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12 pages, 1687 KiB

Open AccessArticle

Mitochondrial Strokes: Diagnostic Challenges and Chameleons

by Chiara Pizzamiglio, Enrico Bugiardini, William L. Macken, Cathy E. Woodward, Michael G. Hanna and Robert D. S. Pitceathly

Genes 2021, 12(10), 1643; https://doi.org/10.3390/genes12101643 - 19 Oct 2021

Cited by 8 | Viewed by 2780

Abstract

Mitochondrial stroke-like episodes (SLEs) are a hallmark of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). They should be suspected in anyone with an acute/subacute onset of focal neurological symptoms at any age and are usually driven by seizures. Suggestive features of an [...] Read more.

Mitochondrial stroke-like episodes (SLEs) are a hallmark of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). They should be suspected in anyone with an acute/subacute onset of focal neurological symptoms at any age and are usually driven by seizures. Suggestive features of an underlying mitochondrial pathology include evolving MRI lesions, often originating within the posterior brain regions, the presence of multisystemic involvement, including diabetes, deafness, or cardiomyopathy, and a positive family history. The diagnosis of MELAS has important implications for those affected and their relatives, given it enables early initiation of appropriate treatment and genetic counselling. However, the diagnosis is frequently challenging, particularly during the acute phase of an event. We describe four cases of mitochondrial strokes to highlight the considerable overlap that exists with other neurological disorders, including viral and autoimmune encephalitis, ischemic stroke, and central nervous system (CNS) vasculitis, and discuss the clinical, laboratory, and imaging features that can help distinguish MELAS from these differential diagnoses. Full article

(This article belongs to the Special Issue Expanding the Genetic Landscape of Mitochondrial Diseases)

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12 pages, 1264 KiB

Open AccessArticle

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

by Marcello Bellusci, Abraham J Paredes-Fuentes, Eduardo Ruiz-Pesini, Beatriz Gómez, MITOSPAIN Working Group, Miguel A Martín, Julio Montoya and Rafael Artuch

Genes 2021, 12(10), 1590; https://doi.org/10.3390/genes12101590 - 9 Oct 2021

Cited by 9 | Viewed by 6053

Abstract

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. [...] Read more.

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. Full article

(This article belongs to the Special Issue Expanding the Genetic Landscape of Mitochondrial Diseases)

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19 pages, 1106 KiB

Open AccessArticle

Mitochondrial Genetic Heterogeneity in Leber’s Hereditary Optic Neuropathy: Original Study with Meta-Analysis

by Rajan Kumar Jha, Chhavi Dawar, Qurratulain Hasan, Akhilesh Pujar, Gaurav Gupta, Venugopalan Y. Vishnu, Ramesh Kekunnaya and Kumarasamy Thangaraj

Genes 2021, 12(9), 1300; https://doi.org/10.3390/genes12091300 - 24 Aug 2021

Cited by 9 | Viewed by 4045

Abstract

Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disorder that causes loss of central vision. Three primary variants (m.3460G>A, m.11778G>A, and m.14484T>C) and about 16 secondary variants are responsible for LHON in the majority of the cases. We investigated the complete mitochondrial DNA [...] Read more.

Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disorder that causes loss of central vision. Three primary variants (m.3460G>A, m.11778G>A, and m.14484T>C) and about 16 secondary variants are responsible for LHON in the majority of the cases. We investigated the complete mitochondrial DNA (mtDNA) sequences of 189 LHON patients and found a total of 54 disease-linked pathogenic variants. The primary variants m.11778G>A and m.14484T>C were accountable for only 14.81% and 2.64% cases, respectively. Patients with these two variants also possessed additional disease-associated variants. Among 156 patients who lacked the three primary variants, 16.02% harboured other LHON-associated variants either alone or in combination with other disease-associated variants. Furthermore, we observed that none of the haplogroups were explicitly associated with LHON. We performed a meta-analysis of m.4216T>C and m.13708G>A and found a significant association of these two variants with the LHON phenotype. Based on this study, we recommend the use of complete mtDNA sequencing to diagnose LHON, as we found disease-associated variants throughout the mitochondrial genome. Full article

(This article belongs to the Special Issue Expanding the Genetic Landscape of Mitochondrial Diseases)

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13 pages, 1867 KiB

Open AccessArticle

Application of Genome Sequencing from Blood to Diagnose Mitochondrial Diseases

by Rocio Rius, Alison G. Compton, Naomi L. Baker, AnneMarie E. Welch, David Coman, Maina P. Kava, Andre E. Minoche, Mark J. Cowley, David R. Thorburn and John Christodoulou

Genes 2021, 12(4), 607; https://doi.org/10.3390/genes12040607 - 20 Apr 2021

Cited by 7 | Viewed by 4861

Abstract

Mitochondrial diseases can be caused by pathogenic variants in nuclear or mitochondrial DNA-encoded genes that often lead to multisystemic symptoms and can have any mode of inheritance. Using a single test, Genome Sequencing (GS) can effectively identify variants in both genomes, but it [...] Read more.

