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Current Neurology and Neuroscience... May 2021We aim to summarize the sleep disorders reported in patients affected by primary mitochondrial dysfunctions and describe the association with their clinical and... (Review)
Review
PURPOSE OF REVIEW
We aim to summarize the sleep disorders reported in patients affected by primary mitochondrial dysfunctions and describe the association with their clinical and molecular characteristics.
RECENT FINDINGS
Sleep complaints are prevalent in mitochondrial disorders. Sleep-disordered breathing is the main sleep disorder reported in mitochondrial diseases. OSA and CSA are, respectively, more frequently associated with patients characterized by the prevalent involvement of the skeletal muscle and the predominant involvement of the central nervous system. Other sleep disorders, such as restless legs syndrome, have been rarely described. Sleep disorders are frequently associated with primary mitochondrial disorders, and the clinical phenotypes affect the type of sleep disturbance associated with the mitochondrial dysfunction. A polysomnographic study should be performed in every subject with this neurogenetic disorder both at diagnosis and during follow-up for the numerous adverse clinical outcomes associated with sleep disorders and the frailty of mitochondrial patients.
Topics: Humans; Mitochondrial Diseases; Polysomnography; Restless Legs Syndrome; Sleep Apnea Syndromes; Sleep Wake Disorders
PubMed: 33948737
DOI: 10.1007/s11910-021-01121-2 -
DNA Repair Jul 2014Human mitochondria harbor an essential, high copy number, 16,569 base pair, circular DNA genome that encodes 13 gene products required for electron transport and... (Review)
Review
Human mitochondria harbor an essential, high copy number, 16,569 base pair, circular DNA genome that encodes 13 gene products required for electron transport and oxidative phosphorylation. Mutation of this genome can compromise cellular respiration, ultimately resulting in a variety of progressive metabolic diseases collectively known as 'mitochondrial diseases'. Mutagenesis of mtDNA and the persistence of mtDNA mutations in cells and tissues is a complex topic, involving the interplay of DNA replication, DNA damage and repair, purifying selection, organelle dynamics, mitophagy, and aging. We briefly review these general elements that affect maintenance of mtDNA, and we focus on nuclear genes encoding the mtDNA replication machinery that can perturb the genetic integrity of the mitochondrial genome.
Topics: DNA Damage; DNA Replication; DNA, Mitochondrial; Genome, Mitochondrial; Humans; Mitochondrial Diseases; Mutagenesis; Mutation; Oxidative Phosphorylation
PubMed: 24780559
DOI: 10.1016/j.dnarep.2014.03.010 -
FEBS Letters Apr 2021Mitochondrial disorders are monogenic disorders characterized by a defect in oxidative phosphorylation and caused by pathogenic variants in one of over 340 different... (Review)
Review
Mitochondrial disorders are monogenic disorders characterized by a defect in oxidative phosphorylation and caused by pathogenic variants in one of over 340 different genes. The implementation of whole-exome sequencing has led to a revolution in their diagnosis, duplicated the number of associated disease genes, and significantly increased the diagnosed fraction. However, the genetic etiology of a substantial fraction of patients exhibiting mitochondrial disorders remains unknown, highlighting limitations in variant detection and interpretation, which calls for improved computational and DNA sequencing methods, as well as the addition of OMICS tools. More intriguingly, this also suggests that some pathogenic variants lie outside of the protein-coding genes and that the mechanisms beyond the Mendelian inheritance and the mtDNA are of relevance. This review covers the current status of the genetic basis of mitochondrial diseases, discusses current challenges and perspectives, and explores the contribution of factors beyond the protein-coding regions and monogenic inheritance in the expansion of the genetic spectrum of disease.
Topics: DNA, Mitochondrial; Humans; Mitochondrial Diseases; Exome Sequencing
PubMed: 33655490
DOI: 10.1002/1873-3468.14068 -
Molecular Genetics and Metabolism Jan 2022Localization within the nervous system provides context for neurological disease manifestations and treatment, with numerous disease mechanisms exhibiting predilect...
