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A 25-year-old man complained of progressive diplopia and limb weakness for 3 years. Mitochondrial myopathy was suspected according to clinical presentation, elevated serum lactate concentration, and muscle histopathology. However, next-generation mtDNA sequencing (mtDNA NGS) of the blood only revealed a likely benign variant in the MT-CO1 gene (m.6510G > A). An mtDNA NGS study on the muscle sample revealed a large mtDNA deletion (m.5788–m.16071). The patient was diagnosed as having CPEO-plus syndrome related to the large mtDNA deletion. Notably, magnetic resonance spectroscopy revealed a doublet peak at 1–2 ppm in his edematous right vastus lateralis, which indicated lactate accumulation. Thus, muscle imaging and appropriate genetic tests facilitated the diagnosis of mitochondrial myopathy., Highlights • Heteroplasmy underlies various presentations of mitochondrial disorders. • Adequate genetic testing in affected tissue with deep phenotyping • MRS could detect a lactate accumulation in mtDNA deletion syndrome.

Mitochondria participate in various metabolic pathways, and their dysregulation results in multiple disorders, including aging-related diseases. However, the metabolic changes and mechanisms of mitochondrial disorders are not fully understood. Here, we found that induced pluripotent stem cells (iPSCs) from a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) showed attenuated proliferation and survival when glycolysis was inhibited. These deficits were rescued by taurine administration. Metabolomic analyses showed that the ratio of the reduced (GSH) to oxidized glutathione (GSSG) was decreased; whereas the levels of cysteine, a substrate of GSH, and oxidative stress markers were upregulated in MELAS iPSCs. Taurine normalized these changes, suggesting that MELAS iPSCs were affected by the oxidative stress and taurine reduced its influence. We also analyzed the retinal pigment epithelium (RPE) differentiated from MELAS iPSCs by using a three-dimensional culture system and found that it showed epithelial mesenchymal transition (EMT), which was suppressed by taurine. Therefore, mitochondrial dysfunction caused metabolic changes, accumulation of oxidative stress that depleted GSH, and EMT in the RPE that could be involved in retinal pathogenesis. Because all these phenomena were sensitive to taurine treatment, we conclude that administration of taurine may be a potential new therapeutic approach for mitochondria-related retinal diseases., Graphical abstract Image 1, Highlights • iPS cell lines were derived from a MELAS patient with the mtDNA A3243G mutation. • Decreased proliferation and survival of MELAS iPSCs were rescued by taurine. • Reduction in GSH/GSSG ratio in MELAS iPSCs was suppressed by taurine. • EMT in MELAS iPSC-derived retinal pigment epithelium was suppressed by taurine. • Oxidative stress markers in MELAS iPSCs and RPE were suppressed by taurine.

A 29-year-old man developed, since the age of 18, exercise intolerance and exercise-induced rhabdomyolysis, with myoglobinuria. Muscle biopsy showed ragged-red fibers. Multiple mitochondrial DNA deletions were detected. The previously reported pathogenic homozygous mutation c.323C>T (p.Thr108Met) in TK2 was identified. This case expands the phenotypic spectrum of TK2 deficiency and indicates that it should be considered in the differential diagnosis of episodic rhabdomyolysis and exercise intolerance, along with other metabolic and mitochondrial myopathies. Since a new treatment is under development, it is essential improving knowledge of the natural history of TK2 deficiency.