Mitochondrial diseases can be caused by pathogenic variants in nuclear or mitochondrial DNA-encoded genes that often lead to multisystemic symptoms and can have any mode of inheritance. Using a single test, Genome Sequencing (GS) can effectively identify variants in both genomes, but it has not yet been universally used as a first-line approach to diagnosing mitochondrial diseases due to related costs and challenges in data analysis. In this article, we report three patients with mitochondrial disease molecularly diagnosed through GS performed on DNA extracted from blood to demonstrate different diagnostic advantages of this technology, including the detection of a low-level heteroplasmic pathogenic variant, an intragenic nuclear DNA deletion, and a large mtDNA deletion. Current technical improvements and cost reductions are likely to lead to an expanded routine diagnostic usage of GS and of the complementary “Omic” technologies in mitochondrial diseases. Full article

(This article belongs to the Special Issue Expanding the Genetic Landscape of Mitochondrial Diseases)

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11 pages, 14281 KiB

Open AccessArticle

Leigh Syndrome Due to NDUFV1 Mutations Initially Presenting as LBSL

by Nurun Nahar Borna, Yoshihito Kishita, Norio Sakai, Yusuke Hamada, Koji Kamagata, Masakazu Kohda, Akira Ohtake, Kei Murayama and Yasushi Okazaki

Genes 2020, 11(11), 1325; https://doi.org/10.3390/genes11111325 - 9 Nov 2020

Cited by 9 | Viewed by 3152

Abstract

Leigh syndrome (LS) is most frequently characterized by the presence of focal, bilateral, and symmetric brain lesions Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare condition, characterized by progressive pyramidal, cerebellar, and dorsal column dysfunction. We describe [...] Read more.

Leigh syndrome (LS) is most frequently characterized by the presence of focal, bilateral, and symmetric brain lesions Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare condition, characterized by progressive pyramidal, cerebellar, and dorsal column dysfunction. We describe a case with infantile-onset neurodegeneration, psychomotor retardation, irritability, hypotonia, and nystagmus. Brain MRI demonstrated signal abnormalities in the deep cerebral white matter, corticospinal and dorsal column tracts, and pyramids, which resemble the MRI pattern of a severe form of LBSL, and involvement of basal ganglia and thalamus that resemble the radiological features of LS. We identified biallelic loss-of-function mutations, one novel (c.756delC, p.Thr253Glnfs*44) and another reported (c.1156C > T, p.Arg386Cys), in NDUFV1 (NADH:Ubiquinone Oxidoreductase Core Subunit V1) by exome sequencing. Biochemical and functional analyses revealed lactic acidosis, complex I (CI) assembly and enzyme deficiency, and a loss of NDUFV1 protein. Complementation assays restored the NDUFV1 protein, CI assembly, and CI enzyme levels. The clinical and radiological features of this case are compatible with the phenotype of LS and LBSL associated with NDUFV1 mutations. Full article

(This article belongs to the Special Issue Expanding the Genetic Landscape of Mitochondrial Diseases)

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Review

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18 pages, 1549 KiB

Open AccessReview

Gaining Insight into Mitochondrial Genetic Variation and Downstream Pathophysiology: What Can i(PSCs) Do?

by Jesse D. Moreira, Deepa M. Gopal, Darrell N. Kotton and Jessica L. Fetterman

Genes 2021, 12(11), 1668; https://doi.org/10.3390/genes12111668 - 22 Oct 2021

Cited by 4 | Viewed by 2868

Abstract

Mitochondria are specialized organelles involved in energy production that have retained their own genome throughout evolutionary history. The mitochondrial genome (mtDNA) is maternally inherited and requires coordinated regulation with nuclear genes to produce functional enzyme complexes that drive energy production. Each mitochondrion contains [...] Read more.

