bims-curels Biomed News
on Leigh syndrome
Issue of 2023–02–26
25 papers selected by
Cure Mito Foundation
  1. Neuroimaging in mitochondrial disease.
  2. Leigh syndrome.
  3. Clinical trials in mitochondrial diseases.
  4. Genetics of mitochondrial diseases: Current approaches for the molecular diagnosis.
  5. Creation of Mitochondrial Disease Models Using Mitochondrial DNA Editing.
  6. Complex neurological and multisystem presentations in mitochondrial disease.
  7. Experimental therapy for mitochondrial diseases.
  8. Cardiac Involvement in Mitochondrial Disorders.
  9. Anti-AQP4-IgG-positive Leigh syndrome: A case report and review of the literature.
  10. Mitochondrial disease in neurology-Past, present, and future.
  11. Genomic Strategies in Mitochondrial Diagnostics.
  12. Currently available therapies in mitochondrial disease.
  13. Clinical features of epileptic seizures in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.
  14. Peripheral neuropathy in mitochondrial disease.
  15. Blood biomarkers of mitochondrial disease-One for all or all for one?
  16. Mitochondrial DNA Sequencing and Heteroplasmy Quantification by Next Generation Sequencing.
  17. Stroke-like episodes in adult mitochondrial disease.
  18. Reproductive options in mitochondrial disease.
  19. Laboratory and metabolic investigations.
  20. Rare diseases of epigenetic origin: Challenges and opportunities.
  21. Modeling the enigma of complex disease etiology.
  22. Manipulation of Murine Mitochondrial DNA Heteroplasmy with mtZFNs.
  23. Disease mechanisms as Subtypes: Mitochondrial and bioenergetic dysfunction.
  24. Ataxia and spastic paraplegia in mitochondrial disease.
  25. Mitochondrial Complex I, a Possible Sensible Site of cAMP Pathway in Aging.
  1. Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00016-6. [Epub ahead of print]194 173-185
    Neuroimaging in mitochondrial disease.
    Felix Distelmaier, Thomas Klopstock.
      The anatomic complexity of the brain in combination with its high energy demands makes this organ specifically vulnerable to defects of mitochondrial oxidative phosphorylation. Therefore, neurodegeneration is a hallmark of mitochondrial diseases. The nervous system of affected individuals typically shows selective regional vulnerability leading to distinct patterns of tissue damage. A classic example is Leigh syndrome, which causes symmetric alterations of basal ganglia and brain stem. Leigh syndrome can be caused by different genetic defects (>75 known disease genes) with variable disease onset ranging from infancy to adulthood. Other mitochondrial diseases are characterized by focal brain lesions, which is a core feature of MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). Apart from gray matter, also white matter can be affected by mitochondrial dysfunction. White matter lesions vary depending on the underlying genetic defect and may progress into cystic cavities. In view of the recognizable patterns of brain damage in mitochondrial diseases, neuroimaging techniques play a key role in diagnostic work-up. In the clinical setting, magnetic resonance imaging (MRI) and MR spectroscopy (MRS) are the mainstay of diagnostic work-up. Apart from visualization of brain anatomy, MRS allows the detection of metabolites such as lactate, which is of specific interest in the context of mitochondrial dysfunction. However, it is important to note that findings like symmetric basal ganglia lesions on MRI or a lactate peak on MRS are not specific, and that there is a broad range of disorders that can mimic mitochondrial diseases on neuroimaging. In this chapter, we will review the spectrum of neuroimaging findings in mitochondrial diseases and discuss important differential diagnoses. Moreover, we will give an outlook on novel biomedical imaging tools that may provide interesting insights into mitochondrial disease pathophysiology.
    Keywords:  Brain; Central nervous system; Leigh disease; Magnetic resonance imaging; Neurodegeneration; OXPHOS
    DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00016-6
  2. Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00015-4. [Epub ahead of print]194 43-63
    Leigh syndrome.
    Shamima Rahman.
      Leigh syndrome, or subacute necrotizing encephalomyelopathy, was initially recognized as a neuropathological entity in 1951. Bilateral symmetrical lesions, typically extending from the basal ganglia and thalamus through brainstem structures to the posterior columns of the spinal cord, are characterized microscopically by capillary proliferation, gliosis, severe neuronal loss, and relative preservation of astrocytes. Leigh syndrome is a pan-ethnic disorder usually with onset in infancy or early childhood, but late-onset forms occur, including in adult life. Over the last six decades it has emerged that this complex neurodegenerative disorder encompasses more than 100 separate monogenic disorders associated with enormous clinical and biochemical heterogeneity. This chapter discusses clinical, biochemical and neuropathological aspects of the disorder, and postulated pathomechanisms. Known genetic causes, including defects of 16 mitochondrial DNA (mtDNA) genes and approaching 100 nuclear genes, are categorized into disorders of subunits and assembly factors of the five oxidative phosphorylation enzymes, disorders of pyruvate metabolism and vitamin and cofactor transport and metabolism, disorders of mtDNA maintenance, and defects of mitochondrial gene expression, protein quality control, lipid remodeling, dynamics, and toxicity. An approach to diagnosis is presented, together with known treatable causes and an overview of current supportive management options and emerging therapies on the horizon.
