origin, function, and biology, which are key to understanding the genetic basis of mitochondrial disease. However, the primary purpose of this review is to describe the recent advances related to the diagnosis, genetic basis, and prevention of mitochondrial disease, highlighting the newly described disease genes and the evolving methodologies aimed at preventing mitochondrial DNA disease transmission.
Topics: DNA, Mitochondrial; Female; Humans; Male; Mitochondrial Diseases; Mutation
PubMed: 28415858
DOI: 10.1146/annurev-genom-091416-035426 -
Orphanet Journal of Rare Diseases Jun 2022Mitochondrial diseases are a group of rare, heterogeneous diseases caused by gene mutations in both nuclear and mitochondrial genomes that result in defects in... (Review)
Review
Mitochondrial diseases are a group of rare, heterogeneous diseases caused by gene mutations in both nuclear and mitochondrial genomes that result in defects in mitochondrial function. They are responsible for significant morbidity and mortality as they affect multiple organ systems and particularly those with high energy-utilizing tissues, such as the nervous system, skeletal muscle, and cardiac muscle. Virtually no effective treatments exist for these patients, despite the urgent need. As the majority of these conditions are monogenic and caused by mutations in nuclear genes, gene replacement is a highly attractive therapeutic strategy. Adeno-associated virus (AAV) is a well-characterized gene replacement vector, and its safety profile and ability to transduce quiescent cells nominates it as a potential gene therapy vehicle for several mitochondrial diseases. Indeed, AAV vector-based gene replacement is currently being explored in clinical trials for one mitochondrial disease (Leber hereditary optic neuropathy) and preclinical studies have been published investigating this strategy in other mitochondrial diseases. This review summarizes the preclinical findings of AAV vector-based gene replacement therapy for mitochondrial diseases including Leigh syndrome, Barth syndrome, ethylmalonic encephalopathy, and others.
Topics: Barth Syndrome; Dependovirus; Genetic Therapy; Humans; Mitochondrial Diseases; Optic Atrophy, Hereditary, Leber
PubMed: 35668433
DOI: 10.1186/s13023-022-02324-7 -
Current Opinion in Pediatrics Dec 2010Mitochondrial diseases are individually uncommon, but collectively pose a significant burden on human health. Primary mitochondrial disease is caused by defects in the... (Review)
Review
PURPOSE OF REVIEW
Mitochondrial diseases are individually uncommon, but collectively pose a significant burden on human health. Primary mitochondrial disease is caused by defects in the mitochondrial DNA-encoded genes or in nuclear genes whose products are imported into the mitochondrion. Great strides have been made in determining the cause of mitochondrial disorders, but the clinical ability to diagnose these conditions lags behind because of phenotypic overlap between distinct genetic entities and the complexity and invasiveness of standard diagnostic testing. In this review, we evaluate new findings in mitochondrial genetics, recent developments in mitochondrial disease diagnostic testing, and emerging ideas for mitochondrial disease therapies.
RECENT FINDINGS
Clinical cohort studies have revealed important themes in patient care relative to manifestations of mitochondrial disease. Significant strides have also been made toward creating embryos free from the risk of maternally inherited mitochondrial DNA-based disease. Several new genetic causes of both nuclear and mitochondrial DNA-based diseases have been identified in the past year. In addition, novel insights have emerged from basic studies of mitochondrial biology that hold promise for the development of targeted mitochondrial disease therapies.
SUMMARY
Research on mitochondrial biology and disease continues to improve the clinical capacity to diagnose the heterogeneous group of mitochondrial diseases that afflict the pediatric population. This research also provides a framework for future approaches to devise effective mitochondrial disease therapies.
Topics: Antioxidants; DNA, Mitochondrial; Humans; Mitochondrial Diseases
PubMed: 21045694
DOI: 10.1097/MOP.0b013e3283402e21 -
Current Opinion in Endocrinology,... Feb 2024Primary mitochondrial diseases are one of the most prevalent groups of multisystem genetic disorders. Endocrinopathies associated with mitochondrial diseases may have... (Review)
Review
PURPOSE OF REVIEW
Primary mitochondrial diseases are one of the most prevalent groups of multisystem genetic disorders. Endocrinopathies associated with mitochondrial diseases may have clinical features that are distinct from the more common forms. We provide an overview of mitochondrial disorder genetics and phenotypes, focusing on recent studies regarding identification and treatment of associated endocrinopathies.
RECENT FINDINGS
Known endocrine phenotypes of mitochondrial disorders continue to expand, and now include growth hormone deficiency, hypogonadism, precocious puberty, hypoparathyroidism, hypo- and hyperthyroidism, diabetes, and adrenal insufficiency. Recent studies suggest several genotype-phenotype correlations, including those related to nuclear variants. Diagnosis is important, as special considerations should be made in the management of endocrinopathies in mitochondrial patients. Finally, new mitochondrial replacement strategies may soon be available for women interested in preventing mitochondrial disease transmission to offspring.
