scholarly journals Diagnosing pediatric mitochondrial disease: lessons from 2,000 exomes

2021 ◽  
Author(s):  
Sarah L Stenton ◽  
Masaru Shimura ◽  
Dorota Piekutowska-Abramczuk ◽  
Peter Freisinger ◽  
Felix Distelmaier ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Molecular Diagnosis ◽  
Mitochondrial Disease ◽  
Mitochondrial Diseases ◽  
Improve Patient Care ◽  
Disease Genes ◽  
Common Denominator ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Genes Encoding

Background: The spectrum of mitochondrial disease is genetically and phenotypically diverse, resulting from pathogenic variants in over 400 genes, with aerobic energy metabolism defects as a common denominator. Such heterogeneity poses a significant challenge in making an accurate diagnosis, critical for precision medicine. Methods: In an international collaboration initiated by the European Network for Mitochondrial Diseases (GENOMIT) we recruited 2,023 pediatric patients at 11 specialist referral centers between October 2010 and January 2021, accumulating exome sequencing and HPO-encoded phenotype data. An exome-wide search for variants in known and potential novel disease genes, complemented by functional studies, followed ACMG guidelines. Results: 1,109 cases (55%) received a molecular diagnosis, of which one fifth have potential disease-modifying treatments (236/1,109, 21%). Functional studies enabled diagnostic uplift from 36% to 55% and discovery of 62 novel disease genes. Pathogenic variants were identified within genes encoding mitochondrial proteins or RNAs in 801 cases (72%), while, given extensive phenotype overlap, the remainder involved proteins targeted to other cellular compartments. To delineate genotype-phenotype associations, our data was complemented with registry and literature data to develop GENOMITexplorer, an open access resource detailing patient- (n=3,940), gene- (n=427), and variant-level (n=1,492) associations (prokischlab.github.io/GENOMITexplorer/). Conclusions: Reaching a molecular diagnosis was essential for implementation of precision medicine and clinical trial eligibility, underlining the need for genome-wide screening given inability to accurately define mitochondrial diseases clinically. Key to diagnostic success were functional studies, encouraging early acquisition of patient-derived tissues and routine integration of high-throughput functional data to improve patient care by uplifting diagnostic rate.

Advancing genomic approaches to the molecular diagnosis of mitochondrial disease

2018 ◽  
Vol 62 (3) ◽  
pp. 399-408 ◽  
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.

scholarly journals Modulating Mitophagy in Mitochondrial Disease

2019 ◽  
Vol 25 (40) ◽  
pp. 5597-5612 ◽  
Author(s):  
Eszter Dombi ◽  
Heather Mortiboys ◽  
Joanna Poulton
Keyword(s):  
Signaling Pathways ◽  
Mitochondrial Disease ◽  
Coenzyme Q ◽  
Mitochondrial Diseases ◽  
Degradation Pathway ◽  
Selective Degradation ◽  
Genes Encoding ◽  
Phosphoinositide 3 Kinase ◽  
Quality Control Mechanism ◽  
Amp Activated Protein Kinase

Mitochondrial diseases may result from mutations in the maternally-inherited mitochondrial DNA (mtDNA) or from mutations in nuclear genes encoding mitochondrial proteins. Their bi-genomic nature makes mitochondrial diseases a very heterogeneous group of disorders that can present at any age and can affect any type of tissue. The autophagic-lysosomal degradation pathway plays an important role in clearing dysfunctional and redundant mitochondria through a specific quality control mechanism termed mitophagy. Mitochondria could be targeted for autophagic degradation for a variety of reasons including basal turnover for recycling, starvation induced degradation, and degradation due to damage. While the core autophagic machinery is highly conserved and common to most pathways, the signaling pathways leading to the selective degradation of damaged mitochondria are still not completely understood. Type 1 mitophagy due to nutrient starvation is dependent on PI3K (phosphoinositide 3-kinase) for autophagosome formation but independent of mitophagy proteins, PINK1 (PTEN-induced putative kinase 1) and Parkin. Whereas type 2 mitophagy that occurs due to damage is dependent on PINK1 and Parkin but does not require PI3K. Autophagy and mitophagy play an important role in human disease and hence could serve as therapeutic targets for the treatment of mitochondrial as well as neurodegenerative disorders. Therefore, we reviewed drugs that are known modulators of autophagy (AICAR and metformin) and may affect this by activating the AMP-activated protein kinase signaling pathways. Furthermore, we reviewed the data available on supplements, such as Coenzyme Q and the quinone idebenone, that we assert rescue increased mitophagy in mitochondrial disease by benefiting mitochondrial function.

scholarly journals Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders

2018 ◽  
Vol 4 (1) ◽  
pp. e212 ◽  
Author(s):  
Gloria T. Haskell ◽  
Michael C. Adams ◽  
Zheng Fan ◽  
Krunal Amin ◽  
Roberto J. Guzman Badillo ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Molecular Diagnosis ◽  
Diagnostic Yield ◽  
Neuromuscular Disorders ◽  
Gene List ◽  
Disease Genes ◽  
Causative Gene ◽  
Pathogenic Variants ◽  
Prior Testing ◽  
Genome Scale

ObjectiveTo evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs).MethodsWe performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup.ResultsThe overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis.ConclusionsGenome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.

Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease

2021 ◽  
Author(s):  
Wen-Qiang Zheng ◽  
Signe Vandal Pedersen ◽  
Kyle Thompson ◽  
Emanuele Bellacchio ◽  
Courtney E French ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Clinical Phenotype ◽  
Homology Modelling ◽  
Mitochondrial Diseases ◽  
Trna Synthetase ◽  
Unrelated Patient ◽  
Mitochondrial Translation ◽  
Respiratory Chain Enzyme ◽  
Functional Studies ◽  
Pathogenic Variants

Abstract TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNAThr and clearing mischarged Ser-tRNAThr during mitochondrial translation. Pathogenic variants in TARS2 have hitherto been reported in a pair of siblings and an unrelated patient with an early onset mitochondrial encephalomyopathy and a combined respiratory chain enzyme deficiency in muscle. We here report five additional unrelated patients with TARS2-related mitochondrial diseases, expanding the clinical phenotype to also include epilepsy, dystonia, hyperhidrosis and severe hearing impairment. Additionally, we document seven novel TARS2 variants—one nonsense variant and six missense variants—that we demonstrate are pathogenic and causal of the disease presentation based on population frequency, homology modelling and functional studies that show the effects of the pathogenic variants on TARS2 stability and/or function.

scholarly journals Ancient mitochondrial DNA pathogenic variants putatively associated with mitochondrial disease

2020 ◽  
Author(s):  
Draga Toncheva ◽  
Dimitar Serbezov ◽  
Sena Karachanak-Yankova ◽  
Desislava Nesheva
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Disease ◽  
Novel Mutation ◽  
Mitochondrial Diseases ◽  
Type Model ◽  
Human Populations ◽  
Neolithic Period ◽  
Pathogenic Variants ◽  
Pathogenic Effect ◽  
Mtdna Variants

AbstractMitochondrial DNA variants associated with diseases are widely studied in contemporary populations, but their prevalence has not yet been investigated in ancient populations. The publicly available AmtDB database contains 1443 ancient mtDNA Eurasian genomes from different periods. The objective of this study was to use this data to establish the presence of pathogenic mtDNA variants putatively associated with mitochondrial diseases in ancient populations. The clinical significance, pathogenicity prediction and contemporary frequency of mtDNA variants were determined using online platforms. The analyzed ancient mtDNAs contain six variants designated as being “confirmed pathogenic” in modern patients. The oldest of these, m.7510T>C in the MT-TS1 gene, was found in a sample from the Neolithic period dated 5800-5400 BCE. All six have well established clinical association, and their pathogenic effect is corroborated by very low population frequencies in contemporary populations. In addition, ten variants designated as possibly or likely pathogenic were detected. The oldest of these were two variants in the MT-TD gene, m.7543A>G and m.7554G>A, from Neolithic samples dated 8205-7700 BCE. A novel mutation in contemporary populations, m.4440G>A in the MT-TM gene, is established in 12 ancient mtDNA samples from different periods ranging from 2800 BCE to 920 CE. The pathogenic effect of these possibly/likely pathogenic mutations is not yet well established, and further research is warranted. All detected mutations putatively associated with mitochondrial disease in ancient mtDNA samples are in tRNA coding genes. Most of these mutations are in a mt-tRNA type (Model 2) that is characterized by loss of D-loop/T-loop interaction. Seven mutations are located in CS-Anticodon stem, 4 are located in AS-Acceptor stem, 2 in TS-TΨC stem, and single mutations are found in DL-Dihydrouridine Loop, CL-Anticodon Loop and DS-Dihydrouridine stem. Exposing pathogenic variants in ancient human populations expands our understanding of their origin.

scholarly journals Blackout in the powerhouse: clinical phenotypes associated with defects in the assembly of OXPHOS complexes and the mitoribosome

2020 ◽  
Vol 477 (21) ◽  
pp. 4085-4132
Author(s):  
Daniella H. Hock ◽  
David R. L. Robinson ◽  
David A. Stroud
Keyword(s):  
Mitochondrial Disease ◽  
Mitochondrial Diseases ◽  
Basic Research ◽  
Post Translational Modification ◽  
Mitochondrial Ribosomes ◽  
Heterogenous Group ◽  
Mitochondrial Ribosome ◽  
Genes Encoding ◽  
Severity Of The Disease ◽  
Almost All