    Keywords:  Diagnosis; Genetics; History; Leigh syndrome; Neuropathology; Pathomechanisms; Subacute necrotizing encephalomyelopathy; Treatment
    DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00015-4
  3. Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00002-6. [Epub ahead of print]194 229-250
    Clinical trials in mitochondrial diseases.
    Amel Karaa, Thomas Klopstock.
      Primary mitochondrial diseases are some of the most common and complex inherited inborn errors of metabolism. Their molecular and phenotypic diversity has led to difficulties in finding disease-modifying therapies and clinical trial efforts have been slow due to multiple significant challenges. Lack of robust natural history data, difficulties in finding specific biomarkers, absence of well-validated outcome measures, and small patient numbers have made clinical trial design and conduct difficult. Encouragingly, new interest in treating mitochondrial dysfunction in common diseases and regulatory incentives to develop therapies for rare conditions have led to significant interest and efforts to develop drugs for primary mitochondrial diseases. Here, we review past and present clinical trials and future strategies of drug development in primary mitochondrial diseases.
    Keywords:  Antioxidants; Clinical trials; Gene therapy; Mitochondria; Mitochondrial biogenesis; Mitophagy; Nucleosides; Primary mitochondrial disease; Treatment
    DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00002-6
  4. Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00011-7. [Epub ahead of print]194 141-165
    Genetics of mitochondrial diseases: Current approaches for the molecular diagnosis.
    Lea D Schlieben, Holger Prokisch.
      Mitochondrial diseases are a genetically and phenotypically variable set of monogenic disorders. The main characteristic of mitochondrial diseases is a defective oxidative phosphorylation. Both nuclear and mitochondrial DNA encode the approximately 1500 mitochondrial proteins. Since identification of the first mitochondrial disease gene in 1988 a total of 425 genes have been associated with mitochondrial diseases. Mitochondrial dysfunctions can be caused both by pathogenic variants in the mitochondrial DNA or the nuclear DNA. Hence, besides maternal inheritance, mitochondrial diseases can follow all modes of Mendelian inheritance. The maternal inheritance and tissue specificity distinguish molecular diagnostics of mitochondrial disorders from other rare disorders. With the advances made in the next-generation sequencing technology, whole exome sequencing and even whole-genome sequencing are now the established methods of choice for molecular diagnostics of mitochondrial diseases. They reach a diagnostic rate of more than 50% in clinically suspected mitochondrial disease patients. Moreover, next-generation sequencing is delivering a constantly growing number of novel mitochondrial disease genes. This chapter reviews mitochondrial and nuclear causes of mitochondrial diseases, molecular diagnostic methodologies, and their current challenges and perspectives.
    Keywords:  Diagnostic; Genetic; Heteroplasmy; Mitochondrial DNA; Mitochondrial disease; Multi-omic; Mutation
    DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00011-7
  5. Biomedicines. 2023 Feb 12. pii: 532. [Epub ahead of print]11(2):
    Creation of Mitochondrial Disease Models Using Mitochondrial DNA Editing.
    Victoria A Khotina, Andrey Y Vinokurov, Mariam Bagheri Ekta, Vasily N Sukhorukov, Alexander N Orekhov.
      Mitochondrial diseases are a large class of human hereditary diseases, accompanied by the dysfunction of mitochondria and the disruption of cellular energy synthesis, that affect various tissues and organ systems. Mitochondrial DNA mutation-caused disorders are difficult to study because of the insufficient number of clinical cases and the challenges of creating appropriate models. There are many cellular models of mitochondrial diseases, but their application has a number of limitations. The most proper and promising models of mitochondrial diseases are animal models, which, unfortunately, are quite rare and more difficult to develop. The challenges mainly arise from the structural features of mitochondria, which complicate the genetic editing of mitochondrial DNA. This review is devoted to discussing animal models of human mitochondrial diseases and recently developed approaches used to create them. Furthermore, this review discusses mitochondrial diseases and studies of metabolic disorders caused by the mitochondrial DNA mutations underlying these diseases.
    Keywords:  animal model; cellular model; gene editing; mitochondrial diseases; mitochondrial mutations
    DOI:  https://doi.org/10.3390/biomedicines11020532
  6. Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00003-8. [Epub ahead of print]194 117-124
    Complex neurological and multisystem presentations in mitochondrial disease.
    Michelangelo Mancuso.