Mitochondria are specialized organelles involved in energy production that have retained their own genome throughout evolutionary history. The mitochondrial genome (mtDNA) is maternally inherited and requires coordinated regulation with nuclear genes to produce functional enzyme complexes that drive energy production. Each mitochondrion contains 5–10 copies of mtDNA and consequently, each cell has several hundreds to thousands of mtDNAs. Due to the presence of multiple copies of mtDNA in a mitochondrion, mtDNAs with different variants may co-exist, a condition called heteroplasmy. Heteroplasmic variants can be clonally expanded, even in post-mitotic cells, as replication of mtDNA is not tied to the cell-division cycle. Heteroplasmic variants can also segregate during germ cell formation, underlying the inheritance of some mitochondrial mutations. Moreover, the uneven segregation of heteroplasmic variants is thought to underlie the heterogeneity of mitochondrial variation across adult tissues and resultant differences in the clinical presentation of mitochondrial disease. Until recently, however, the mechanisms mediating the relation between mitochondrial genetic variation and disease remained a mystery, largely due to difficulties in modeling human mitochondrial genetic variation and diseases. The advent of induced pluripotent stem cells (iPSCs) and targeted gene editing of the nuclear, and more recently mitochondrial, genomes now provides the ability to dissect how genetic variation in mitochondrial genes alter cellular function across a variety of human tissue types. This review will examine the origins of mitochondrial heteroplasmic variation and propagation, and the tools used to model mitochondrial genetic diseases. Additionally, we discuss how iPSC technologies represent an opportunity to advance our understanding of human mitochondrial genetics in disease. Full article

(This article belongs to the Special Issue Expanding the Genetic Landscape of Mitochondrial Diseases)

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14 pages, 684 KiB

Open AccessReview

Interrogating Mitochondrial Biology and Disease Using CRISPR/Cas9 Gene Editing

by Jia-Xin Tang, Angela Pyle, Robert W. Taylor and Monika Oláhová

Genes 2021, 12(10), 1604; https://doi.org/10.3390/genes12101604 - 12 Oct 2021

Cited by 8 | Viewed by 5614

Abstract

Mitochondrial disease originates from genetic changes that impact human bodily functions by disrupting the mitochondrial oxidative phosphorylation system. MitoCarta is a curated and published inventory that sheds light on the mitochondrial proteome, but the function of some mitochondrially-localised proteins remains poorly characterised. Consequently, [...] Read more.

Mitochondrial disease originates from genetic changes that impact human bodily functions by disrupting the mitochondrial oxidative phosphorylation system. MitoCarta is a curated and published inventory that sheds light on the mitochondrial proteome, but the function of some mitochondrially-localised proteins remains poorly characterised. Consequently, various gene editing systems have been employed to uncover the involvement of these proteins in mitochondrial biology and disease. CRISPR/Cas9 is an efficient, versatile, and highly accurate genome editing tool that was first introduced over a decade ago and has since become an indispensable tool for targeted genetic manipulation in biological research. The broad spectrum of CRISPR/Cas9 applications serves as an attractive and tractable system to study genes and pathways that are essential for the regulation and maintenance of mitochondrial health. It has opened possibilities of generating reliable cell and animal models of human disease, and with further exploitation of the technology, large-scale genomic screenings have uncovered a wealth of fundamental mechanistic insights. In this review, we describe the applications of CRISPR/Cas9 system as a genome editing tool to uncover new insights into pathomechanisms of mitochondrial diseases and/or biological processes involved in mitochondrial function. Full article

(This article belongs to the Special Issue Expanding the Genetic Landscape of Mitochondrial Diseases)

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25 pages, 2009 KiB

Open AccessReview

Molecular Insights into Mitochondrial Protein Translocation and Human Disease

by Eduardo Ruiz-Pesini, Julio Montoya and David Pacheu-Grau

Genes 2021, 12(7), 1031; https://doi.org/10.3390/genes12071031 - 1 Jul 2021

Cited by 2 | Viewed by 4240

Abstract

In human mitochondria, mtDNA encodes for only 13 proteins, all components of the OXPHOS system. The rest of the mitochondrial components, which make up approximately 99% of its proteome, are encoded in the nuclear genome, synthesized in cytosolic ribosomes and imported into mitochondria. [...] Read more.

In human mitochondria, mtDNA encodes for only 13 proteins, all components of the OXPHOS system. The rest of the mitochondrial components, which make up approximately 99% of its proteome, are encoded in the nuclear genome, synthesized in cytosolic ribosomes and imported into mitochondria. Different import machineries translocate mitochondrial precursors, depending on their nature and the final destination inside the organelle. The proper and coordinated function of these molecular pathways is critical for mitochondrial homeostasis. Here, we will review molecular details about these pathways, which components have been linked to human disease and future perspectives on the field to expand the genetic landscape of mitochondrial diseases. Full article

(This article belongs to the Special Issue Expanding the Genetic Landscape of Mitochondrial Diseases)

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