Diagnosis of ‘possible’ mitochondrial disease: an existential crisis

Primary genetic mitochondrial diseases are often difficult to diagnose, and the term ‘possible’ mitochondrial disease is used frequently by clinicians when such a diagnosis is suspected. There are now many known phenocopies of mitochondrial disease. Advances in genomic testing have shown that some patients with a clinical phenotype and biochemical abnormalities suggesting mitochondrial disease may have other genetic disorders. In instances when a genetic diagnosis cannot be confirmed, a diagnosis of ‘possible’ mitochondrial disease may result in harm to patients and their families, creating anxiety, delaying appropriate diagnosis and leading to inappropriate management or care. A categorisation of ‘diagnosis uncertain’, together with a specific description of the metabolic or genetic abnormalities identified, is preferred when a mitochondrial disease cannot be genetically confirmed.

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Advancing genomic approaches to the molecular diagnosis of mitochondrial disease

Essays in Biochemistry ◽

10.1042/ebc20170110 ◽

2018 ◽

Vol 62 (3) ◽

pp. 399-408 ◽

Cited By ~ 23

Author(s):

Sarah Louise Stenton ◽

Holger Prokisch

Keyword(s):

Molecular Diagnosis ◽

Mitochondrial Disease ◽

Genetic Diagnosis ◽

Mitochondrial Diseases ◽

Candidate Gene Approach ◽

Disease Genes ◽

Variant Interpretation ◽

Diagnostic Challenge ◽

Whole Exome ◽

Prior Analysis

Mitochondrial diseases present a diagnostic challenge due to their clinical and genetic heterogeneity. Achieving comprehensive molecular diagnosis via a conventional candidate-gene approach is likely, therefore, to be labour- and cost-intensive given the expanding number of mitochondrial disease genes. The advent of whole exome sequencing (WES) and whole genome sequencing (WGS) hold the potential of higher diagnostic yields due to the universality and unbiased nature of the methods. However, these approaches are subject to the escalating challenge of variant interpretation. Thus, integration of functional ‘multi-omics’ data, such as transcriptomics, is emerging as a powerful complementary tool in the diagnosis of mitochondrial disease patients for whom extensive prior analysis of DNA sequencing has failed to return a genetic diagnosis.

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Oxygraphy Versus Enzymology for the Biochemical Diagnosis of Primary Mitochondrial Disease

Metabolites ◽

10.3390/metabo9100220 ◽

2019 ◽

Vol 9 (10) ◽

pp. 220

Author(s):

Matthew J Bird ◽

Isabelle Adant ◽

Petra Windmolders ◽

Ingrid Vander Elst ◽

Catarina Felgueira ◽

...

Keyword(s):

Mitochondrial Disease ◽

Genetic Disorders ◽

Genetic Diagnosis ◽

Fibroblast Cell ◽

Specific Information ◽

Mitochondrial Oxidative Phosphorylation ◽

Biochemical Tests ◽

Sequencing Technologies ◽

Generation Sequencing ◽

Fibroblast Cell Lines

Primary mitochondrial disease (PMD) is a large group of genetic disorders directly affecting mitochondrial function. Although next generation sequencing technologies have revolutionized the diagnosis of these disorders, biochemical tests remain essential and functional confirmation of the critical genetic diagnosis. While enzymological testing of the mitochondrial oxidative phosphorylation (OXPHOS) complexes remains the gold standard, oxygraphy could offer several advantages. To this end, we compared the diagnostic performance of both techniques in a cohort of 34 genetically defined PMD patient fibroblast cell lines. We observed that oxygraphy slightly outperformed enzymology for sensitivity (79 ± 17% versus 68 ± 15%, mean and 95% CI), and had a better discriminatory power, identifying 58 ± 17% versus 35 ± 17% as “very likely” for oxygraphy and enzymology, respectively. The techniques did, however, offer synergistic diagnostic prediction, as the sensitivity rose to 88 ± 11% when considered together. Similarly, the techniques offered varying defect specific information, such as the ability of enzymology to identify isolated OXPHOS deficiencies, while oxygraphy pinpointed PDHC mutations and captured POLG mutations that were otherwise missed by enzymology. In summary, oxygraphy provides useful information for the diagnosis of PMD, and should be considered in conjunction with enzymology for the diagnosis of PMD.