Objective To describe the clinical and molecular features of a group of Argentinian pediatric patients with mitochondrial DNA (mtDNA) disorders, and to evaluate the results of the implementation of a classical approach for the molecular diagnosis of mitochondrial diseases. Methods Clinical data from 27 patients with confirmed mtDNA pathogenic variants were obtained from a database of 89 patients with suspected mitochondrial disease, registered from 2014 to 2020. Clinical data, biochemical analysis, neuroimaging findings, muscle biopsy and molecular studies were analyzed. Results Patients were 18 females and 9 males, with ages at onset ranging from 1 week to 14 years (median = 4 years). The clinical phenotypes were: mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome (n = 11), Leigh syndrome (n = 5), Kearns-Sayre syndrome (n = 3), Chronic Progressive External Ophthalmoplegia (n = 2), Leber hereditary optic neuropathy (n = 2), myoclonic epilepsy associated with ragged-red fibers (n = 1) and reversible infantile myopathy with cytochrome-C oxidase deficiency (n = 3). Most of the patients harbored pathogenic single nucleotide variants, mainly involving mt-tRNA genes, such as MT-TL1, MT-TE and MT-TK. Other point variants were found in complex I subunits, like MT-ND6, MT-ND4, MT-ND5; or in MT-ATP6. The m.13513G > A variant in MT-ND5 and the m.9185 T > C variant in MT-ATP6 were apparently de novo. The rest of the patients presented large scale-rearrangements, either the “common” deletion or a larger deletion. Conclusions This study highlights the clinical and genetic heterogeneity of pediatric mtDNA disorders. All the cases presented with classical phenotypes, being MELAS the most frequent. Applying classical molecular methods, it was possible to achieve a genetic diagnosis in 30% of the cases, suggesting that this is an effective first approach, especially for those centers from low-middle income countries, leaving NGS studies for those patients with inconclusive results.

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a clinical syndrome associated with mitochondrial disorders (MIDs). This report illustrates a case of MELAS syndrome with hypothyroidism and psychiatric disorders, which is different from the common clinical manifestations of MELAS syndrome, such as exercise intolerance, migraine-like headaches, hearing loss and seizures etc. There are considerable interests in the possibility that mitochondrial dysfunction may play a role in the pathogenesis of endocrine dysfunctions and psychiatric disorders in MELAS syndrome., Highlights • We presented an adult MELAS patient with a mutation at A3243G point. • Hypothyroidism and psychiatric disorder were observed as accompanying symptoms. • MRI findings were typical and provided clues to diagnose the underlying MELAS.

The electrodiagnostic tests performed in a patient with suspected muscle disease should provide reliable answers to the addressed questions: (1) differentiate a myopathic disorder from a neuropathic one and (2) precise the nature and cause of the myopathy. Answer to the first question mainly requires needle electromyography (EMG) of 4–6 muscles. Recordings may include extraction and measurements of motor unit potentials (MUPs). Reduced MUP spike duration indicates a lack of active muscle fibers within the motor units, and is the most reliable sign of myopathy. Needle EMG will also guide toward the etiology of the myopathy through the topographical distribution (proximal, distal, etc.) of abnormal EMG tracings and the identification of electrical activity at rest, especially fibrillation and myotonic discharges which guide toward evolutive myopathies and myotonic syndromes, respectively. The study of sensory nerve conduction should involve two to three nerves in order to disclose the coexistence of a sensory neuropathy (particularly in mitochondrial myopathies). If the diagnosis remains uncertain, functional provocative tests should be performed: 3 Hz repetitive nerve stimulation to search for a myasthenic syndrome, repeated short exercise (combined with cooling if necessary) in the case of myotonic syndrome; long exercise test if periodic paralysis is suspected.

Disorders of muscle account for a substantial proportion of infants affected with hypotonia and weakness. Although a relatively large number of myopathic disorders may cause manifestations in the neonatal period, only a few disorders account for most of the cases observed. Myotonic dystrophy is the most frequent. Myopathic disorders with nondiagnostic histology include congenital muscular dystrophy, facioscapulohumeral dystrophy, polymyositis, and minimal change myopathy; those with a diagnostic histology include core myopathies, nemaline myopathy, myotubular myopathy, congenital fiber type disproportion, mitochondrial myopathies, and metabolic myopathies. Several disorders of the neuromuscular apparatus are restricted to a small portion of the motor system; restricted disorders that are not established as caused principally by trauma are considered in this chapter. Detection of any of these disorders is valuable for purposes of genetic counseling, determination of prognosis, and institution of therapy.

