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British Medical Bulletin 2013In the last 10 years the field of mitochondrial genetics has widened, shifting the focus from rare sporadic, metabolic disease to the effects of mitochondrial DNA... (Review)
Review
INTRODUCTION
In the last 10 years the field of mitochondrial genetics has widened, shifting the focus from rare sporadic, metabolic disease to the effects of mitochondrial DNA (mtDNA) variation in a growing spectrum of human disease. The aim of this review is to guide the reader through some key concepts regarding mitochondria before introducing both classic and emerging mitochondrial disorders.
SOURCES OF DATA
In this article, a review of the current mitochondrial genetics literature was conducted using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). In addition, this review makes use of a growing number of publically available databases including MITOMAP, a human mitochondrial genome database (www.mitomap.org), the Human DNA polymerase Gamma Mutation Database (http://tools.niehs.nih.gov/polg/) and PhyloTree.org (www.phylotree.org), a repository of global mtDNA variation.
AREAS OF AGREEMENT
The disruption in cellular energy, resulting from defects in mtDNA or defects in the nuclear-encoded genes responsible for mitochondrial maintenance, manifests in a growing number of human diseases.
AREAS OF CONTROVERSY
The exact mechanisms which govern the inheritance of mtDNA are hotly debated.
GROWING POINTS
Although still in the early stages, the development of in vitro genetic manipulation could see an end to the inheritance of the most severe mtDNA disease.
Topics: DNA, Mitochondrial; Databases, Nucleic Acid; Humans; Mitochondria; Mitochondrial Diseases; Mutation
PubMed: 23704099
DOI: 10.1093/bmb/ldt017 -
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 -
Orphanet Journal of Rare Diseases Jul 2021No curative therapy for mitochondrial disease (MD) exists, prioritizing supportive treatment for symptom relief. In animal and cell models ketones decrease oxidative... (Review)
Review
BACKGROUND
No curative therapy for mitochondrial disease (MD) exists, prioritizing supportive treatment for symptom relief. In animal and cell models ketones decrease oxidative stress, increase antioxidants and scavenge free radicals, putting ketogenic diets (KDs) on the list of management options for MD. Furthermore, KDs are well-known, safe and effective treatments for epilepsy, a frequent symptom of MD. This systematic review evaluates efficacy and safety of KD for MD.
METHODS
We searched Pubmed, Cochrane, Embase and Cinahl (November 2020) with search terms linked to MD and KD. From the identified records, we excluded studies on Pyruvate Dehydrogenase Complex deficiency. From these eligible reports, cases without a genetically confirmed diagnosis and cases without sufficient data on KD and clinical course were excluded. The remaining studies were included in the qualitative analysis.
RESULTS
Only 20 cases (14 pediatric) from the 694 papers identified met the inclusion criteria (one controlled trial (n = 5), 15 case reports). KD led to seizure control in 7 out of 8 cases and improved muscular symptoms in 3 of 10 individuals. In 4 of 20 cases KD reversed the clinical phenotype (e.g. cardiomyopathy, movement disorder). In 5 adults with mitochondrial DNA deletion(s) related myopathy rhabdomyolysis led to cessation of KD. Three individuals with POLG mutations died while being on KD, however, their survival was not different compared to individuals with POLG mutations without KD.
CONCLUSION
Data on efficacy and safety of KD for MD is too scarce for general recommendations. KD should be considered in individuals with MD and therapy refractory epilepsy, while KD is contraindicated in mitochondrial DNA deletion(s) related myopathy. When considering KD for MD the high rate of adverse effects should be taken into account, but also spectacular improvements in individual cases. KD is a highly individual management option in this fragile patient group and requires an experienced team. To increase knowledge on this-individually-promising management option more (prospective) studies using adequate outcome measures are crucial.