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Endocrine manifestations and new developments in mitochondrial disease

Endocrine Reviews ◽

10.1210/endrev/bnab036 ◽

2021 ◽

Author(s):

Yi Shiau Ng ◽

Albert Zishen Lim ◽

Grigorios Panagiotou ◽

Doug M Turnbull ◽

Mark Walker

Keyword(s):

Mitochondrial Disease ◽

Genetic Diagnosis ◽

Mitochondrial Diseases ◽

Next Generation ◽

Research Activity ◽

New Developments ◽

Organ Systems ◽

Life Threatening ◽

Mitochondrial Dna Variants

Abstract Mitochondrial diseases are a group of common inherited diseases causing disruption of oxidative phosphorylation. Some patients with mitochondrial disease have endocrine manifestations, with diabetes being predominant but also include hypogonadism, hypoadrenalism and hypoparathyroidism. There have been major developments in mitochondrial disease over the last decade that have major implications for all patients. The collection of large cohorts of patients has better defined the phenotype of mitochondrial diseases and the majority of patients with endocrine abnormalities have involvement of several other systems. This means that patients with mitochondrial disease and endocrine manifestations need specialist follow up because some of the other manifestations, such as stroke-like episodes and cardiomyopathy, are potentially life threatening. Also, the development and follow up of large cohorts of patients means that there are clinical guidelines for the management of patients with mitochondrial disease. There is also considerable research activity to identify novel therapies for the treatment of mitochondrial disease. The revolution in genetics, with the introduction of next generation sequencing, has made genetic testing more available and establishing a precise genetic diagnosis is important since it will affect the risk for involvement for different organ systems. Establishing a genetic diagnosis is also crucial since there are important reproductive options have been developed which will prevent the transmission of mitochondrial disease due to mitochondrial DNA variants to the next generation.

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The Power of Options: The Solution for Healthier Society and Better Economy

Research in Health Science ◽

10.22158/rhs.v2n4p350 ◽

2017 ◽

Vol 2 (4) ◽

pp. 350

Author(s):

Dr. Saleh A. S. AL-Abdulhadi

Keyword(s):

Reproductive Medicine ◽

Genetic Disorders ◽

Genetic Diagnosis ◽

Community Services ◽

Human Oocyte ◽

Genetic Composition ◽

Vitro Fertilization ◽

Genetic Abnormalities ◽

New Frontier

<p><em>Preimplantation Genetic Diagnosis (PGD) testing is the practice of obtaining a cellular biopsy sample from a developing human oocyte or embryo, acquired via a cycle of In Vitro Fertilization (IVF); evaluating the genetic composition of this sample; and using this information to determine which embryos will be optimal for subsequent uterine transfer. PGD has become an increasingly useful adjunct to IVF procedures. The ability to provide couples who are known carriers of genetic abnormalities the opportunity to deliver healthy babies has opened a new frontier in reproductive medicine. The purpose of the PGD is enables us to choose which embryos will be implanted into the mother. In the present study we investigate the frequency of application of this technique in the kingdom and GCC to find out, the population awareness of these technique and the advantages which could apply to the community. We also interested to know frequencies of centers and studies in this field. This epidemiological study helps to improve social awareness and community services toward reducing frequencies of genetic disorders. </em></p>

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Advances in mt-tRNA Mutation-Caused Mitochondrial Disease Modeling: Patients’ Brain in a Dish

Frontiers in Genetics ◽

10.3389/fgene.2020.610764 ◽

2021 ◽

Vol 11 ◽

Author(s):

Suleva Povea-Cabello ◽

Marina Villanueva-Paz ◽

Juan M. Suárez-Rivero ◽

Mónica Álvarez-Córdoba ◽

Irene Villalón-García ◽

...

