Mitochondrial Diseases

Mitochondrial DNA depletion syndromes (MDSs) form a group of autosomal recessive disorders characterized by profoundly decreased mitochondrial DNA copy numbers in affected tissues. Three main clinical presentations are known: myopathic, encephalomyopathic and hepatocerebral. The first is associated with mutations in thymidine kinase 2 (TK2) and p53-induced ribonucleotide reductase B subunit (RRM2B); the second with mutations in succinate synthase A (SUCLA2) and B (SUCLG1); the third with mutations in Twinkle (PEO1), pol-γA (POLG1), deoxyguanosine kinase (DGUOK) and MPV17 (MPV17). In this work, we review the MDS-associated phenotypes and present our own experience of 32 MDS patients, with the aim of defining the mutation frequency of the known genes, the clinical spectrum of the diseases, and the genotype–phenotype correlations. Five of our patients carried previously unreported mutations in one of the eight MDS genes.

Mutations in human mitochondrial DNA (mtDNA) can cause mitochondrial disease and have been associated with neurodegenerative disorders, cancer, diabetes and aging. Yet our progress toward delineating the precise contributions of mtDNA mutations to these conditions is impeded by the limited availability of faithful transmitochondrial animal models. Here, we report a method for the isolation of mutations in mouse mtDNA and its implementation for the generation of a collection of over 150 cell lines suitable for the production of transmitochondrial mice. This method is based on the limited mutagenesis of mtDNA by proofreading-deficient DNA-polymerase γ followed by segregation of the resulting highly heteroplasmic mtDNA population by means of intracellular cloning. Among generated cell lines, we identify nine which carry mutations affecting the same amino acid or nucleotide positions as in human disease, including a mutation in the ND4 gene responsible for 70% of Leber Hereditary Optic ...

The expression of mitochondrial components is controlled by an intricate interplay between nuclear transcription factors and retrograde signaling from mitochondria. The role of mitochondrial DNA (mtDNA) and mtDNA-encoded proteins in mitochondrial biogenesis is, however, poorly understood and thus far has mainly been studied in transformed cell lines. We treated primary human fibroblasts with ethidium bromide (EtBr) or chloramphenicol for six weeks to inhibit mtDNA replication or mitochondrial protein synthesis, respectively, and investigated how the cells recovered from these insults two weeks after removal of the drugs. Although cellular growth and mitochondrial gene expression were severely impaired after both inhibitor treatments we observed marked differences in mitochondrial structure,membrane potential, glycolysis, gene expression, and redox status between fibroblasts treated with EtBr and chloramphenicol. Following removal of the drugs we further detected clear differences in expression of both mtDNA-encoded genes and nuclear transcription factors that control mitochondrial biogenesis, suggesting that the cells possess different compensatory mechanisms to recover from drug-induced mitochondrial dysfunction. Our data reveal new aspects of the interplay between mitochondrial retrograde signaling and the expression of nuclear regulators of mitochondrial biogenesis, a process with direct relevance to mitochondrial diseases and chloramphenicol toxicity in humans.

The objective of this study was to estimate the prevalence of autistic spectrum disorder (ASD) and identify its clinical characterization, and medical conditions in a paediatric population in Portugal. A school survey was conducted in elementary schools, targeting 332 808 school-aged children in the mainland and 10 910 in the Azores islands. Referred children were directly assessed using the Diagnostic and Statistical Manual of Mental Disorders (4th edn), the Autism Diagnostic Interview–Revised, and the Childhood Autism Rating Scale. Clinical history and a laboratory investigation was performed. In parallel, a systematic multi-source search of children known to have autism was carried out in a restricted region. The global prevalence of ASD per 10 000 was 9.2 in mainland, and 15.6 in the Azores, with intriguing regional differences. A diversity of associated medical conditions was documented in 20%, with an unexpectedly high rate of mitochondrial respiratory chain disorders.