Topics: Adult; Animals; Child; Diet, Ketogenic; Drug Resistant Epilepsy; Epilepsy; Humans; Mitochondrial Diseases; Prospective Studies
PubMed: 34217336
DOI: 10.1186/s13023-021-01927-w -
Neurotherapeutics : the Journal of the... Jan 2024Mitochondrial diseases encompass a heterogeneous group of disorders with a wide range of clinical manifestations, most classically resulting in neurological, muscular,... (Review)
Review
Mitochondrial diseases encompass a heterogeneous group of disorders with a wide range of clinical manifestations, most classically resulting in neurological, muscular, and metabolic abnormalities, but having the potential to affect any organ system. Over the years, substantial progress has been made in identifying and characterizing various biomarkers associated with mitochondrial diseases. This review summarizes the current knowledge of mitochondrial biomarkers based on a literature review and discusses the evidence behind their use in clinical practice. A total of 13 biomarkers were thoroughly reviewed including lactate, pyruvate, lactate:pyruvate ratio, creatine kinase, creatine, amino acid profiles, glutathione, malondialdehyde, GDF-15, FGF-21, gelsolin, neurofilament light-chain, and circulating cell-free mtDNA. Most biomarkers had mixed findings depending on the study, especially when considering their utility for specific mitochondrial diseases versus mitochondrial conditions in general. However, in large biomarker comparison studies, GDF-15 followed by FGF-21, seem to have the greatest value though they are still not perfect. As such, additional studies are needed, especially in light of newer biomarkers that have not yet been thoroughly investigated. Understanding the landscape of biomarkers in mitochondrial diseases is crucial for advancing early detection, improving patient management, and developing targeted therapies.
Topics: Humans; Growth Differentiation Factor 15; Mitochondrial Diseases; Biomarkers; Pyruvic Acid; Lactic Acid; DNA, Mitochondrial
PubMed: 38295557
DOI: 10.1016/j.neurot.2024.e00325 -
Brain : a Journal of Neurology Apr 2022In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of... (Observational Study)
Observational Study
In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of mitochondrial stroke-like episodes and to identify associated risk predictors. Between January 1998 and June 2018, we identified 111 patients with genetically determined mitochondrial disease who developed stroke-like episodes. Post-mortem cases of mitochondrial disease (n = 26) were identified from Newcastle Brain Tissue Resource. The primary outcome was to interrogate the clinico-radiopathological correlates and prognostic indicators of stroke-like episode in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). The secondary objective was to develop a multivariable prediction model to forecast stroke-like episode risk. The most common genetic cause of stroke-like episodes was the m.3243A>G variant in MT-TL1 (n = 66), followed by recessive pathogenic POLG variants (n = 22), and 11 other rarer pathogenic mitochondrial DNA variants (n = 23). The age of first stroke-like episode was available for 105 patients [mean (SD) age: 31.8 (16.1)]; a total of 35 patients (32%) presented with their first stroke-like episode ≥40 years of age. The median interval (interquartile range) between first and second stroke-like episodes was 1.33 (2.86) years; 43% of patients developed recurrent stroke-like episodes within 12 months. Clinico-radiological, electrophysiological and neuropathological findings of stroke-like episodes were consistent with the hallmarks of medically refractory epilepsy. Patients with POLG-related stroke-like episodes demonstrated more fulminant disease trajectories than cases of m.3243A>G and other mitochondrial DNA pathogenic variants, in terms of the frequency of refractory status epilepticus, rapidity of progression and overall mortality. In multivariate analysis, baseline factors of body mass index, age-adjusted blood m.3243A>G heteroplasmy, sensorineural hearing loss and serum lactate were significantly associated with risk of stroke-like episodes in patients with the m.3243A>G variant. These factors informed the development of a prediction model to assess the risk of developing stroke-like episodes that demonstrated good overall discrimination (area under the curve = 0.87, 95% CI 0.82-0.93; c-statistic = 0.89). Significant radiological and pathological features of neurodegeneration were more evident in patients harbouring pathogenic mtDNA variants compared with POLG: brain atrophy on cranial MRI (90% versus 44%, P < 0.001) and reduced mean brain weight (SD) [1044 g (148) versus 1304 g (142), P = 0.005]. Our findings highlight the often idiosyncratic clinical, radiological and EEG characteristics of mitochondrial stroke-like episodes. Early recognition of seizures and aggressive instigation of treatment may help circumvent or slow neuronal loss and abate increasing disease burden. The risk-prediction model for the m.3243A>G variant can help inform more tailored genetic counselling and prognostication in routine clinical practice.