Localization within the nervous system provides context for neurological disease manifestations and treatment, with numerous disease mechanisms exhibiting predilect locations. In contrast, the molecular function of most disease-causing genes is generally considered dissociated from such brain regional correlations because most genes are expressed throughout the brain. We tested the factual basis for this dissociation by discerning between two distinct genetic disease mechanism possibilities: One, gene-specific, in which genetic disorders are poorly localizable because they are multiform at the molecular level, with each mutant gene acting more widely or complexly than via mere loss or gain of one function. The other, more general, where aspects shared by groups of genes such as membership in a gene set that sustains a concerted biological process accounts for a common or localizable phenotype. We analyzed mitochondrial substrate disorders as a paradigm of apparently heterogeneous diseases when considered from the point of view of their manifestations and individual function of their causal genes. We used publicly available transcriptomes, disease phenotypes published in peer-reviewed journals and Human Ontology classifications for 27 mitochondrial substrate metabolism diseases and analyzed if these disorders manifest common phenotypes and if this relates to common brain regions or cells as demarcated by their transcriptome. The most frequent phenotypic manifestations and brain structures involved were almost stereotypic regardless of the individual gene affected, correlating with the regional abundance of the transcriptome that served mitochondrial substrate metabolism. This also applied to the transcriptome of inhibitory neurons, which are dysfunctional in some mitochondrial diseases. This stands in contrast with resistance to dementia atrophy from other causes, which is known to also associate with greater expression of a similar fraction of the transcriptome. The results suggest that brain region or cell type dysfunction stemming from a broad process such as mitochondrial substrate metabolism is more relevant for disease manifestations than individual gene participation in specific molecular function.
Topics: Brain; Humans; Mitochondrial Diseases; Neurons; Phenotype; Transcriptome
PubMed: 34972656
DOI: 10.1016/j.ymgme.2021.12.008 -
Archives of Disease in Childhood. Fetal... May 2022Neonatal-onset mitochondrial disease has not been fully characterised owing to its heterogeneity. We analysed neonatal-onset mitochondrial disease in Japan to clarify... (Observational Study)
Observational Study
OBJECTIVE
Neonatal-onset mitochondrial disease has not been fully characterised owing to its heterogeneity. We analysed neonatal-onset mitochondrial disease in Japan to clarify its clinical features, molecular diagnosis and prognosis.
DESIGN
Retrospective observational study from January 2004 to March 2020.
SETTING
Population based.
PATIENTS
Patients (281) with neonatal-onset mitochondrial disease diagnosed by biochemical and genetic approaches.
INTERVENTIONS
None.
MAIN OUTCOME MEASURES
Disease types, initial symptoms, biochemical findings, molecular diagnosis and prognosis.
RESULTS
Of the 281 patients, multisystem mitochondrial disease was found in 194, Leigh syndrome in 26, cardiomyopathy in 38 and hepatopathy in 23 patients. Of the 321 initial symptoms, 236 occurred within 2 days of birth. Using biochemical approaches, 182 patients were diagnosed by mitochondrial respiratory chain enzyme activity rate and 89 by oxygen consumption rate. The remaining 10 patients were diagnosed using a genetic approach. Genetic analysis revealed 69 patients had nuclear DNA variants in 36 genes, 11 of 15 patients had mitochondrial DNA variants in five genes and four patients had single large deletion. The Cox proportional hazards regression analysis showed the effects of Leigh syndrome (HR=0.15, 95% CI 0.04 to 0.63, p=0.010) and molecular diagnosis (HR=1.87, 95% CI 1.18 to 2.96, p=0.008) on survival.
CONCLUSIONS
Neonatal-onset mitochondrial disease has a heterogenous aetiology. The number of diagnoses can be increased, and clarity regarding prognosis can be achieved by comprehensive biochemical and molecular analyses using appropriate tissue samples.