Mitochondrial disease can manifest as acute encephalopathy triggered by febrile illnesses, which increase energy demand and reveal the underlying failure of the respiratory chain to produce adenosine triphosphate (ATP). Metabolic decompensation also occurs in other inherited metabolic diseases, such as amino acid, organic acid, carbohydrate, and β-oxidation deficits. Two subgroups of mitochondrial diseases are demonstrative: Leigh syndrome/encephalopathy (LS) and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome.

cited By 0; International audience; With interest we read the article by Zanolini et al. about a 21 year-old male with isolated myopathy due to the ND2 mutation m.4831G > A. We have the following comments and concerns.We do not agree that the patient had myopathy as the sole manifestation of the mitochondrial disorder (MID). The patient started with vomiting during exercise since age 17 years, a frequent manifestation of MIDs particularly in patients with MELAS and possibly associated with lactic acidosis. Additionally, he had bone abnormalities, manifesting as high arched palate and malocclusion of teeth [1]. Furthermore, exercise-induced supraventricular tachycardia suggests cardiac involvement. The patient thus has to be classified as mitochondrial multiorgan disorder syndrome (MIMODS).

Mitochondrial disorders represent a heterogeneous group of diseases caused by a dysfunction of oxidative phosphorylation in the mitochondria, the double membrane-bound organelles that generate energy in eukaryotic cells. This group collectively may involve any mode of inheritance, may present from the neonatal period to adulthood, and can clinically affect nearly every organ system. Symptoms are variable and evolve over time and may include developmental delay, myopathy, encephalopathy, seizures, ataxia, sensorineural hearing loss, ophthalmoplegia, retinopathy, diabetes mellitus, liver failure, cardiomyopathy, exercise intolerance, and gastric dysmotility. Given the variability of clinical presentations, establishing the diagnosis of a mitochondrial disorder is frequently challenging. Diagnostic delay or misdiagnosis is common. Mutations in 37 mitochondrial genes or over 100 nuclear genes can result in overlapping phenotypes. The reverse is also true with the same genetic mutation causing different clinical presentations. Not uncommonly, extensive laboratory evaluation is required including lactate and pyruvate levels, plasma amino acid profiles, urine organic acid profiles, plasma acylcarnitine profiles, and specific enzymatic analysis of skin and muscle. Neuroimaging is often needed. Recent developments in whole-exome sequencing have revolutionized diagnosis and expanded the molecular spectrum with discovery of new conditions. Although some symptomatic improvement may be achieved by the use of specialized vitamin and cofactor therapies as well as supportive illness management, there is no cure for these conditions and some can be fatal. Improvements in quality of life and survival can be achieved with multidisciplinary clinical management.

The proband case was noted to be anemic at 23 years of age, unresponsive to erythropoietin injections, and investigations ultimately revealed that she had ringed sideroblasts. She had reduced exercise tolerance but has otherwise been healthy, although she had a spinal fusion for scoliosis in mid-adolescence and has endometriosis. Her general physical examination was unremarkable, and she was of normal intellect. EKG and echocardiograph have been normal.

The acronym, MERRF, or myoclonus epilepsy and ragged red fiber disease, represents one of the early mitochondrial syndromes, whose molecular genetic basis was first established in 1990 by Shoffner and coworkers. Pathogenic mutations in the mitochondrial tRNA Lys may cause the MERRF syndrome. Myoclonus and epilepsy, most often medically intractable epilepsy, are hallmarks of the illness. Other features of the illness may include retinitis pigmentosa, progressive external ophthalmoplegia, sensorineural hearing loss, dementia, ataxia, cervical lipomatosis, cardiac conduction defects (Wolff-Parkinson-White syndrome and others), lipomatosis, neuropathy, cardiomyopathy, and a myopathy. MERRF cases may have features that overlap other mitochondrial disorders. The diagnostic evaluation requires recognizing the clinical phenotype and performing confirmatory genetic testing. Although the name of this disorder includes the words ragged red fibers, a microscopic description of the appearance of the muscle fibers in many cases is currently not part of the case's evaluation, as the illness can be confirmed by genetic testing without the need for a muscle biopsy. Treatment is symptomatic, with myoclonus best treated with benzodiazepines and the seizures treated with medications best for myoclonic epilepsy and generalized epilepsy, such as lamotrigine, zonisamide, levetiracetam, and lacosamide. The use of electroencephalography (EEG) is often important to distinguish between myoclonus and myoclonic seizures, as the treatment for myoclonus would be aimed at symptom relief, whereas the treatment for seizures would be to prevent or lessen their frequency. The EEG can also distinguish subclinical seizures from the neuropsychological effects of medication use and dementia. There are no curative therapies at this time.

Mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) is a multisystem disease secondary to mitochondrial DNA mutations. A majority (80%) of cases with MELAS are positive for the common m.3243A>G mutation in tRNALeu(UUR). Typical features of MELAS include normal early psychomotor development, stroke-like episodes prior to the onset of 40 years, encephalopathy (characterized by seizures, dementia, or both), myopathy, recurrent headaches, and recurrent vomiting. Cases may also present with other features common to mitochondrial disease, including short stature, sensorineural hearing loss, diabetes, gastrointestinal manifestations, ocular manifestations, cardiac manifestations, and acute decompensation following a metabolic stressor. Over time, a culmination of stroke-like episodes results in significant neurological disability. The pathophysiology of stroke-like episodes suggests a role of nitric oxide deficiency and endothelial dysfunction resulting in segmental vasoconstriction. The diagnosis of MELAS is commonly made through confirmation of the genetic mutation but can be suggested by biochemical alterations, radiological findings, and morphological alterations of muscle.

Megaconial congenital muscular dystrophy is a disease caused by pathogenic mutations in the gene encoding choline kinase beta (CHKB). Microscopically, the disease is hallmarked by the presence of enlarged mitochondria at the periphery of skeletal muscle fibres leaving the centre devoid of mitochondria. Clinical characteristics are delayed motor development, intellectual disability and dilated cardiomyopathy in half of reported cases. This study describes a patient presenting with the cardinal clinical features, in whom a homozygous nonsense mutation (c.248_249insT; p.Arg84Profs*209) was identified in CHKB and who was treated by heart transplantation. Microscopic evaluation of skeletal and heart muscles typically showed enlarged mitochondria. Spectrophotometric evaluation in both tissues revealed a mild decrease of all OXPHOS complexes. Using BN-PAGE analysis followed by activity staining subcomplexes of complex V were detected in both tissues, indicating incomplete complex V assembly. Mitochondrial DNA content was not depleted in analysed tissues. This is the first report describing the microscopic and biochemical abnormalities in the heart from an affected patient. A likely hypothesis is that the biochemical findings are caused by an abnormal lipid profile in the inner mitochondrial membrane resulting from a defective choline kinase B activity.

Mitochondria can be negatively affected by inactivity, toxins, and genetic diseases. Many diseases of inactivity (metabolic syndrome, obesity, and type 2 diabetes) can be prevented by strengthening our mitochondria with exercise. Many inherited mitochondrial disorders have been identified. Mitochondria are suspected of having a role in degenerative diseases of the brain. Mitochondria are important in understanding cancer because they are at the center of apoptosis (programmed cell death) and tumor cells have altered metabolism, skewed toward growth rather than energy production. Mitochondria are complicated biological entities and are very sensitive to a multitude of chemical toxins. Mitochondrial toxins can be divided into environmental/dietary toxins and medication-related toxins and are detailed here so the athlete can best avoid them. Mitochondrial toxicity cut short Greg LeMond’s racing career.

Hereditary myopathies are subclassified in muscular dystrophies with and without myotonia, distal myopathies and metabolic myopathies summarizing myopathies caused by disorders in glycogen, lipid and purine metabolism, mitochondrial myopathies and often also endocrine and/or toxic-metabolic myopathies. Muscle strength, muscle endurance and aerobic training modalities, single or combined, had been evaluated in different studies mainly lasting several months with patient groups suffering from different diseases from above. All revealed positive effects in motor and ADL functions over the training period with nearly no negative side effects. Eccentric or intensive muscle exercise should be avoided. Sports and exercise programs, low resistance intensity and repetition rates must be individually adapted. As concomittant cardial or respiratory disorders are common in myopathies, (sports)medical examinations and long term care has to meet special demands.