      Mitochondrial diseases typically involve organs highly dependent on aerobic metabolism and are often progressive with high morbidity and mortality. In the previous chapters of this book, classical mitochondrial phenotypes and syndromes are extensively described. However, these well-known clinical pictures are more the exception rather than the rule in mitochondrial medicine. In fact, more complex, unspecified, incomplete, and/or overlap clinical entities may be even more frequent, with multisystem appearance or progression. In this chapter, we describe some complex neurological presentations, as well as the multisystem manifestations of mitochondrial diseases, ranging from the brain to the other organs.
    Keywords:  Cardiomyopathies; Hearing loss; Leukoencephalopathies; Mitochondrial diseases; Multisystem involvement; Parkinsonism; mtDNA
    DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00003-8
  7. Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00013-0. [Epub ahead of print]194 259-277
    Experimental therapy for mitochondrial diseases.
    Carlo Viscomi, Massimo Zeviani.
      Mitochondrial diseases are extremely heterogeneous genetic disorders due to faulty oxidative phosphorylation (OxPhos). No cure is currently available for these conditions, beside supportive interventions aimed at relieving complications. Mitochondria are under a double genetic control carried out by the mitochondrial DNA (mtDNA) and by nuclear DNA. Thus, not surprisingly, mutations in either genome can cause mitochondrial disease. Although mitochondria are usually associated with respiration and ATP synthesis, they play fundamental roles in a large number of other biochemical, signaling, and execution pathways, each being a potential target for therapeutic interventions. These can be classified as general therapies, i.e., potentially applicable to a number of different mitochondrial conditions, or therapies tailored to a single disease, i.e., personalized approaches, such as gene therapy, cell therapy, and organ replacement. Mitochondrial medicine is a particularly lively research field, and the last few years witnessed a steady increase in the number of clinical applications. This chapter will present the most recent therapeutic attempts emerged from preclinical work and an update of the currently ongoing clinical applications. We think that we are starting a new era in which the etiologic treatment of these conditions is becoming a realistic option.
    Keywords:  AAV; Gene therapy; Mitochondrial biogenesis; Mitochondrial disease; Mitophagy; OxPhos; Rapamycin
    DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00013-0
  8. Curr Heart Fail Rep. 2023 Feb 18.
    Cardiac Involvement in Mitochondrial Disorders.
    Tudor-Alexandru Popoiu, Jan Dudek, Christoph Maack, Edoardo Bertero.
       PURPOSE OF REVIEW: We review pathophysiology and clinical features of mitochondrial disorders manifesting with cardiomyopathy.
    RECENT FINDINGS: Mechanistic studies have shed light into the underpinnings of mitochondrial disorders, providing novel insights into mitochondrial physiology and identifying new therapeutic targets. Mitochondrial disorders are a group of rare genetic diseases that are caused by mutations in mitochondrial DNA (mtDNA) or in nuclear genes that are essential to mitochondrial function. The clinical picture is extremely heterogeneous, the onset can occur at any age, and virtually, any organ or tissue can be involved. Since the heart relies primarily on mitochondrial oxidative metabolism to fuel contraction and relaxation, cardiac involvement is common in mitochondrial disorders and often represents a major determinant of their prognosis.
    Keywords:  Cardiolipin; Cardiomyopathy; Electron transport chain; Mitochondrial DNA; Mitochondrial disease
    DOI:  https://doi.org/10.1007/s11897-023-00592-3
  9. Front Pediatr. 2023 ;11 1046731
    Anti-AQP4-IgG-positive Leigh syndrome: A case report and review of the literature.
    Jun Chen, Jianjun Wang, Jing Gan, Rong Luo, Zuozhen Yang, Mengmeng Liang, Xiaolu Chen.
       Background: Leigh syndrome (LS; OMIM: 256000) is a progressive neurodegenerative disease caused by genetic mutations resulting in mitochondrial oxidative phosphorylation defects. The prognosis is poor, with most children dying before the age of 2 years. MT-ATP6 variants are the most common mitochondrial DNA mutations in LS. MT-ATP6 variant-induced LS may trigger autoimmunity, and immunotherapy might be effective. Here, we present the first pediatric case of anti-aquaporin 4 (AQP4)-IgG-positive LS caused by an MT-ATP6 variant.
    Case: A 1-year-old boy was hospitalized due to recurrent fever, cough, and developmental regression. Two months previously, he had developed reduced responses to stimulation and psychomotor retardation. After admission, his condition deteriorated and respiratory failure ensued. Magnetic resonance imaging of the brain showed symmetrical small patchy abnormal signals around the third ventricle, pons, and dorsal periaqueductal gray matter in the dorsal medulla. Laboratory tests revealed anti-AQP4-IgG antibodies. Anti-infection, immunoglobulin, and glucocorticoid therapy were administered for symptomatic treatment. Genetic testing revealed a de novo homogeneous pathogenic variant of MT-ATP6 (m.9176T > C, mutation ratio: 99.97%). The patient was diagnosed with anti-AQP4-IgG-positive LS, treated with "cocktail therapy" (vitamins B1, B2, C, and E, l-carnitine, and coenzyme Q10), and discharged after his condition improved. A literature review revealed that LS-induced mitochondrial defects can impact the immune system; hence, immunotherapy and early mitochondrial cocktail therapy may improve outcomes.