Mitochondria produce the bulk of the energy used by almost all eukaryotic cells through oxidative phosphorylation (OXPHOS) which occurs on the four complexes of the respiratory chain and the F1–F0 ATPase. Mitochondrial diseases are a heterogenous group of conditions affecting OXPHOS, either directly through mutation of genes encoding subunits of OXPHOS complexes, or indirectly through mutations in genes encoding proteins supporting this process. These include proteins that promote assembly of the OXPHOS complexes, the post-translational modification of subunits, insertion of cofactors or indeed subunit synthesis. The latter is important for all 13 of the proteins encoded by human mitochondrial DNA, which are synthesised on mitochondrial ribosomes. Together the five OXPHOS complexes and the mitochondrial ribosome are comprised of more than 160 subunits and many more proteins support their biogenesis. Mutations in both nuclear and mitochondrial genes encoding these proteins have been reported to cause mitochondrial disease, many leading to defective complex assembly with the severity of the assembly defect reflecting the severity of the disease. This review aims to act as an interface between the clinical and basic research underpinning our knowledge of OXPHOS complex and ribosome assembly, and the dysfunction of this process in mitochondrial disease.

scholarly journals Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1083
Author(s):  
Emanuela Bottani ◽  
Costanza Lamperti ◽  
Alessandro Prigione ◽  
Valeria Tiranti ◽  
Nicola Persico ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Metabolic Diseases ◽  
Primary Source ◽  
Mitochondrial Diseases ◽  
Atp Synthesis ◽  
Clinical Results ◽  
Limited Information ◽  
Large Variability ◽  
Genes Encoding ◽  
Organ Specific

Primary mitochondrial diseases (PMD) refer to a group of severe, often inherited genetic conditions due to mutations in the mitochondrial genome or in the nuclear genes encoding for proteins involved in oxidative phosphorylation (OXPHOS). The mutations hamper the last step of aerobic metabolism, affecting the primary source of cellular ATP synthesis. Mitochondrial diseases are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. The limited information of the natural history, the limitations of currently available preclinical models, coupled with the large variability of phenotypical presentations of PMD patients, have strongly penalized the development of effective therapies. However, new therapeutic strategies have been emerging, often with promising preclinical and clinical results. Here we review the state of the art on experimental treatments for mitochondrial diseases, presenting “one-size-fits-all” approaches and precision medicine strategies. Finally, we propose novel perspective therapeutic plans, either based on preclinical studies or currently used for other genetic or metabolic diseases that could be transferred to PMD.

scholarly journals Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes

2021 ◽  
Author(s):  
Silvia Martin-Almedina ◽  
Kazim Ogmen ◽  
Ege Sackey ◽  
Dionysios Grigoriadis ◽  
Christina Karapouliou ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Fetal Hydrops ◽  
Clinical Phenotypes ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Disease Mechanisms ◽  
Novel Variants ◽  
Uncertain Significance ◽  
Clinical Phenotyping

Abstract Purpose Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level. Methods Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity. Results Pathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the phosphorylation capability of the receptor. There was some phenotype–genotype correlation; however, previously unreported intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops (LRFH) and CM-AVM2 in the same family were observed. Conclusion This study highlights the usefulness of protein expression and subcellular localization studies to predict EPHB4 variant pathogenesis. Our accurate clinical phenotyping expands our interpretation of the Janus-faced spectrum of EPHB4-related disorders, introducing the discovery of cases with overlapping phenotypes.

scholarly journals One4Two®: An Integrated Molecular Approach to Optimize Infertile Couples’ Journey

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 60
Author(s):  
Valeria D’Argenio ◽  
Federica Cariati ◽  
Rossella Tomaiuolo
Keyword(s):  
Disease Genes ◽  
Diagnostic Efficacy ◽  
Whole Process ◽  
Pathogenic Variants ◽  
Limiting Step ◽  
Number Of Genes ◽  
Infertile Couples ◽  
Next Generation Sequencing Ngs ◽  
And Diffusion ◽  
Generation Sequencing

The current diagnostic path of infertile couples is long lasting and often ineffective. Genetic tests, in particular, appear as a limiting step due to their jeopardized use on one side, and to the limited number of genes evaluated on the other. In this context, the development and diffusion, also in routine diagnostic settings, of next generation sequencing (NGS)-based methods for the analyses of several genes in multiple subjects at a time is improving the diagnostic sensitivity of molecular analyses. Thus, we developed One4Two®, a custom NGS panel to optimize the diagnostic journey of infertile couples. The panel validation was carried out in three steps analyzing a total of 83 subjects. Interestingly, all the previously identified variants were confirmed, assessing the analytic sensitivity of the method. Moreover, additional pathogenic variants have been identified underlying the diagnostic efficacy of the proposed method. One4Two® allows the simultaneous analysis of infertility-related genes, disease-genes of common inherited diseases, and of polymorphisms related to therapy outcome. Thus, One4Two® is able to improve the diagnostic journey of infertile couples by simplifying the whole process not only for patients, but also for laboratories and reproduction specialists moving toward an even more personalized medicine.

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

Children ◽  
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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