The Genetic Landscape of Mitochondrial Diseases in Spain: A Nationwide Call

The frequency of mitochondrial diseases (MD) has been scarcely documented, and only a few studies have reported data in certain specific geographical areas. In this study, we arranged a nationwide call in Spain to obtain a global estimate of the number of cases. A total of 3274 cases from 49 Spanish provinces were reported by 39 centres. Excluding duplicated and unsolved cases, 2761 patients harbouring pathogenic mutations in 140 genes were recruited between 1990 and 2020. A total of 508 patients exhibited mutations in nuclear DNA genes (75% paediatric patients) and 1105 in mitochondrial DNA genes (33% paediatric patients). A further 1148 cases harboured mutations in the MT-RNR1 gene (56% paediatric patients). The number of reported cases secondary to nuclear DNA mutations increased in 2014, owing to the implementation of next-generation sequencing technologies. Between 2014 and 2020, excepting MT-RNR1 cases, the incidence was 6.34 (95% CI: 5.71–6.97) cases per million inhabitants at the paediatric age and 1.36 (95% CI: 1.22–1.50) for adults. In conclusion, this is the first study to report nationwide epidemiological data for MD in Spain. The lack of identification of a remarkable number of mitochondrial genes necessitates the systematic application of high-throughput technologies in the routine diagnosis of MD.

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Treatment for mitochondrial diseases

Reviews in the Neurosciences ◽

10.1515/revneuro-2020-0034 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Tongling Liufu ◽

Zhaoxia Wang

Keyword(s):

Clinical Trials ◽

Nuclear Dna ◽

Mitochondrial Diseases ◽

Cochrane Collaboration ◽

Potential Bias ◽

Leber Hereditary Optic Neuropathy ◽

Pharmacological Agents ◽

Unpublished Studies ◽

New Treatment ◽

Allotopic Expression

AbstractMitochondrial diseases are predominantly caused by mutations of mitochondrial or nuclear DNA, resulting in multisystem defects. Current treatments are largely supportive, and the disorders progress relentlessly. Nutritional supplements, pharmacological agents and physical therapies have been used in different clinical trials, but the efficacy of these interventions need to be further evaluated. Several recent reviews discussed some of the interventions but ignored bias in those trials. This review was conducted to discover new studies and grade the original studies for potential bias with revised Cochrane Collaboration guidelines. We focused on seven published studies and three unpublished studies; eight of these studies showed improvement in outcome measurements. In particular, two of the interventions have been tested in studies with strict design, which we believe deserve further clinical trials with a large sample. Additionally, allotopic expression of the ND4 subunit seemed to be an effective new treatment for patients with Leber hereditary optic neuropathy.

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The Role of Mitochondria in Carcinogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms22105100 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5100

Author(s):

Paulina Kozakiewicz ◽

Ludmiła Grzybowska-Szatkowska ◽

Marzanna Ciesielka ◽

Jolanta Rzymowska

Keyword(s):

Prostate Cancer ◽

Mitochondrial Dna ◽

Nuclear Dna ◽

Dna Polymorphisms ◽

Gene Encoding ◽

Dna Mutations ◽

Nadh Ubiquinone Oxidoreductase ◽

Gene Coi ◽

The Impact

The mitochondria are essential for normal cell functioning. Changes in mitochondrial DNA (mtDNA) may affect the occurrence of some chronic diseases and cancer. This process is complex and not entirely understood. The assignment to a particular mitochondrial haplogroup may be a factor that either contributes to cancer development or reduces its likelihood. Mutations in mtDNA occurring via an increase in reactive oxygen species may favour the occurrence of further changes both in mitochondrial and nuclear DNA. Mitochondrial DNA mutations in postmitotic cells are not inherited, but may play a role both in initiation and progression of cancer. One of the first discovered polymorphisms associated with cancer was in the gene NADH-ubiquinone oxidoreductase chain 3 (mt-ND3) and it was typical of haplogroup N. In prostate cancer, these mutations and polymorphisms involve a gene encoding subunit I of respiratory complex IV cytochrome c oxidase subunit 1 gene (COI). At present, a growing number of studies also address the impact of mtDNA polymorphisms on prognosis in cancer patients. Some of the mitochondrial DNA polymorphisms occur in both chronic disease and cancer, for instance polymorphism G5913A characteristic of prostate cancer and hypertension.