    Conclusion: Anti-AQP4-IgG-positive LS is very rare. Patients with LS with the m.9176T  > C variant of MT-ATP6 may be susceptible to autoimmune damage of the central nervous system. Early cocktail therapy combined with immunotherapy may improve their prognosis.
    Keywords:  Leigh syndrome; MT-ATP6; anti-AQP4–IgG; case report; m.9176T > C
    DOI:  https://doi.org/10.3389/fped.2023.1046731
  10. Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00001-4. [Epub ahead of print]194 3-6
    Mitochondrial disease in neurology-Past, present, and future.
    Patrick F Chinnery.
      This chapter provides a overview of this volume of the Handbook of Clinical Neurology, placing recent advances in our understanding of mitochondrial disorders in a historical context, and speculates about the future.
    Keywords:  Clinical medicine; Diagnosis; Genomics; Mitochondria; Mitochondrial diseases; Neurology; Treatments; mtDNA
    DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00001-4
  11. Methods Mol Biol. 2023 ;2615 397-425
    Genomic Strategies in Mitochondrial Diagnostics.
    Dasha Deen, Charlotte L Alston, Gavin Hudson, Robert W Taylor, Angela Pyle.
      Pathogenic variants in both mitochondrial and nuclear genes contribute to the clinical and genetic heterogeneity of mitochondrial diseases. There are now pathogenic variants in over 300 nuclear genes linked to human mitochondrial diseases. Nonetheless, diagnosing mitochondrial disease with a genetic outcome remains challenging. However, there are now many strategies that help us to pinpoint causative variants in patients with mitochondrial disease. This chapter describes some of the approaches and recent advancements in gene/variant prioritization using whole-exome sequencing (WES).
    Keywords:  Clinical reporting; Genetic diagnosis; Genomics; Mitochondrial disease; Variant annotation; Variant detection; Whole-exome sequencing
    DOI:  https://doi.org/10.1007/978-1-0716-2922-2_27
  12. Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00007-5. [Epub ahead of print]194 189-206
    Currently available therapies in mitochondrial disease.
    Cornelia Kornblum, Costanza Lamperti, Sumit Parikh.
      Mitochondrial diseases are a heterogeneous group of multisystem disorders caused by impaired mitochondrial function. These disorders occur at any age and involve any tissue, typically affecting organs highly dependent on aerobic metabolism. Diagnosis and management are extremely difficult due to various underlying genetic defects and a wide range of clinical symptoms. Preventive care and active surveillance are strategies to try to reduce morbidity and mortality by timely treatment of organ-specific complications. More specific interventional therapies are in early phases of development and no effective treatment or cure currently exists. A variety of dietary supplements have been utilized based on biological logic. For several reasons, few randomized controlled trials have been completed to assess the efficacy of these supplements. The majority of the literature on supplement efficacy represents case reports, retrospective analyses and open-label studies. We briefly review selected supplements that have some degree of clinical research support. In mitochondrial diseases, potential triggers of metabolic decompensation or medications that are potentially toxic to mitochondrial function should be avoided. We shortly summarize current recommendations on safe medication in mitochondrial diseases. Finally, we focus on the frequent and debilitating symptoms of exercise intolerance and fatigue and their management including physical training strategies.
    Keywords:  Dietary supplements; Drugs; Exercise intolerance; Exercise training; Fatigue; Management; Medication; Mitochondrial disease; Surveillance; Therapy; Treatment
    DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00007-5
  13. Seizure. 2023 Feb 18. pii: S1059-1311(23)00055-9. [Epub ahead of print]106 110-116
    Clinical features of epileptic seizures in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.
    Xiaxin Yang, Anqi Sun, Kunqian Ji, Xiaotang Wang, Xue Yang, Xiuhe Zhao.
       BACKGROUND AND PURPOSE: This study aimed to characterize the clinical features of epilepsy in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and analyze the clinical determinants for drug-resistant epilepsy in MELAS.
    METHODS: A single-center, retrospective study was conducted to investigate the clinical features of epilepsy in patients with MELAS. Collected variables included seizure semiology, electroencephalography (EEG), muscle biopsy, genetic testing, neuroimaging findings, resting serum lactic value and modified Rankin scale (mRS) of patients with MELAS. We also investigated the differences between the adult-onset group and the child-onset group and analyzed the risk factors for drug-resistant epilepsy in MELAS.