SUMMARY
Patients with multiple endocrinopathies or atypical endocrinopathies should be evaluated for primary mitochondrial disease, as a diagnosis may impact management of these individuals.
Topics: Humans; Female; Endocrine System Diseases; Diabetes Mellitus; Puberty, Precocious; Mitochondrial Diseases; Hyperthyroidism; Adrenal Insufficiency
PubMed: 38047549
DOI: 10.1097/MED.0000000000000848 -
Biochimica Et Biophysica Acta Dec 2009Mitochondria are an essential organelle, not only to the human cell, but to all eukaryotic life. This essentiality is reflected in the large number of mutations in genes... (Review)
Review
Mitochondria are an essential organelle, not only to the human cell, but to all eukaryotic life. This essentiality is reflected in the large number of mutations in genes encoding mitochondrial proteins that lead to disease. Aside from their relevance to disease, mitochondria are, given their endosymbiotic origin, very interesting from an evolutionary point of view. Here, in the year that marks the bicentenary of Darwin's birth and the 150th anniversary of the publication of "On the origin of species" we review approaches that implicitly or explicitly use evolutionary analyses to find new genes involved in mitochondrial disease and to predict their function and involvement in pathways. We show how the phenotypic spectrum of mitochondrial disease is linked to the evolutionary origin of mitochondrial proteins, how combinations of evolutionary data and genomics data have been used to predict the mitochondrial proteome and functional links between the mitochondrial proteins and how the evolution of the mitochondrial proteome has been used to predict new mitochondrial disease genes. For the latter we review and reanalyze the eukaryotic evolution of the NADH:ubiquinone oxidoreductase (complex I) and the proteins involved in its assembly.
Topics: Biological Evolution; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Proteome
PubMed: 19328849
DOI: 10.1016/j.bbadis.2009.03.005 -
Frontiers in Bioscience (Landmark... Mar 2017Mitochondria, are the powerhouses of cells, have their own DNA (mtDNA), regulate the transport of metabolites and ions, and impact cell physiology, survival, and death.... (Review)
Review
Mitochondria, are the powerhouses of cells, have their own DNA (mtDNA), regulate the transport of metabolites and ions, and impact cell physiology, survival, and death. Mitochondrial dysfunction, including impaired oxidative phosphorylation, preferentially affects heart function due to an imbalance of energy supply and demand. Recently, mitochondrial mutations and associated mitochondrial dysfunction were suggested as a causal factor of cardiac manifestations. Oxidative stress largely influences mtDNA stability due to oxidative modifications of mtDNA. Furthermore, the continuous replicative state of mtDNA and presence of minimal nucleoid structure render mitochondria vulnerable to oxidative damage and subsequent mutations, which impair mitochondrial functions. However, the occurrence of mtDNA heteroplasmy in the same mitochondrion or cell and presence of nuclear DNA-encoded mtDNA repair systems raise questions regarding whether oxidative stress-mediated mtDNA mutations are the major driving force in accumulation of mtDNA mutations. Here, we address the possible causes of mitochondrial DNA mutations and their involvement in cardiac manifestations. Current strategies for treatment related to mitochondrial mutations and/or dysfunction in cardiac manifestations are briefly discussed.
Topics: Animals; DNA Damage; DNA Repair; DNA, Mitochondrial; Heart Diseases; Humans; Mitochondria, Heart; Mitochondrial Diseases; Mutation; Oxidative Stress
PubMed: 28199200
DOI: 10.2741/4541 -
Experimental Cell Research Jul 2014Mitochondrial DNA diseases are common neurological conditions caused by mutations in the mitochondrial genome or nuclear genes responsible for its maintenance. Current... (Review)
Review
Mitochondrial DNA diseases are common neurological conditions caused by mutations in the mitochondrial genome or nuclear genes responsible for its maintenance. Current treatments for these disorders are focussed on the management of the symptoms, rather than the correction of biochemical defects caused by the mutation. This review focuses on the molecular effects of mutations, the symptoms they cause and current work focusing on the development of targeted treatments for mitochondrial DNA disease.