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Mitochondrial DNA Replacement Techniques to Prevent Human Mitochondrial Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22020551 ◽

2021 ◽

Vol 22 (2) ◽

pp. 551

Author(s):

Luis Sendra ◽

Alfredo García-Mares ◽

María José Herrero ◽

Salvador F. Aliño

Keyword(s):

Mitochondrial Dna ◽

Nuclear Dna ◽

Genetic Disorders ◽

Mitochondrial Diseases ◽

Legal Regulation ◽

Donor Oocyte ◽

Legal Position ◽

Ethical And Legal Issues ◽

Mitochondrial Replacement Techniques ◽

Do So

Background: Mitochondrial DNA (mtDNA) diseases are a group of maternally inherited genetic disorders caused by a lack of energy production. Currently, mtDNA diseases have a poor prognosis and no known cure. The chance to have unaffected offspring with a genetic link is important for the affected families, and mitochondrial replacement techniques (MRTs) allow them to do so. MRTs consist of transferring the nuclear DNA from an oocyte with pathogenic mtDNA to an enucleated donor oocyte without pathogenic mtDNA. This paper aims to determine the efficacy, associated risks, and main ethical and legal issues related to MRTs. Methods: A bibliographic review was performed on the MEDLINE and Web of Science databases, along with searches for related clinical trials and news. Results: A total of 48 publications were included for review. Five MRT procedures were identified and their efficacy was compared. Three main risks associated with MRTs were discussed, and the ethical views and legal position of MRTs were reviewed. Conclusions: MRTs are an effective approach to minimizing the risk of transmitting mtDNA diseases, but they do not remove it entirely. Global legal regulation of MRTs is required.

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Understanding mitochondrial myopathies: a review

PeerJ ◽

10.7717/peerj.4790 ◽

2018 ◽

Vol 6 ◽

pp. e4790 ◽

Cited By ~ 6

Author(s):

Abhimanyu S. Ahuja

Keyword(s):

Speech Therapy ◽

Nuclear Dna ◽

Severe Disease ◽

Mitochondrial Diseases ◽

The Body ◽

Genetic Mutations ◽

Mitochondrial Myopathies ◽

Positive Side ◽

Organ Systems ◽

New Research

Mitochondria are small, energy-producing structures vital to the energy needs of the body. Genetic mutations cause mitochondria to fail to produce the energy needed by cells and organs which can cause severe disease and death. These genetic mutations are likely to be in the mitochondrial DNA (mtDNA), or possibly in the nuclear DNA (nDNA). The goal of this review is to assess the current understanding of mitochondrial diseases. This review focuses on the pathology, causes, risk factors, symptoms, prevalence data, symptomatic treatments, and new research aimed at possible preventions and/or treatments of mitochondrial diseases. Mitochondrial myopathies are mitochondrial diseases that cause prominent muscular symptoms such as muscle weakness and usually present with a multitude of symptoms and can affect virtually all organ systems. There is no cure for these diseases as of today. Treatment is generally supportive and emphasizes symptom management. Mitochondrial diseases occur infrequently and hence research funding levels tend to be low in comparison with more common diseases. On the positive side, quite a few genetic defects responsible for mitochondrial diseases have been identified, which are in turn being used to investigate potential treatments. Speech therapy, physical therapy, and respiratory therapy have been used in mitochondrial diseases with variable results. These therapies are not curative and at best help with maintaining a patient’s current abilities to move and function.

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The heart in neuromuscular disease: primary mitochondrial diseases

ESC CardioMed ◽

10.1093/med/9780198784906.003.0369 ◽

2018 ◽

pp. 1528-1530

Author(s):

Denis Duboc

Keyword(s):