Las enfermedades mitocondriales se caracterizan desde el punto de vista clínico por su variabilidad y heterogeneidad, ya que los síntomas más frecuentes son los dependientes de los numerosos tejidos que requieren una alta demanda energética. Pueden aparecer a cualquier edad y su curso es progresivo. La diversibilidad clínica y la afectación multisistémica son signos orientativos para la sospecha diagnóstica, en particular durante la edad pediátrica. Hay entidades claramente identificadas como el síndrome de Kearns-Sayre. En el la biopsia muscular muestra fibras rojas rasgadas y aproximadamente el 80% de los casos presentan deleción del ADN mitocondrial de forma esporádica. En el estudio de imagen se observan áreas de baja densidad en núcleos de la base que no se realzan tras la administración de contraste en tomografía computarizada (TC) y focos simétricos hiperintensos a dichos niveles en resonancia magnética (RM) potenciada en T2. Se presenta el caso de un paciente con síndrome de Kearns-Sayre, en el que las alteraciones radiológicas contribuyeron a establecer el diagnóstico. : Clinical presentation of mitochondrial disorders is heterogeneous because the affected organs are those depending on a high rate of aerobic metabolism. They can appear at any age and evolution is progressive. Signs that guide diagnostic suspicion, especially in the pediatric age group, are heterogeneous clinical presentation and multisystem involvement. Within the spectrum of diseases caused by mitochondrial myopathy, there are clearly defined syndromes such as Kearns-Sayre syndrome. Muscle biopsy shows ragged red fibers and approximately 80 % of patients present sporadic deletions in mitochondrial DNA. Imaging studies reveal areas of hypointensity in basal ganglia and midbrain that are not visible after administration of contrast enhancement in computed tomography, and symmetric T2 hyperintensity lesions in these areas in magnetic resonance imaging. We present a patient with Kearns-Sayre syndrome, in whom radiological alterations were helpful in reaching the diagnosis.

Oxygen extraction fraction (OEF) is defined as the ratio of blood oxygen that a tissue takes from the blood flow to maintain function and morphological integrity. OEF reflects the efficiency of oxygen utilization by the tissue and, therefore, is a hemodynamic measure in brain ischemia. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a common mitochondrial disorder. It is characterized by neurological remissions and relapses and associated with progressive neurocognitive deficits. Because of abnormalities of mitochondrial function in MELAS, defects in the oxidative metabolic pathways of energy production decrease the cerebral oxygen utilization and lead to the reduction of OEF. Quantification of OEF can reflect the functional status of cerebral mitochondria and provide insight into the pathophysiological changes in the brain in MELAS. In light of recent advances in MRI, the discovery of the blood–oxygen level-dependent signal has allowed development of MRI methods targeted toward quantitative OEF imaging. A new MR sequence, termed the gradient-echo sampling of spin echo, was successfully developed to enable quantitative assessment of the OEF in the brain tissue. MR OEF imaging in patients with MELAS detects extensive OEF reduction in the stroke-like lesions, as well as in the normal-appearing brain regions. More severe dysfunction of the mitochondria in the stroke-like lesions was implied at the onset of the stroke-like episode. Determination of OEF throughout the episode demonstrated a chronological change in mitochondrial function in individual cases. Such neuroimaging findings might provide some clues in the investigation of the underlying mechanisms of stroke-like episodes.

SummaryMitochondria are highly mobile and dynamic organelles that continually fuse and divide. These processes allow mitochondria to exchange contents, including mitochondrial DNA (mtDNA). Here we examine the functions of mitochondrial fusion in differentiated skeletal muscle through conditional deletion of the mitofusins Mfn1 and Mfn2, mitochondrial GTPases essential for fusion. Loss of the mitofusins causes severe mitochondrial dysfunction, compensatory mitochondrial proliferation, and muscle atrophy. Mutant mice have severe mtDNA depletion in muscle that precedes physiological abnormalities. Moreover, the mitochondrial genomes of the mutant muscle rapidly accumulate point mutations and deletions. In a related experiment, we find that disruption of mitochondrial fusion strongly increases mitochondrial dysfunction and lethality in a mouse model with high levels of mtDNA mutations. With its dual function in safeguarding mtDNA integrity and preserving mtDNA function in the face of mutations, mitochondrial fusion is likely to be a protective factor in human disorders associated with mtDNA mutations.PaperClip

A defining characteristic of the extraocular muscles is their fast and constant activity. To sustain it, energy demands by the contractile apparatus must be met by energy supply pathways. We have just begun to outline major differences in the relative importance of some pathways, such as the use of lactate for aerobic metabolism, loss of creatine kinase as an ATP buffering system, and the use of mitochondria as calcium sinks. More importantly, there is now concrete evidence demonstrating divergence in mitochondrial composition and function between extraocular and prototypical skeletal muscles. These differences are likely to influence the contractile function of the extraocular muscles and may determine their preferential involvement in some congenital and age-related mitochondrial myopathies.