Keyword(s):

Mitochondrial Disease ◽

Disease Modeling ◽

Genetic Disorders ◽

Genetic Diseases ◽

Mitochondrial Diseases ◽

Pathological Feature ◽

Mtdna Mutations ◽

Induced Pluripotent ◽

Induced Neurons ◽

Merrf Syndrome

Mitochondrial diseases are a heterogeneous group of rare genetic disorders that can be caused by mutations in nuclear (nDNA) or mitochondrial DNA (mtDNA). Mutations in mtDNA are associated with several maternally inherited genetic diseases, with mitochondrial dysfunction as a main pathological feature. These diseases, although frequently multisystemic, mainly affect organs that require large amounts of energy such as the brain and the skeletal muscle. In contrast to the difficulty of obtaining neuronal and muscle cell models, the development of induced pluripotent stem cells (iPSCs) has shed light on the study of mitochondrial diseases. However, it is still a challenge to obtain an appropriate cellular model in order to find new therapeutic options for people suffering from these diseases. In this review, we deepen the knowledge in the current models for the most studied mt-tRNA mutation-caused mitochondrial diseases, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and MERRF (myoclonic epilepsy with ragged red fibers) syndromes, and their therapeutic management. In particular, we will discuss the development of a novel model for mitochondrial disease research that consists of induced neurons (iNs) generated by direct reprogramming of fibroblasts derived from patients suffering from MERRF syndrome. We hypothesize that iNs will be helpful for mitochondrial disease modeling, since they could mimic patient’s neuron pathophysiology and give us the opportunity to correct the alterations in one of the most affected cellular types in these disorders.

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An automatic diagnostic system for pediatric genetic disorders developed by linking genotype and phenotype information

10.1101/2021.08.26.21261185 ◽

2021 ◽

Author(s):

Xinran Dong ◽

Bingbing Wu ◽

Huijun Wang ◽

Lin Yang ◽

Xiang Chen ◽

...

Keyword(s):

Clinical Phenotype ◽

Genetic Disorders ◽

Quantitative Description ◽

Genetic Diagnosis ◽

Diagnostic System ◽

Causal Gene ◽

Bayes Model ◽

Phenotype Data ◽

Precision Recall Curve ◽

Pediatric Disorders

Background: Quantitatively describe the phenotype spectrum of pediatric disorders has remarkable power to assist genetic diagnosis. Here, we developed a matrix which provide this quantitative description of genomic-phenotypic association and constructed an automatic system to assist the diagnose of pediatric genetic disorders. Results: 20,580 patients with genetic diagnostic conclusions from the Children's Hospital of Fudan University during 2015 to 2019 were reviewed. Based on that, a phenotype spectrum matrix -- cGPS (clinical Gene's Preferential Synopsis) -- was designed by Naive Bayes model to quantitatively describe genes' contribution to clinical phenotype categories. Further, for patients who have both genomic and phenotype data, we designed a ConsistencyScore based on cGPS. ConsistencyScore aimed to figure out genes that were more likely to be the genetic causal of the patient's phenotype and to prioritize the causal gene among all candidates. When using the ConsistencyScore in each sample to predict the causal gene for patients, the AUC could reach 0.975 for ROC (95% CI 0.972-0.976 and 0.575 for precision-recall curve (95% CI 0.541-0.604). Further, the performance of ConsistencyScore was evaluated on another cohort with 2,323 patients, which could rank the causal gene of the patient as the first for 75.00% (95% CI 70.95%-79.07%) of the 296 positively genetic diagnosed patients. The causal gene of 97.64% (95% CI 95.95%-99.32%) patients could be ranked within top 10 by ConsistencyScore, which is much higher than existing algorithms (p <0.001). Conclusions: cGPS and ConsistencyScore offer useful tools to prioritize disease-causing genes for pediatric disorders and show great potential in clinical applications.