Topics: DNA, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proton-Translocating ATPases; Point Mutation; RNA, Transfer, Leu; Sequence Deletion
PubMed: 24675282
DOI: 10.1016/j.yexcr.2014.03.012 -
Cold Spring Harbor Perspectives in... Apr 2013The inability to replicate mitochondrial genomes (mtDNA) by the mitochondrial DNA polymerase (pol γ) leads to a subset of mitochondrial diseases. Many mutations in... (Review)
Review
The inability to replicate mitochondrial genomes (mtDNA) by the mitochondrial DNA polymerase (pol γ) leads to a subset of mitochondrial diseases. Many mutations in POLG, the gene that encodes pol γ, have been associated with mitochondrial diseases such as myocerebrohepatopathy spectrum (MCHS) disorders, Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and progressive external ophthalmoplegia (PEO). This chapter explores five important topics in POLG-related disease: (1) clinical symptoms that identify and distinguish POLG-related diseases, (2) molecular characterization of defects in polymerase activity by POLG disease variants, (3) the importance of holoenzyme formation in disease presentation, (4) the role of pol γ exonuclease activity and mutagenesis in disease and aging, and (5) novel approaches to therapy and avoidance of toxicity based on primary research in pol γ replication.
Topics: Animals; Crystallography, X-Ray; DNA Polymerase gamma; DNA Replication; DNA, Mitochondrial; DNA-Directed DNA Polymerase; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Mice; Mitochondrial Diseases; Mutagenesis; Mutation; Oxidative Stress; Phenotype
PubMed: 23545419
DOI: 10.1101/cshperspect.a011395 -
Journal of Child Neurology Apr 2016Ophthalmologic manifestations of mitochondrial disorders are frequently neglected or overlooked because they are often not regarded as part of the phenotype. This review... (Review)
Review
Ophthalmologic manifestations of mitochondrial disorders are frequently neglected or overlooked because they are often not regarded as part of the phenotype. This review aims at summarizing and discussing the etiology, pathogenesis, diagnosis, and treatment of ophthalmologic manifestations of mitochondrial disorders. Review of publications about ophthalmologic involvement in mitochondrial disorders by search of Medline applying appropriate search terms. The eye is frequently affected by syndromic as well as nonsyndromic mitochondrial disorders. Primary and secondary ophthalmologic manifestations can be differentiated. The most frequent ophthalmologic manifestations of mitochondrial disorders include ptosis, progressive external ophthalmoplegia, optic atrophy, retinopathy, and cataract. More rarely occurring are nystagmus and abnormalities of the cornea, ciliary body, intraocular pressure, the choroidea, or the brain secondarily affecting the eyes. It is important to recognize and diagnose ophthalmologic manifestations of mitochondrial disorders as early as possible because most are accessible to symptomatic treatment with partial or complete short-term or long-term beneficial effect. Ophthalmologic manifestations of mitochondrial disorders need to be appropriately diagnosed to initiate the most effective management and guarantee optimal outcome.
Topics: Eye; Eye Diseases; Humans; MEDLINE; Mitochondrial Diseases
PubMed: 26275973
DOI: 10.1177/0883073815599263 -
European Journal of Neurology Aug 2019Bowel symptoms are well documented in mitochondrial disease. However, data concerning other pelvic organs is limited. A large case-control study has therefore been...
BACKGROUND AND PURPOSE
Bowel symptoms are well documented in mitochondrial disease. However, data concerning other pelvic organs is limited. A large case-control study has therefore been undertaken to determine the presence of lower urinary tract symptoms (LUTS) and sexual dysfunction in adults with genetically confirmed mitochondrial disease.
METHODS
Adults with genetically confirmed mitochondrial disease and control subjects were recruited from a specialist mitochondrial clinic. The presence and severity of LUTS and their impact on quality of life, in addition to sexual dysfunction and bowel symptoms, were captured using four validated questionnaires. Subgroup analysis was undertaken in patients harbouring the m.3243A>G MT-TL1 mitochondrial DNA mutation. A subset of patients underwent urodynamic studies to further characterize their LUTS.
RESULTS
Data from 58 patients and 19 controls (gender and age matched) were collected. Adults with mitochondrial disease had significantly more overactive bladder (81.5% vs. 56.3%, P = 0.039) and low stream (34.5% vs. 5.3%, P = 0.013) urinary symptoms than controls. Urodynamic studies in 10 patients confirmed that bladder storage symptoms predominate. Despite high rates of LUTS, none of the patient group was receiving treatment. Female patients and those harbouring the m.3243A>G MT-TL1 mutation experienced significantly more sexual dysfunction than controls (53.1% vs. 11.1%, P = 0.026, and 66.7% vs. 26.3%, P = 0.011, respectively).
CONCLUSIONS
Lower urinary tract symptoms are common but undertreated in adult mitochondrial disease, and female patients and those harbouring the m.3243A>G MT-TL1 mutation experience sexual dysfunction. Given their impact on quality of life, screening for and treating LUTS and sexual dysfunction in adults with mitochondrial disease are strongly recommended.
Topics: Adult; Case-Control Studies; Female; Humans; Lower Urinary Tract Symptoms; Male; Middle Aged; Mitochondrial Diseases; Quality of Life; Surveys and Questionnaires
PubMed: 30884027
DOI: 10.1111/ene.13952