Inherited disorders of mitochondrial energy metabolism form a large and heterogeneous group of metabolic diseases. More than 250 gene defects have been reported to date and this number continues to grow. Mitochondrial diseases can be grouped into (1) disorders of oxidative phosphorylation (OXPHOS) subunits and their assembly factors, (2) defects of mitochondrial DNA, RNA and protein synthesis, (3) defects in the substrate-generating upstream reactions of OXPHOS, (4) defects in relevant cofactors and (5) defects in mitochondrial homeostasis. Deficiency of more than one respiratory chain enzyme is a common finding. Combined defects are found in 49 % of the known disease-causing genes of mitochondrial energy metabolism and in 57 % of patients with OXPHOS defects identified in our diagnostic centre. Combined defects of complexes I, III, IV and V are typically due to deficiency of mitochondrial DNA replication, RNA metabolism or translation. Defects in cofactors can result in combined de...

Eine Kombination synergistischer Maßnahmen (Mitochondria Optimization Protocol (MitOPro)) ermöglicht einen bisher wenig bekannten, aber signifikanten physiologi-schen " Shortcut " zur Stimulation und Unterstützung des zellulären Energiestoff-wechsels. Ergebnis ist die methodische Zerstörung veralteter, erschöpfter Mito-chondrien und die beschleunigte Vermehrung gesunder, physiologisch " jüngerer " Mi-tochondrien in den Zellen. Dies erreicht man durch die Kombination eines speziellen Sauerstofftrainings mit einer dem Genotyp entsprechenden Ernährung (Nutrigeno-mik) und der gezielten Unterstützung durch spezifische Nahrungsergänzungen. Die-se Methode kann sowohl bei gesunden als auch bei kranken Menschen angewendet werden.

Inflammation Mastery, 4th Edition is printed in beautiful full-color and is loaded with images, diagrams, photos, and colorful emphasis. Thousands of citations are provided in the footnotes for easy access. See PDF document for table of contents, samples, and index.

Treating Pain and Inflammation Naturally – Part 9 [Abstract]: Building upon previous reviews in this Journal, this new review discusses advances in our understanding of natural/nonpharmacologic treatments for disorders of pain and inflammation by extending the information detailed in Part 6, discussing the role of the microbiome and dysbiosis in musculoskeletal disorders of persistent pain and inflammation. Following the introduction, a survey of the history of and recent developments in the study of the microbiome and dysbiosis will be provided; thereafter, fibromyalgia will be used as an example of dysbiosis-induced disease, exemplifying dysbiotic mitochondriopathy along with microbe-induced microglial activation as the cause of central sensitization and pain amplification. [This document was relocated July 2019 because a hyperlink in the document needed to be updated and multiple attempts to upload to the original location (various attempts, with different browsers, etc). Previous version had 1,832 Views as of July 2019.]

Availability: http://www.amazon.com/dp/1522951008/
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Purpose and audience: This book is written to provide essential information to doctors and patients dealing with chronic pain generally, migraine and fibromyalgia specifically. The information is also relevant for cluster headache, myofascial pain syndrome, and complex regional pain syndrome. With hundreds of citations to the biomedical research literature, this book provides unique insights into the causes of and solutions for migraine and fibromyalgia as prototypic pain disorders chiefly characterised by central sensitization, glial activation, and mitochondrial dysfunction. Clinicians and patients alike will gain insights that are immediately applicable for the treatment of these conditions. Importantly, the focus of Dr Vasquez’s Functional Inflammology Protocol is to skillfully address—in a structured manner—the underlying causes of pain and inflammation, not simply to alleviate pain/inflammation via drug dependency. This book details the pathophysiology and essential treatment components; additional explanations and updates are provided via video lectures and tutorials.
About this book: This book is an excerpt from Chapter 5 of Dr Vasquez’s most recent 1,200-page textbook, Inflammation Mastery, 4th Edition (2016). The information in this book has been developed over many years starting from Dr Vasquez’s teaching notes in Orthopedics and Rheumatology in 2000 and 2001, then in Integrative Orthopedics (2004, 2012), Musculoskeletal Pain: Expanded Clinical Strategies (Institute for Functional Medicine, 2008), Functional Medicine Rheumatology (2014), and Human Microbiome and Dysbiosis in Clinical Disease (2015).