    RESULTS: We studied 97 patients (56 males: 41 females) with confirmed MELAS. Epileptic seizure occurred in 100.0% of patients and the initial symptom of 69.1% patients was epileptic seizure. The average age of disease onset was 21.0 years, ranging from 2 to 60 years. The seizure types of these patients with MELAS were variable, with generalized onset (51.5%) to be the most common type. The EEG changes in the patients with MELAS were mainly slow wave (90.9%) and epileptiform discharge (68.2%). The child-onset group with earlier seizure onset presented significantly higher resting serum lactic value (p = 0.0048) and lower incidence of stroke-like lesion in the brain (p = 0.003), especially in the temporal lobe (p < 0.001), compared with the adult-onset group. Importantly, drug-resistant epilepsy in MELAS was demonstrated to be closely related to the earlier age of seizure onset (p = 0.013), as well as the higher mRS score (p < 0.001) and higher resting serum lactic value (p = 0.009).
    CONCLUSION: Early identification of MELAS should be considered among individuals with recurrent epilepsy through clinical screening. Age of seizure onset and resting serum lactic value may predict the development of drug-resistant epilepsy in MELAS. Close observation and appropriate anti-epileptic treatment are indispensable for individuals with MELAS to improve the prognosis. Further studies with larger sample size are required to further evaluate the risk factors of drug-resistant epilepsy in MELAS and provide guidance on treatment of MELAS.
    Keywords:  Drug-resistant epilepsy; EEG; Epilepsy; MELAS
    DOI:  https://doi.org/10.1016/j.seizure.2023.02.014
  14. Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00014-2. [Epub ahead of print]194 99-116
    Peripheral neuropathy in mitochondrial disease.
    Rita Horvath, Jessica Medina, Mary M Reilly, Michael E Shy, Stephan Zuchner.
      Mitochondria are essential for the health and viability of both motor and sensory neurons and their axons. Processes that disrupt their normal distribution and transport along axons will likely cause peripheral neuropathies. Similarly, mutations in mtDNA or nuclear encoded genes result in neuropathies that either stand alone or are part of multisystem disorders. This chapter focuses on the more common genetic forms and characteristic clinical phenotypes of "mitochondrial" peripheral neuropathies. We also explain how these various mitochondrial abnormalities cause peripheral neuropathy. In a patient with a neuropathy either due to a mutation in a nuclear or an mtDNA gene, clinical investigations aim to characterize the neuropathy and make an accurate diagnosis. In some patients, this may be relatively straightforward, where a clinical assessment and nerve conduction studies followed by genetic testing is all that is needed. In others, multiple investigations including a muscle biopsy, CNS imaging, CSF analysis, and a wide range of metabolic and genetic tests in blood and muscle may be needed to establish diagnosis.
    Keywords:  Axonal transport; Charcot–Marie–Tooth disease; Mitochondrial DNA; Mitochondrial fusion/fission; Nuclear mitochondrial genes; Respiratory chain enzymes
    DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00014-2
  15. Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00006-3. [Epub ahead of print]194 251-257
    Blood biomarkers of mitochondrial disease-One for all or all for one?
    Anu Suomalainen.
      The mitochondrial disease group consists of different disorders with unprecedented variability of clinical manifestations and tissue-specific symptoms. Their tissue-specific stress responses vary depending on the patients' age and type of dysfunction. These responses include secretion of metabolically active signal molecules to systemic circulation. Such signals-metabolites or metabokines-can be also utilized as biomarkers. During the past 10 years, metabolite and metabokine biomarkers have been described for mitochondrial disease diagnosis and follow-up, to complement the conventional blood biomarkers lactate, pyruvate and alanine. These new tools include metabokines FGF21 and GDF15; cofactors (NAD-forms); sets of metabolites (multibiomarkers) and the full metabolome. FGF21 and GDF15 are messengers of mitochondrial integrated stress response that together outperform the conventional biomarkers in specificity and sensitivity for muscle-manifesting mitochondrial diseases. Metabolite or metabolomic imbalance (e.g., NAD+ deficiency) is a secondary consequence to the primary cause in some diseases, but relevant as a biomarker and a potential indicator of therapy targets. For therapy trials, the optimal biomarker set needs to be tailored to match the disease of interest. The new biomarkers have increased the value of blood samples in mitochondrial disease diagnosis and follow-up, enabling prioritization of patients to different diagnostic paths and having crucial roles in follow-up of therapy effect.
    Keywords:  Bbiomarker; Diagnosis; Disease progression; FGF21; GDF15; Metabolomics; Mitochondrial disease; Multibiomarker; NAD; Treatment
    DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00006-3
  16. Methods Mol Biol. 2023 ;2615 381-395
    Mitochondrial DNA Sequencing and Heteroplasmy Quantification by Next Generation Sequencing.
    Andrea Legati, Daniele Ghezzi, Carlo Viscomi.