Publisher Summary This chapter presents the investigation of metabolic myopathies. Glycogen storage disorders (the glycogenoses) are a group of rare inherited metabolic diseases due to abnormal synthesis or breakdown of glycogen. Most affect single cytoplasmic enzymes, with the exception of α-glucosidase (acid maltase) deficiency which involves the lysosomal glycogen degradation pathway. The glycogen storage disorders generally present clinically in one of two ways: exercise intolerance, muscle cramps and intermittent rhabdomyolysis, or progressive proximal weakness. Defects of mitochondrial oxidative phosphorylation are an important cause of muscle disease and are often described as mitochondrial myopathies. The biochemistry and genetics of these disorders are much more complex than either glycogen storage disorders or fatty acid oxidation, predominantly due to the involvement of the mitochondrial genome (mtDNA). In addition, mitochondrial oxidative phosphorylation disorders — all of which are characterized by the inability of the cell to produce enough ATP on account of respiratory chain dysfunction—may present with a vast array of different clinical features, which makes them enter the differential diagnosis of many different neurological conditions.

Many of the assisted reproductive techniques associated with maternal aging, disease states, or implantation failure aim to correct poor developmental capacity. These techniques are highly invasive and require the exchange of nuclear or cytoplasmic material from a donor oocyte to compensate for deficiencies inherent in the affected individual. These techniques are based on the assumption that the cytoplasm of the donor oocyte can effectively substitute the necessary component(s) to enable development to proceed. Several studies have attempted to inject cytoplasm from "normal" (young) donors, into aged eggs, again assuming that beneficial components of the cytoplasm are transferred to restore developmental capacity. These invasive assisted reproduction technology (ART) procedures aim to eliminate chromosomal abnormalities, improve the quality of oocytes deficient in some important cytoplasmic factors necessary for maturation and/or subsequent development, and eliminate maternally inherited diseases (particularly mitochondrial myopathies). However, in order to develop such ART, understanding the processes involving mitochondrial DNA replication and transcription is imperative, as asynchrony between mitochondrial and nuclear genomes may cause problems in mitochondrial function, localization, and biogenesis.

Publisher Summary Alterations in biological and functional properties of skeletal muscle occur with aging, leading to the loss of muscle mass and force generating capacity, which is one of the most common causes of frailty and health problems in the elderly. Skeletal muscle mass and force-generating capacity is reduced with aging even in normal individuals resulting in frailty in the elderly. This natural condition is called sarcopenia. The correlates of sarcopenia at the cellular level are muscle fiber atrophy and loss, together with functional impairment in the intracellular contractile mechanisms of the muscle fibers. These changes are determined by alterations in the rate of protein synthesis and degradation, and by oxidative stress, hormonal influences, genetic alterations and changes in vascular supply all of which are affected during aging. Combination of these changes produces a unique milieu in the senescent muscle cell which favors the development of late-onset diseases such as s-IBM. The most frequent muscular conditions and diseases of the elderly organism are camptocormia, late onset mitochondrial myopathy, oculopharyngeal muscular dystrophy and sporadic inclusion body myositis.