Topics: Adult; DNA, Mitochondrial; Humans; MELAS Syndrome; Mitochondrial Diseases; Mutation; Retrospective Studies; Stroke
PubMed: 34927673
DOI: 10.1093/brain/awab353 -
Journal of Translational Medicine Jun 2016Whole-exome sequencing (WES) has led to an exponential increase in identification of causative variants in mitochondrial disorders (MD).
BACKGROUND
Whole-exome sequencing (WES) has led to an exponential increase in identification of causative variants in mitochondrial disorders (MD).
METHODS
We performed WES in 113 MD suspected patients from Polish paediatric reference centre, in whom routine testing failed to identify a molecular defect. WES was performed using TruSeqExome enrichment, followed by variant prioritization, validation by Sanger sequencing, and segregation with the disease phenotype in the family.
RESULTS
Likely causative mutations were identified in 67 (59.3 %) patients; these included variants in mtDNA (6 patients) and nDNA: X-linked (9 patients), autosomal dominant (5 patients), and autosomal recessive (47 patients, 11 homozygotes). Novel variants accounted for 50.5 % (50/99) of all detected changes. In 47 patients, changes in 31 MD-related genes (ACAD9, ADCK3, AIFM1, CLPB, COX10, DLD, EARS2, FBXL4, MTATP6, MTFMT, MTND1, MTND3, MTND5, NAXE, NDUFS6, NDUFS7, NDUFV1, OPA1, PARS2, PC, PDHA1, POLG, RARS2, RRM2B, SCO2, SERAC1, SLC19A3, SLC25A12, TAZ, TMEM126B, VARS2) were identified. The ACAD9, CLPB, FBXL4, PDHA1 genes recurred more than twice suggesting higher general/ethnic prevalence. In 19 cases, variants in 18 non-MD related genes (ADAR, CACNA1A, CDKL5, CLN3, CPS1, DMD, DYSF, GBE1, GFAP, HSD17B4, MECP2, MYBPC3, PEX5, PGAP2, PIGN, PRF1, SBDS, SCN2A) were found. The percentage of positive WES results rose gradually with increasing probability of MD according to the Mitochondrial Disease Criteria (MDC) scale (from 36 to 90 % for low and high probability, respectively). The percentage of detected MD-related genes compared with non MD-related genes also grew with the increasing MD likelihood (from 20 to 97 %). Molecular diagnosis was established in 30/47 (63.8 %) neonates and in 17/28 (60.7 %) patients with basal ganglia involvement. Mutations in CLPB, SERAC1, TAZ genes were identified in neonates with 3-methylglutaconic aciduria (3-MGA) as a discriminative feature. New MD-related candidate gene (NDUFB8) is under verification.
CONCLUSIONS
We suggest WES rather than targeted NGS as the method of choice in diagnostics of MD in children, including neonates with 3-MGA aciduria, who died without determination of disease cause and with limited availability of laboratory data. There is a strong correlation between the degree of MD diagnosis by WES and MD likelihood expressed by the MDC scale.
Topics: Biopsy; Child; Child, Preschool; DNA, Mitochondrial; Exome; Female; Humans; Infant; Infant, Newborn; Male; Metabolism, Inborn Errors; Mitochondrial Diseases; Muscles; Mutation; Pediatrics; Pedigree; Sequence Analysis, DNA
PubMed: 27290639
DOI: 10.1186/s12967-016-0930-9 -
The Journal of Pathology Jan 2017Mitochondria are double-membrane-bound organelles that are present in all nucleated eukaryotic cells and are responsible for the production of cellular energy in the... (Review)
Review
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.