Topics: DNA, Mitochondrial; Humans; Infant, Newborn; Leigh Disease; Mitochondrial Diseases; Mutation; Prognosis
PubMed: 34625524
DOI: 10.1136/archdischild-2021-321633 -
Developmental Disabilities Research... 2010Coenzyme Q(10) (CoQ(10)) is an essential electron carrier in the mitochondrial respiratory chain and an important antioxidant. Deficiency of CoQ(10) is a clinically and... (Review)
Review
Coenzyme Q(10) (CoQ(10)) is an essential electron carrier in the mitochondrial respiratory chain and an important antioxidant. Deficiency of CoQ(10) is a clinically and molecularly heterogeneous syndrome, which, to date, has been found to be autosomal recessive in inheritance and generally responsive to CoQ(10) supplementation. CoQ(10) deficiency has been associated with five major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) cerebellar ataxia, (4) isolated myopathy, and (5) nephrotic syndrome. In a few patients, pathogenic mutations have been identified in genes involved in the biosynthesis of CoQ(10) (primary CoQ(10) deficiencies) or in genes not directly related to CoQ(10) biosynthesis (secondary CoQ(10) deficiencies). Respiratory chain defects, ROS production, and apoptosis contribute to the pathogenesis of primary CoQ(10) deficiencies. In vitro and in vivo studies are necessary to further understand the pathogenesis of the disease and to develop more effective therapies.
Topics: Atrophy; Cerebellum; Child; Chromosome Aberrations; DNA Mutational Analysis; Developmental Disabilities; Disease Progression; Genes, Recessive; Humans; Infant, Newborn; Kidney Diseases; Kidney Glomerulus; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Spinocerebellar Degenerations; Ubiquinone
PubMed: 20818733
DOI: 10.1002/ddrr.108 -
Journal of Internal Medicine Jun 2020Mitochondrial diseases are extremely heterogeneous genetic conditions characterized by faulty oxidative phosphorylation (OXPHOS). OXPHOS deficiency can be the result of... (Review)
Review
Mitochondrial diseases are extremely heterogeneous genetic conditions characterized by faulty oxidative phosphorylation (OXPHOS). OXPHOS deficiency can be the result of mutation in mtDNA genes, encoding either proteins (13 subunits of the mitochondrial complexes I, III, IV and V) or the tRNA and rRNA components of the in situ mtDNA translation. The remaining mitochondrial disease genes are in the nucleus, encoding proteins with a huge variety of functions, from structural subunits of the mitochondrial complexes, to factors involved in their formation and regulation, components of the mtDNA replication and expression machinery, biosynthetic enzymes for the biosynthesis or incorporation of prosthetic groups, components of the mitochondrial quality control and proteostasis, enzymes involved in the clearance of toxic compounds, factors involved in the formation of the lipid milieu, etc. These different functions represent potential targets for 'general' therapeutic interventions, as they may be adapted to a number of different mitochondrial conditions. This is in contrast with 'tailored', personalized therapeutic approaches, such as gene therapy, cell therapy and organ replacement, that can be useful only for individual conditions. This review will present the most recent concepts emerged from preclinical work and the attempts to translate them into the clinics. The common notion that mitochondrial disorders have no cure is currently challenged by a massive effort of scientists and clinicians, and we do expect that thanks to this intensive investigation work and tangible results for the development of strategies amenable to the treatment of patients with these tremendously difficult conditions are not so far away.
Topics: Animals; Antioxidants; Genetic Therapy; Humans; Mitochondria; Mitochondrial Diseases; Nucleotides; Translational Research, Biomedical
PubMed: 32100338
DOI: 10.1111/joim.13046 -
Journal of Medical Genetics May 2021The nucleotide binding protein-like () gene was first reported as a cause of mitochondrial complex I deficiency (MIM 613621, 618242) in 2010. To date, only eight... (Review)
Review
BACKGROUND
The nucleotide binding protein-like () gene was first reported as a cause of mitochondrial complex I deficiency (MIM 613621, 618242) in 2010. To date, only eight patients have been reported with this mitochondrial disorder. Five other patients were recently reported to have disease but their clinical picture was different from the first eight patients. Here, we report clinical and genetic findings in five additional patients (four families).