Mitochondrial disorders are an important group of genetic conditions characterized by impaired oxidative phosphorylation. Mitochondrial disorders come with an impressive variability of symptoms, organ involvement, and clinical course, which considerably impact the quality of life and quite often shorten the lifespan expectancy. Although the last 20years have witnessed an exponential increase in understanding the genetic and biochemical mechanisms leading to disease, this has not resulted in the development of effective therapeutic approaches, amenable of improving clinical course and outcome of these conditions to any significant extent. Therapeutic options for mitochondrial diseases still remain focused on supportive interventions aimed at relieving complications. However, new therapeutic strategies have recently been emerging, some of which have shown potential efficacy at the pre-clinical level. This review will present the state of the art on experimental therapy for mitochondri...

Originally published as © Vasquez A. Microbial Origins of Fibromyalgia. Naturopathic Doctor News and Reviews 2016 Apr ndnr.com/pain-medicine/microbial-origins-of-fibromyalgia derived from Inflammation Mastery, 4th Edition excerpted as Pain Revolution (full-color) and Brain Inflammation (discounted grayscale printing). Copyright © 2014-present by Dr Alex Vasquez https://www.InflammationMastery.com/fibromyalgia 
See related video archive at https://www.inflammationmastery.com/fibromyalgia-migraine-videos-news

An ongoing challenge in children presenting with motor delay/impairment early in life is to identify neurogenetic disorders with a clinical phenotype, which can be misdiagnosed as cerebral palsy (CP). To help distinguish patients in these two groups, conventional magnetic resonance imaging of the brain has been of great benefit in "unmasking" many of these genetic etiologies and has provided important clues to differential diagnosis in others. Recent advances in molecular genetics such as chromosomal microarray and next-generation sequencing have further revolutionized the understanding of etiology by more precisely classifying these disorders with a molecular cause. In this paper, we present a review of neurogenetic disorders masquerading as cerebral palsy evaluated at one institution. We have included representative case examples children presenting with dyskinetic, spastic, and ataxic phenotypes, with the intent to highlight the time-honored approach of using clinical t...

The mitochondria of the oocyte are a prominent source of energy metabolism as well as mitochondrial DNA that will later populate the cells of the offspring. Recent discoveries provided new insight into the physiology of the mitochondria and its unique genetics. The concept of heteroplasmy defined as the presence of more than one type of mitochondrial genome, is gaining increasing recognition as an important contributor to several complex morbidities, age-related reproductive dysfunction and aging. Understanding the changes caused by pathogenic mutations as well as identifying defects occurring during reproductive aging will enhance our knowledge of the role of mitochondria as organelles in germ cell biology. In this review, we summarize the current state of knowledge about the role of mitochondria in embryo and fetal development.

Beyond the disorders recognized as mitochondrial diseases, abnormalities in function and/or ultrastructure of mitochondria have been reported in several unrelated pathologies. These encompass ageing, malformations, and a number of genetic or acquired diseases, as diabetes and cardiologic, haematologic, organ-specific (e.g., eye or liver), neurologic and psychiatric, autoimmune, and dermatologic disorders. The mechanistic grounds for mitochondrial dysfunction (MDF) along with the occurrence of oxidative stress (OS) have been investigated within the pathogenesis of individual disorders or in groups of interrelated disorders. We attempt to review broad-ranging pathologies that involve mitochondrial-specific deficiencies or rely on cytosol-derived prooxidant states or on autoimmune-induced mitochondrial damage. The established knowledge in these subjects warrants studies aimed at elucidating several open questions that are highlighted in the present review. The relevance of OS and MDF i...