      Over the last 10 years, next generation sequencing (NGS) became the gold standard for both diagnosis and discovery of new disease genes responsible for heterogeneous disorders, such as mitochondrial encephalomyopathies. The application of this technology to mtDNA mutations poses extra challenges compared to other genetic conditions because of the peculiarities of mitochondrial genetics and the requirement for proper NGS data management and analysis. Here, we describe a detailed, clinically relevant protocol to sequence the whole mtDNA and quantify heteroplasmy levels of mtDNA variants, starting from total DNA through the generation of a single PCR amplicon.
    Keywords:  Heteroplasmy; Mitochondrial DNA; Mitochondrial disease; Mitochondrial haplogroups; Next generation sequencing; Single amplicon
    DOI:  https://doi.org/10.1007/978-1-0716-2922-2_26
  17. Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00005-1. [Epub ahead of print]194 65-78
    Stroke-like episodes in adult mitochondrial disease.
    Yi Shiau Ng, Gráinne S Gorman.
      Stroke-like episode is a paroxysmal neurological manifestation which affects a specific group of patients with mitochondrial disease. Focal-onset seizures, encephalopathy, and visual disturbances are prominent findings associated with stroke-like episodes, with a predilection for the posterior cerebral cortex. The most common cause of stroke-like episodes is the m.3243A>G variant in MT-TL1 gene followed by recessive POLG variants. This chapter aims to review the definition of stroke-like episode and delineate the clinical phenomenology, neuroimaging and EEG findings typically seen in patients. In addition, several lines of evidence supporting neuronal hyper-excitability as the key mechanism of stroke-like episodes are discussed. The management of stroke-like episodes should focus on aggressive seizure management and treatment for concomitant complications such as intestinal pseudo-obstruction. There is no robust evidence to prove the efficacy of l-arginine for both acute and prophylactic settings. Progressive brain atrophy and dementia are the sequalae of recurrent stroke-like episode, and the underlying genotype in part predicts prognosis.
    Keywords:  MELAS; Neuronal hyper-excitability; POLG; Seizures; Status epilepticus; m.3243A>G
    DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00005-1
  18. Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00004-X. [Epub ahead of print]194 207-228
    Reproductive options in mitochondrial disease.
    Hubert J M Smeets, Suzanne C E H Sallevelt, Mary Herbert.
      Mitochondrial diseases require customized approaches for reproductive counseling, addressing differences in recurrence risks and reproductive options. The majority of mitochondrial diseases is caused by mutations in nuclear genes and segregate in a Mendelian way. Prenatal diagnosis (PND) or preimplantation genetic testing (PGT) are available to prevent the birth of another severely affected child. In at least 15%-25% of cases, mitochondrial diseases are caused by mitochondrial DNA (mtDNA) mutations, which can occur de novo (25%) or be maternally inherited. For de novo mtDNA mutations, the recurrence risk is low and PND can be offered for reassurance. For maternally inherited, heteroplasmic mtDNA mutations, the recurrence risk is often unpredictable, due to the mitochondrial bottleneck. PND for mtDNA mutations is technically possible, but often not applicable given limitations in predicting the phenotype. Another option for preventing the transmission of mtDNA diseases is PGT. Embryos with mutant load below the expression threshold are being transferred. Oocyte donation is another safe option to prevent the transmission of mtDNA disease to a future child for couples who reject PGT. Recently, mitochondrial replacement therapy (MRT) became available for clinical application as an alternative to prevent the transmission of heteroplasmic and homoplasmic mtDNA mutations.
    Keywords:  Mitochondrial bottleneck; Mitochondrial disease; Mitochondrial replacement therapy; Preimplantation genetic diagnosis; Prenatal diagnosis; Reproductive options; mtDNA disease
    DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00004-X
  19. Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00012-9. [Epub ahead of print]194 167-172
    Laboratory and metabolic investigations.
    Eva Morava, Devin Oglesbee.
      Clinical variability and substantial overlap between mitochondrial disorders and other genetic disorders and inborn errors make the clinical and metabolic diagnosis of mitochondrial disorders quite challenging. Evaluating specific laboratory markers is essential in the diagnostic process, but mitochondrial disease can be present in the absence of any abnormal metabolic markers. In this chapter, we share the current consensus guidelines for metabolic investigations, including investigations in blood, urine, and the cerebral spinal fluid and discuss different diagnostic approaches. As personal experience might significantly vary and there are different recommendations published as diagnostic guidelines, the Mitochondrial Medicine Society developed a consensus approach based on literature review for metabolic diagnostics in a suspected mitochondrial disease. According to the guidelines, the work-up should include the assessment of complete blood count, creatine phosphokinase, transaminases, albumin, postprandial lactate and pyruvate (lactate/pyruvate ratio when the lactate level is elevated), uric acid, thymidine, amino acids, acylcarnitines in blood, and urinary organic acids (especially screening for 3-methylglutaconic acid). Urine amino acid analysis is recommended in mitochondrial tubulopathies. CSF metabolite analysis (lactate, pyruvate, amino acids, and 5-methyltetrahydrofolate) should be included in the presence of central nervous system disease. We also suggest a diagnostic strategy based on the mitochondrial disease criteria (MDC) scoring system in mitochondrial disease diagnostics; evaluating muscle-, neurologic-, and multisystem involvement, and the presence of metabolic markers and abnormal imaging. The consensus guideline encourages a primary genetic approach in diagnostics and only suggests a more invasive diagnostic approach with tissue biopsies (histology, OXPHOS measurements, etc.) after nonconclusive genetic testing.