Neuromuscular Disease ◽

Nuclear Dna ◽

Single Cells ◽

Mitochondrial Diseases ◽

Respiratory Chain Complexes ◽

Base Pairs ◽

Daughter Cells ◽

Dna Molecule ◽

Chain Complexes ◽

Genes Encoding

Mitochondria are responsible for energy production in most eukaryotic cells. Each cell contains at least one mitochondrion and every mitochondrion contains two to ten copies of a circular DNA molecule (mitochondrial DNA or mtDNA). Cardiomyocytes contain approximately 10,000 mtDNA copies. MtDNA is composed of around 16,500 base pairs and 37 genes encoding 13 subunits of the respiratory chain complexes I, III, IV, and V, 22 mitochondrial tRNAs and 2 rRNAs. With each cell division, mitochondria and mtDNA are randomly distributed to daughter cells. In humans, mitochondria are inherited exclusively from the mother. In healthy people mtDNA copies are usually identical at birth (homoplasmy) but with ageing, mtDNA is particularly prone to somatic mutation because, unlike nuclear DNA, it is continuously replicated, even in non-dividing tissues such as myocardium. This can lead to the propagation of somatic mutations within single cells by a process called clonal expansion. In addition, mtDNA lacks an extensive DNA repair mechanism.

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Mitochondrial DNA Variation Dictates Expressivity and Progression of Nuclear DNA Mutations Causing Cardiomyopathy

Cell Metabolism ◽

10.1016/j.cmet.2018.08.002 ◽

2019 ◽

Vol 29 (1) ◽

pp. 78-90.e5 ◽

Cited By ~ 22

Author(s):

Meagan J. McManus ◽

Martin Picard ◽

Hsiao-Wen Chen ◽

Hans J. De Haas ◽

Prasanth Potluri ◽

...

Keyword(s):

Mitochondrial Dna ◽

Nuclear Dna ◽

Dna Variation ◽

Dna Mutations

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Role of Mitochondrial Genome Mutations in Pathogenesis of Carotid Atherosclerosis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/6934394 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7 ◽

Cited By ~ 15

Author(s):

Margarita A. Sazonova ◽

Vasily V. Sinyov ◽

Anastasia I. Ryzhkova ◽

Elena V. Galitsyna ◽

Zukhra B. Khasanova ◽

...

Keyword(s):

Mitochondrial Genome ◽

Carotid Atherosclerosis ◽

Nuclear Dna ◽

Nucleotide Substitutions ◽

Single Nucleotide ◽

Atherosclerotic Lesions ◽

Dna Mutations ◽

Blood Leukocyte ◽

Study Participants

Mutations of mtDNA, due to their higher frequency of occurrence compared to nuclear DNA mutations, are the most promising biomarkers for assessing predisposition of the occurrence and development of atherogenesis. The aim of the present article was an analysis of correlation of several mitochondrial genome mutations with carotid atherosclerosis. Leukocytes from blood of study participants from Moscow polyclinics were used as research material. The sample size was 700 people. The sample members were diagnosed with “atherosclerosis” on the basis of ultrasonographic examination and biochemical and molecular cell tests. DNA was isolated from blood leukocyte samples of the study participants. PCR fragments of DNA, containing the region of 11 investigated mutations, were pyrosequenced. The heteroplasmy level of these mutations was detected. Statistical analysis of the obtained results was performed using the software package SPSS 22.0. According to the obtained results, an association of mutations m.652delG, m.3336C>T, m.12315G>A, m.14459G>A m.15059G>A with carotid atherosclerosis was found. These mutations can be biomarkers for assessing predisposition to this disease. Additionally, two single nucleotide substitutions (m.13513G>A and m.14846G>A), negatively correlating with atherosclerotic lesions, were detected. These mutations may be potential candidates for gene therapy of atherosclerosis and its risk factors.

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The Brain is Hypothermic in Patients with Mitochondrial Diseases

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.38 ◽

2014 ◽

Vol 34 (5) ◽

pp. 915-920 ◽

Cited By ~ 8

Author(s):

Mario Rango ◽

Andrea Arighi ◽

Cristiana Bonifati ◽

Roberto Del Bo ◽

Giacomo Comi ◽

...