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Epilepsy in Mitochondrial Diseases—Current State of Knowledge on Aetiology and Treatment

Children ◽

10.3390/children8070532 ◽

2021 ◽

Vol 8 (7) ◽

pp. 532

Author(s):

Dorota Wesół-Kucharska ◽

Dariusz Rokicki ◽

Aleksandra Jezela-Stanek

Keyword(s):

Oxidative Phosphorylation ◽

Mitochondrial Dysfunction ◽

Mitochondrial Disease ◽

Clinical Picture ◽

Poor Prognosis ◽

Treatment Options ◽

Mitochondrial Diseases ◽

Energy Deficit ◽

Atp Production ◽

Current State

Mitochondrial diseases are a heterogeneous group of diseases resulting from energy deficit and reduced adenosine triphosphate (ATP) production due to impaired oxidative phosphorylation. The manifestation of mitochondrial disease is usually multi-organ. Epilepsy is one of the most common manifestations of diseases resulting from mitochondrial dysfunction, especially in children. The onset of epilepsy is associated with poor prognosis, while its treatment is very challenging, which further adversely affects the course of these disorders. Fortunately, our knowledge of mitochondrial diseases is still growing, which gives hope for patients to improve their condition in the future. The paper presents the pathophysiology, clinical picture and treatment options for epilepsy in patients with mitochondrial disease.

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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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Attitudes Toward Pre-implantation Genetic Diagnosis (PGD) for Genetic Disorders Among Potential Users in Malaysia

Science and Engineering Ethics ◽

10.1007/s11948-015-9639-z ◽

2015 ◽

Vol 22 (1) ◽

pp. 133-146 ◽

Cited By ~ 6

Author(s):

Angelina Patrick Olesen ◽

Siti Nurani Mohd Nor ◽

Latifah Amin

Keyword(s):

Genetic Disorders ◽

Genetic Diagnosis

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The Use of CRISPR-Cas9 Technology to Study and Create Cancer Therapeutics

Journal of Student Research ◽

10.47611/jsr.v8i1.519 ◽

2019 ◽

Vol 8 (1) ◽

Author(s):

Andrew J. Kennedy ◽

Jeffrey O. Henderson

Keyword(s):

Genetic Disorders ◽

Treatment Options ◽

Cancer Therapeutics ◽

Current Treatment ◽

Genetic Abnormality ◽

Traditional Treatment ◽

Root Cause ◽

Cancerous Cell ◽

Genetic Abnormalities ◽

Prime Target

Genetic disorders are the result of abnormalities that arise in the human genome at birth or through postnatal random genetic change. These abnormalities can also increase the risk for developing other diseases such as cancerous cell growth. Traditional treatment for genetic disorders has focused on alleviation of symptoms to increase patient welfare rather than treating the root cause, the genetic abnormality. As genetic editing technologies are developed and refined, the prospect of correcting the abnormal genetic sequence is becoming realistic. The CRISPR-Cas9 system has made it possible for researchers to respond to genetic abnormalities quickly by cutting and replacing the abnormal sequence to then contain a healthy sequence and potentially reverse the abnormal phenotype. Cancer, a disease based on genetic dysfunction, is a prime target for genetic editing. Often treated with debilitating radiation, chemotherapy, or surgery, the use of genetic editing has the potential to revolutionize current treatment options. This review will discuss the current outlook of cancer and its treatment with a focus on how CRISPR-Cas9 can be used to edit immunotherapy options that clinicians currently possess. Furthermore, potential dangers of the CRISPR-Cas9 technology and consequences of the system and its unethical use will be discussed. Finally, there will be an evaluation on the future of how CRISPR-Cas9 can be used in medicine.

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