    Keywords:  3MGA; Alanine; Ethylmalonic acid; Lactic acid; Metabolomics; Methylmalonic acid; Mitochondrial disease criteria; Pyruvate; Thymidine
    DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00012-9
  20. Front Genet. 2023 ;14 1113086
    Rare diseases of epigenetic origin: Challenges and opportunities.
    Maggie P Fu, Sarah M Merrill, Mehul Sharma, William T Gibson, Stuart E Turvey, Michael S Kobor.
      Rare diseases (RDs), more than 80% of which have a genetic origin, collectively affect approximately 350 million people worldwide. Progress in next-generation sequencing technology has both greatly accelerated the pace of discovery of novel RDs and provided more accurate means for their diagnosis. RDs that are driven by altered epigenetic regulation with an underlying genetic basis are referred to as rare diseases of epigenetic origin (RDEOs). These diseases pose unique challenges in research, as they often show complex genetic and clinical heterogeneity arising from unknown gene-disease mechanisms. Furthermore, multiple other factors, including cell type and developmental time point, can confound attempts to deconvolute the pathophysiology of these disorders. These challenges are further exacerbated by factors that contribute to epigenetic variability and the difficulty of collecting sufficient participant numbers in human studies. However, new molecular and bioinformatics techniques will provide insight into how these disorders manifest over time. This review highlights recent studies addressing these challenges with innovative solutions. Further research will elucidate the mechanisms of action underlying unique RDEOs and facilitate the discovery of treatments and diagnostic biomarkers for screening, thereby improving health trajectories and clinical outcomes of affected patients.
    Keywords:  DNA methylation; bioinformatics analysis; chromatin remodeler; epigenetics; histone modification; rare disease
    DOI:  https://doi.org/10.3389/fgene.2023.1113086
  21. J Transl Med. 2023 Feb 25. 21(1): 148
    Modeling the enigma of complex disease etiology.
    Lynn M Schriml, Richard Lichenstein, Katharine Bisordi, Cynthia Bearer, J Allen Baron, Carol Greene.
       BACKGROUND: Complex diseases often present as a diagnosis riddle, further complicated by the combination of multiple phenotypes and diseases as features of other diseases. With the aim of enhancing the determination of key etiological factors, we developed and tested a complex disease model that encompasses diverse factors that in combination result in complex diseases. This model was developed to address the challenges of classifying complex diseases given the evolving nature of understanding of disease and interaction and contributions of genetic, environmental, and social factors.
    METHODS: Here we present a new approach for modeling complex diseases that integrates the multiple contributing genetic, epigenetic, environmental, host and social pathogenic effects causing disease. The model was developed to provide a guide for capturing diverse mechanisms of complex diseases. Assessment of disease drivers for asthma, diabetes and fetal alcohol syndrome tested the model.
    RESULTS: We provide a detailed rationale for a model representing the classification of complex disease using three test conditions of asthma, diabetes and fetal alcohol syndrome. Model assessment resulted in the reassessment of the three complex disease classifications and identified driving factors, thus improving the model. The model is robust and flexible to capture new information as the understanding of complex disease improves.
    CONCLUSIONS: The Human Disease Ontology's Complex Disease model offers a mechanism for defining more accurate disease classification as a tool for more precise clinical diagnosis. This broader representation of complex disease, therefore, has implications for clinicians and researchers who are tasked with creating evidence-based and consensus-based recommendations and for public health tracking of complex disease. The new model facilitates the comparison of etiological factors between complex, common and rare diseases and is available at the Human Disease Ontology website.
    Keywords:  Asthma; Diabetes; Disease etiology; Environmental drivers; Fetal alcohol syndrome; Genetics; Pathophysiology
    DOI:  https://doi.org/10.1186/s12967-023-03987-x
  22. Methods Mol Biol. 2023 ;2615 329-344
    Manipulation of Murine Mitochondrial DNA Heteroplasmy with mtZFNs.
    Pavel A Nash, Michal Minczuk.
      Mouse models of mitochondrial DNA mutations hold promise in the development and optimization of mitochondrial gene therapy technology and for gathering pre-clinical data prior to human trials. Their suitability for this purpose stems from the high similarity of human and murine mitochondrial genomes and the increasing availability of rationally designed AAV vectors capable of selectively transducing murine tissues. Our laboratory routinely optimizes mitochondrially targeted zinc finger nucleases (mtZFNs), the compactness of which makes them highly suitable for downstream AAV-based in vivo mitochondrial gene therapy. This chapter discusses the necessary precautions for the robust and precise genotyping of the murine mitochondrial genome as well as the optimization of mtZFNs intended for subsequent use in vivo.