Many drugs used in various branches of medicine, as well as alcohol and other substances of addiction, produce muscular symptoms, either through a direct effect on the skeletal muscles or by interfering with neuromuscular transmission or peripheral nerve function. A variety of chemicals, biological toxins, and venoms are also myotoxic. The mechanisms of action of drugs and toxins on muscle are diverse. Some have a direct toxic effect, either locally after intramuscular injection, or more widely after systemic administration or absorption of the agent. In case of drugs that are not inherently myotoxic, muscle damage may be secondary to an immunological process, to hypokalaemia, or to muscle compression and ischemia during periods of unconsciousness and immobility following a drug overdose. A change in ionic conductance and excitability of the plasma membrane is the basis for the myotonia induced by a number of drugs and chemicals, and for the muscular weakness and hypotonia that occurs in patients who become severely hypokalaemic or hyperkalaemic while taking diuretics or certain other drugs. Some drugs interfere with muscle protein synthesis and degradation. This occurs particularly with the natural and synthetic glucocorticoids that inhibit the synthesis of muscle specific proteins as well as increasing protein degradation. Chloroquine, amiodarone, and a number of other amphiphilic cationic compounds cause a myopathy characterized by autophagic degeneration and phospholipid accumulation in muscle. Various drug-induced disorders are discussed such as myalgia and muscle cramps, myotonia, necrotizing myopathies, acute rhabdomyolysis, mitochondrial myopathy, dyskalemic myopathy, dyskalemic myopathy, autophagic myopathies, and alcoholic myopathy.

Luft disease is both the prototype and the rarest type of mitochondrial disease. The only two affected women had nonthyroidal hypermetabolism due to loose coupling of oxidation and phosphorylation in skeletal muscle mitochondria. Muscle biopsy showed massive mitochondrial proliferation (ragged-red fibers) and ultrastructurally enlarged mitochondria with packed cristae. Polarographic studies of isolated muscle mitochondria showed that they respired maximally even in the absence of physiological activators, thus explaining how much of the energy was wasted as heat. The unique biochemical defect is probably due to a mutation in the nuclear genome, which remains unknown.

Since the first identification in 1988 of pathogenic mitochondrial DNA (mtDNA) mutations, the mitochondrial diseases have emerged as a major clinical entity. The most striking feature of these disorders is their marked heterogeneity, which extends to their clinical, biochemical, and genetic characteristics. The major mitochondrial encephalomyopathies include MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes), MERRF (myoclonic epilepsy with ragged red fibers), KSS/CPEO (Kearns-Sayre syndrome/chronic progressive external ophthalmoplegia), and NARP/MILS (neuropathy, ataxia, and retinitis pigmentosum/maternally inherited Leigh syndrome) and they typically present highly variable multisystem defects that usually involve abnormalities of skeletal muscle and/or the CNS. The primary emphasis here is to review recent investigations of these mitochondrial diseases from the standpoint of how the complexities of mitochondrial genetics and biogenesis might determine their varied features. In addition, the mitochondrial encephalomyopathies are compared and contrasted to Leber hereditary optic neuropathy, a mitochondrial disease in which the pathogenic mtDNA mutations produce a more uniform and focal neuropathology. All of these disorders involve, at some level, a mitochondrial respiratory chain dysfunction. Because mitochondrial genetics differs so strikingly from the Mendelian inheritance of chromosomes, recent research on the origin and subsequent segregation and transmission of mtDNA mutations is reviewed.

Publisher Summary This chapter describes the procedures used for (1) direct cloning of primary human muscle satellite cells, (2) immunofluorescent staining of myoblasts for fluorescence-activated cell sorting (FACS), and (3) analysis of mitochondrial translation products in myoblasts and myotubes. Mutations in mitochondrial DNA (mtDNA) that affect mitochondrial protein translation (large-scale deletions, tRNA point mutations) are associated by many clinical entities classified as mitochondrial encephalomyopathies. Skeletal muscle fibers in patients with these diseases contain heteroplasmic mixtures of wild-type and mutant mtDNAs, inhomogeneously distributed along their length. Skeletal muscle fibers are postmitotic, multinuclear syncytia that cannot be grown in tissue culture. They are surrounded by mononuclear, undifferentiated myoblasts called “satellite cells” that may proliferate in culture. Although a number of different cell types are often available to study the expression of pathogenic mtDNA mutations, two important advantages are gained by using primary myoblast cultures. First, myoblasts can be induced to fuse in culture to form multinucleate myotubes that terminally differentiate and contract, thus, making it possible to study the effects of growth versus terminal differentiation on the expression of mtDNA mutations. Second, because satellite cells are dormant most of the time, the turnover of mitochondria and mtDNA is extremely slow as compared to that in differentiated muscle fibers. Thus, the relative proportions of mutant and wild-type mtDNAs in the satellite cell population reflects the degree of heteroplasmy that existed in the myoblast precursor population during embryological development.