Topics: Brain; DNA, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases; Muscle, Skeletal; Mutation
PubMed: 27659608
DOI: 10.1002/path.4809 -
Developmental Medicine and Child... May 2012Mitochondrial respiratory chain disorders are relatively common inborn errors of energy metabolism, with a combined prevalence of one in 5000. These disorders typically... (Review)
Review
Mitochondrial respiratory chain disorders are relatively common inborn errors of energy metabolism, with a combined prevalence of one in 5000. These disorders typically affect tissues with high energy requirements, and cerebral involvement occurs frequently in childhood, often manifesting in seizures. Mitochondrial diseases are genetically heterogeneous; to date, mutations have been reported in all 37 mitochondrially encoded genes and more than 80 nuclear genes. The major genetic causes of mitochondrial epilepsy are mitochondrial DNA mutations (including those typically associated with the mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS] and myoclonic epilepsy with ragged red fibres [MERRF] syndromes); mutations in POLG (classically associated with Alpers syndrome but also presenting as the mitochondrial recessive ataxia syndrome [MIRAS], spinocerebellar ataxia with epilepsy [SCAE], and myoclonus, epilepsy, myopathy, sensory ataxia [MEMSA] syndromes in older individuals) and other disorders of mitochondrial DNA maintenance; complex I deficiency; disorders of coenzyme Q(10) biosynthesis; and disorders of mitochondrial translation such as RARS2 mutations. It is not clear why some genetic defects, but not others, are particularly associated with seizures. Epilepsy may be the presenting feature of mitochondrial disease but is often part of a multisystem clinical presentation. Mitochondrial epilepsy may be very difficult to manage, and is often a poor prognostic feature. At present there are no curative treatments for mitochondrial disease. Individuals with mitochondrial epilepsy are frequently prescribed multiple anticonvulsants, and the role of vitamins and other nutritional supplements and the ketogenic diet remain unproven.
Topics: Animals; Brain Diseases, Metabolic, Inborn; Child; Child, Preschool; DNA Mutational Analysis; DNA, Mitochondrial; Diagnosis, Differential; Diet, Ketogenic; Epilepsy; Genetic Testing; Genotype; Humans; Infant; MELAS Syndrome; Mice; Mice, Transgenic; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Phenotype; Syndrome
PubMed: 22283595
DOI: 10.1111/j.1469-8749.2011.04214.x -
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 -
The Laryngoscope Dec 2022Hearing loss is a clinical symptom, frequently mentioned in the context of mitochondrial disease. With no cure available for mitochondrial disease, supportive treatment... (Review)
Review
OBJECTIVES
Hearing loss is a clinical symptom, frequently mentioned in the context of mitochondrial disease. With no cure available for mitochondrial disease, supportive treatment of clinical symptoms like hearing loss is of the utmost importance. The aim of this study was to summarize current knowledge on hearing loss in genetically proven mitochondrial disease in children and deduce possible and necessary consequences in patient care.
METHODS
Systematic literature review, including Medline, Embase, and Cochrane library. Review protocol was established and registered prior to conduction (International prospective register of systematic reviews-PROSPERO: CRD42020165356). Conduction of this review was done in accordance with MOOSE criteria.
RESULTS
A total of 23 articles, meeting predefined criteria and providing sufficient information on 75 individuals with childhood onset hearing loss was included for analysis. Both cochlear and retro-cochlear origin of hearing loss can be identified among different types of mitochondrial disease. Analysis was hindered by inhomogeneous reporting and methodical limitations.
CONCLUSION
Overall, the findings do not allow for a general statement on hearing loss in children with mitochondrial disease. Retro-cochlear hearing loss seems to be found more often than expected. A common feature appears to be progression of hearing loss over time. However, hearing loss in these patients shows manifold characteristics. Therefore, awareness of mitochondrial disease as a possible causative background is important for otolaryngologists. Future attempts rely on standardized reporting and long-term follow-up.
LEVEL OF EVIDENCE
NA Laryngoscope, 132:2459-2472, 2022.
Topics: Humans; Hearing Loss; Deafness; Hearing Loss, Sensorineural; Mitochondrial Diseases
PubMed: 35188226
DOI: 10.1002/lary.30067