    Keywords:  Gene therapy; Heteroplasmy; MEF; Mitochondria; Mouse; Zinc Finger nuclease; mtDNA; mtZFN
    DOI:  https://doi.org/10.1007/978-1-0716-2922-2_23
  23. Handb Clin Neurol. 2023 ;pii: B978-0-323-85555-6.00007-2. [Epub ahead of print]193 53-66
    Disease mechanisms as Subtypes: Mitochondrial and bioenergetic dysfunction.
    Patricia Gonzalez-Rodriguez, Enrico Zampese, D James Surmeier.
      Parkinson disease (PD) is the second most common neurodegenerative disease in the world. Despite its enormous human and societal cost, there is no disease-modifying therapy for PD. This unmet medical need reflects our limited understanding of PD pathogenesis. One of the most important clues comes from the recognition that PD motor symptoms arises from the dysfunction and degeneration of a very select group of neurons in the brain. These neurons have a distinctive set of anatomic and physiologic traits that reflect their role in brain function. These traits elevate mitochondrial stress, potentially making them particularly vulnerable to age, as well as to genetic mutations and environmental toxins linked to PD incidence. In this chapter, the literature supporting this model is outlined, along with gaps in our knowledge base. The translational implications of this hypothesis are then discussed, with a focus on why disease-modification trials have failed to date and what this means for the development of new strategies for altering disease course.
    Keywords:  Aging; Calcium; Mitochondria; Neurodegeneration; Selective vulnerability
    DOI:  https://doi.org/10.1016/B978-0-323-85555-6.00007-2
  24. Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00009-9. [Epub ahead of print]194 79-98
    Ataxia and spastic paraplegia in mitochondrial disease.
    Matthis Synofzik, Elena Rugarli, Evan Reid, Rebecca Schüle.
      Degenerative ataxias and hereditary spastic paraplegias (HSPs) form a continuous, often overlapping disease spectrum sharing not only phenotypic features and underlying genes, but also cellular pathways and disease mechanisms. Mitochondrial metabolism presents a major molecular theme underlying both multiple ataxias and HSPs, thus indicating a heightened vulnerability of Purkinje cells, spinocerebellar tracts, and motor neurons to mitochondrial dysfunction, which is of particular interest for translational approaches. Mitochondrial dysfunction might be the primary (upstream) or secondary (downstream) result of a genetic defect, with underlying genetic defects in nuclear-encoded genes being much more frequent than in mtDNA genes in both, ataxias and HSPs. Here, we outline the substantial number of ataxias, spastic ataxias and HSPs caused by mutated genes implicated in (primary or secondary) mitochondrial dysfunction, highlighting several key "mitochondrial" ataxias and HSPs which are of particular interest for their frequency, pathogenesis and translational opportunities. We then showcase prototypic mitochondrial mechanisms by which disruption of these ataxia and HSP genes contributes to Purkinje cells or corticospinal neuron dysfunction, thus elucidating hypotheses on Purkinje cells and corticospinal neuron vulnerability to mitochondrial dysfunction.
    Keywords:  Ataxia; Axon; Cerebellum; Genetic; Genetics; Hereditary spastic paraplegia; Mitochondrion; Motor neuron; Spastic ataxia; Translation
    DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00009-9
  25. Antioxidants (Basel). 2023 Jan 18. pii: 221. [Epub ahead of print]12(2):
    Mitochondrial Complex I, a Possible Sensible Site of cAMP Pathway in Aging.
    Anna Signorile, Domenico De Rasmo.
      In mammals during aging, reactive oxygen species (ROS), produced by the mitochondrial respiratory chain, cause oxidative damage of macromolecules leading to respiratory chain dysfunction, which in turn increases ROS mitochondrial production. Many efforts have been made to understand the role of oxidative stress in aging and age-related diseases. The complex I of the mitochondrial respiratory chain is the major source of ROS production and its dysfunctions have been associated with several forms of neurodegeneration, other common human diseases and aging. Complex I-ROS production and complex I content have been proposed as the major determinants for longevity. The cAMP signal has a role in the regulation of complex I activity and the decrease of ROS production. In the last years, an increasing number of studies have attempted to activate cAMP signaling to treat age-related diseases associated with mitochondrial dysfunctions and ROS production. This idea comes from a long-line of studies showing a main role of cAMP signal in the memory consolidation mechanism and in the regulation of mitochondrial functions. Here, we discuss several evidences on the possible connection between complex I and cAMP pathway in the aging process.
    Keywords:  aging; cAMP; complex I; mitochondria; signaling
    DOI:  https://doi.org/10.3390/antiox12020221
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