Publisher Summary This chapter reviews the evidence for the contribution of mitochondrial dysfunction in neurodegenerative disorders and explores potential mechanisms to circumvent the defects responsible. The respiratory chain and oxidative phosphorylation system comprise five multisubunit protein complexes and two mobile electron carriers located on the mitochondrial inner membrane. Respiratory chain inhibitors may provide valuable models for putative toxins that could be responsible for neuronal degeneration alone or in concert with genetic or other endogenous factors. Inborn metabolic deficiencies of the respiratory chain and mutations of mitochondrial DNA (mtDNA) have now been associated with a large number of human diseases. The archetypal respiratory chain defects are represented clinically by the mitochondrial myopathies and encephalopathies. These include a variety of phenotypes including myopathy, cardiomyopathy, and other presentations. Mitochondrial activity has been assessed in Parkinson's disease (PD) caudate, putamen, globus pallidum, tegmentum, cerebral cortex, and cerebellum. MtDNA analysis for the 5 kb deletion suggested an increase in PD striatum, but samples were not age matched.

Publisher Summary Despite the foundations laid for the study of mitochondrial myopathy and respiratory chain defects by the biochemical studies of mitochondria isolated from muscle biopsy tissue, there are some problems associated with mitochondrial isolation artifacts and a very confusing literature in which patients are categorized by biochemical phenotype. Although recent advances in molecular biology have gone some way to resolving this problem by describing the mitochondrial tRNA mutations responsible for mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and myoclonic epilepsy with ragged red fibers (MERRF) by using tissue culture techniques describes a wide variety of defects in energy metabolism and perform studies that are not feasible with biopsy specimens. This chapter reviews the use of tissue culture techniques in the diagnosis and research of mitochondrial diseases and presents a comparison with the results obtained from muscle biopsy and postmortem material. An approach to the use of cultured cells, particularly skin fibroblasts in the detection of mitochondrial disease, stemmed initially from studies into the etiology of lacticacidemia in childhood rather than the study of mitochondrial myopathies.

Publisher Summary It has been accepted that both molecular genetics and the overlapping clinical features of syndromes generated too many inconsistencies for precise classification. The mitochondrial diseases have generated debate for three decades, ever since they were first recognized. Even today, there is no consensus about the meaning of the popular phrases to describe them: mitochondrial myopathy, mitochondrial encephalomyopathy, mitochondrial cytopathy, or mitochondrial disease. The uncertainty is a measure of the different criteria used to select the syndromes, which were first clinical and biochemical; then morphological definitions, moving from ultrastructure to histochemistry, were used, followed by human genetics and, finally, molecular genetics. This chapter focuses on disorders of the mitochondrial genome and not metabolic conditions caused by abnormalities of nuclear DNA that affect mitochondrial biochemical function.

Publisher Summary This chapter discusses the clinical features, investigation, treatment, and genetic counselling of mitochondrial myopathies. The mitochondrial myopathies are a clinically diverse group of diseases defined historically by the presence of structural mitochondrial abnormalities in biopsied skeletal muscle. The histological hallmark of mitochondrial myopathy is the ragged red fiber (RRF), demonstrated with the modified Gomori trichrome stain, containing peripheral and intermyofibrillar accumulations of abnormal mitochondria. Although the diagnostic importance of muscle biopsy is undisputed, the presence of RRFs as a sole criterion for establishing the diagnosis has been challenged by recent histochemical, biochemical, and genetic advances. RRFs occur in patients with clinical syndromes predominantly or exclusively involving the central nervous system (CNS). Patients may present with psychomotor retardation, dementia, seizures, ataxia, movement disorders, and stroke like episodes, pigmentary retinopathy, deafness, and peripheral neuropathy in various combination. Subsets of clinical features within the spectrum of mitochondrial encephalomyopathies lead to the identification of apparently specific clinicopathological entities. Involvement of tissues other than muscle, nerve, and CNS has further broadened the spectrum of mitochondrial myopathies to include hematological, endocrine, renal, cardiac, gastrointestinal, and metabolic manifestations.