Keyword(s):

Mitochondrial Function ◽

Visual Stimulation ◽

Brain Temperature ◽

Mitochondrial Diseases ◽

High Energy ◽

Phosphate Content ◽

High Energy Phosphate ◽

Dna Mutations ◽

The Brain ◽

Healthy Participants

We sought to study brain temperature in patients with mitochondrial diseases in different functional states compared with healthy participants. Brain temperature and mitochondrial function were monitored in the visual cortex and the centrum semiovale at rest and during and after visual stimulation in seven individuals with mitochondrial diseases ( n = 5 with mitochondrial DNA mutations and n = 2 with nuclear DNA mutations) and in 14 age- and sex-matched healthy control participants using a combined approach of visual stimulation, proton magnetic resonance spectroscopy (MRS), and phosphorus MRS. Brain temperature in control participants exhibited small changes during visual stimulation and a consistent increase, together with an increase in high-energy phosphate content, after visual stimulation. Brain temperature was persistently lower in individuals with mitochondrial diseases than in healthy participants at rest, during activation, and during recovery, without significant changes from one state to another and with a decrease in the high-energy phosphate content. The lowest brain temperature was observed in the patient with the most deranged mitochondrial function. In patients with mitochondrial diseases, the brain is hypothermic because of malfunctioning oxidative phosphorylation. Neuronal activity is reduced at rest, during physiologic brain stimulation, and after stimulation.

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Exogenous artificial DNA forms chromatin structure with active transcription in yeast

Science China Life Sciences ◽

10.1007/s11427-021-2044-x ◽

2021 ◽

Author(s):

Jianting Zhou ◽

Chao Zhang ◽

Ran Wei ◽

Mingzhe Han ◽

Songduo Wang ◽

...

Keyword(s):

Data Storage ◽

Dna Sequences ◽

Chromatin Accessibility ◽

Binding Motifs ◽

Artificial Chromosomes ◽

Sequencing Technologies ◽

Artificial Dna ◽

Active Transcription ◽

Reported Data ◽

Yeast Artificial Chromosomes

AbstractYeast artificial chromosomes (YACs) are important tools for sequencing, gene cloning, and transferring large quantities of genetic information. However, the structure and activity of YAC chromatin, as well as the unintended impacts of introducing foreign DNA sequences on DNA-associated biochemical events, have not been widely explored. Here, we showed that abundant genetic elements like TATA box and transcription factor-binding motifs occurred unintentionally in a previously reported data-carrying chromosome (dChr). In addition, we used state-of-the-art sequencing technologies to comprehensively profile the genetic, epigenetic, transcriptional, and proteomic characteristics of the exogenous dChr. We found that the data-carrying DNA formed active chromatin with high chromatin accessibility and H3K4 tri-methylation levels. The dChr also displayed highly pervasive transcriptional ability and transcribed hundreds of noncoding RNAs. The results demonstrated that exogenous artificial chromosomes formed chromatin structures and did not remain as naked or loose plasmids. A better understanding of the YAC chromatin nature will improve our ability to design better data-storage chromosomes.

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Epidemiology and demographics of juvenile idiopathic arthritis in Africa and Middle East

Pediatric Rheumatology ◽

10.1186/s12969-021-00650-x ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Sulaiman M. Al-Mayouf ◽

Muna Al Mutairi ◽

Kenza Bouayed ◽

Sara Habjoka ◽

Djohra Hadef ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Middle East ◽

Treatment Guidelines ◽

Local Treatment ◽

Epidemiological Data ◽

Joint Inflammation ◽

Global Estimate ◽

Medical Need ◽

Prevalent Subtype ◽

Children And Young Adults

AbstractJuvenile Idiopathic Arthritis (JIA) is a group of chronic heterogenous disorders that manifests as joint inflammation in patients aged <16 years. Globally, approximately 3 million children and young adults are suffering from JIA with prevalence rates consistently higher in girls. The region of Africa and Middle East constitute a diverse group of ethnicities, socioeconomic conditions, and climates which influence the prevalence of JIA. There are only a few studies published on epidemiology of JIA in the region. There is an evident paucity of adequate and latest data from the region. This review summarizes the available data on the prevalence of JIA and its subtypes in Africa and Middle East and discusses unmet needs for patients in this region. A total of 8 journal publications were identified concerning epidemiology and 42 articles describing JIA subtypes from Africa and Middle East were included. The prevalence of JIA in Africa and Middle East was observed to be towards the lower range of the global estimate. We observed that the most prevalent subtype in the region was oligoarticular arthritis. The incidence of uveitis and anti-nuclear antibody (ANA) positivity were found to be lower as compared to the incidence from other regions. There is a huge unmet medical need in the region for reliable epidemiological data, disease awareness, having regional and local treatment guidelines and timely diagnosis. Paucity of the pediatric rheumatologists and economic disparities also contribute to the challenges regarding the management of JIA.

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