METHODS
Whole exome sequencing was used to identify patients with compound heterozygous variants. Functional studies included RNA-Seq transcript analyses, missense variant biochemical analyses in a yeast model () and mitochondrial respiration experiments on patient fibroblasts.
RESULTS
The previously reported c.815-27T>C branch-site mutation was found in all four families. In prior patients, c.166G>A [p.G56R] was always found with c.815-27T>C, but only two of four families had both variants. The second variant found with c.815-27T>C in each family was: c.311T>C [p.L104P] in three patients, c.693+1G>A in one patient and c.545T>C [p.V182A] in one patient. Complex I function in the yeast model was impacted by p.L104P but not p.V182A. Clinical features include onset of neurological symptoms at 3-18 months, global developmental delay, cerebellar dysfunction (including ataxia, dysarthria, nystagmus and tremor) and spasticity. Brain MRI showed cerebellar atrophy. Mitochondrial function studies on patient fibroblasts showed significantly reduced spare respiratory capacity.
CONCLUSION
We report on five new patients with disease, adding to the number and phenotypic variability of patients diagnosed worldwide, and review prior reported patients with pathogenic variants.
Topics: Adolescent; Brain; Child; DNA Mutational Analysis; Female; Humans; Magnetic Resonance Imaging; Male; Mitochondrial Diseases; Mitochondrial Proteins; Pedigree; RNA-Seq; Exome Sequencing; Young Adult
PubMed: 32518176
DOI: 10.1136/jmedgenet-2020-106846 -
Neuroscience and Biobehavioral Reviews Jun 2021Mitochondrial diseases (MDs) are rare, heterogeneous, hereditary and progressive in nature. In addition to the serious somatic symptoms, patients with MD also experience... (Review)
Review
Mitochondrial diseases (MDs) are rare, heterogeneous, hereditary and progressive in nature. In addition to the serious somatic symptoms, patients with MD also experience problems regarding their cognitive functioning and mental health. We provide an overview of all published studies reporting on any aspect of cognitive functioning and/or mental health in patients with MD and their relatives. A total of 58 research articles and 45 case studies were included and critically reviewed. Cognitive impairments in multiple domains were reported. Mental disorders were frequently reported, especially depression and anxiety. Furthermore, most studies showed impairments in self-reported psychological functioning and high prevalence of mental health problems in (matrilineal) relatives. The included studies showed heterogeneity regarding patient samples, measurement instruments and reference groups, making comparisons cautious. Results highlight a high prevalence of cognitive impairments and mental disorders in patients with MD. Recommendations for further research as well as tailored patientcare with standardized follow-up are provided. Key gaps in the literature are identified, of which studies on natural history are of highest importance.
Topics: Cognition; Depression; Humans; Mental Health; Mitochondrial Diseases; Quality of Life
PubMed: 33582231
DOI: 10.1016/j.neubiorev.2021.02.004 -
Annual Review of Genomics and Human... 2010For nearly three decades, the sequence of the human mitochondrial genome (mtDNA) has provided a molecular framework for understanding maternally inherited diseases.... (Review)
Review
For nearly three decades, the sequence of the human mitochondrial genome (mtDNA) has provided a molecular framework for understanding maternally inherited diseases. However, the vast majority of human mitochondrial disorders are caused by nuclear genome defects, which is not surprising since the mtDNA encodes only 13 proteins. Advances in genomics, mass spectrometry, and computation have only recently made it possible to systematically identify the complement of over 1,000 proteins that comprise the mammalian mitochondrial proteome. Here, we review recent progress in characterizing the mitochondrial proteome and highlight insights into its complexity, tissue heterogeneity, evolutionary origins, and biochemical versatility. We then discuss how this proteome is being used to discover the genetic basis of respiratory chain disorders as well as to expand our definition of mitochondrial disease. Finally, we explore future prospects and challenges for using the mitochondrial proteome as a foundation for systems analysis of the organelle.
Topics: Cell Nucleus; Genome, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Proteome
PubMed: 20690818
DOI: 10.1146/annurev-genom-082509-141720