Mitochondrial disorders myopathy

The metabolic myopathies are exceptionally complex. Mitochondrial disorders are usually multisystem disorders, in which metabolic dysfunction affects muscle, liver, CNS, and special senses (especially vision) in almost any combination. There is evidence that some forms of mitochondrial disease are inherited, and the preponderance of maternal rather than paternal inheritance is consistent with an abnormality in the mitochondrial genome because almost all (and perhaps all) mitochondria are derived from the ovum. 

Human creatine kinase -MM MAK33 IgGl Cardiac disease, mitochondrial disorders, inflammatory myopathies, myasthenia, polymyositis, McArdle s disease, NMJ disorders, muscular dystrophy, ALS, hypo and hyperthyroid disorders, central core disease, acid maltase deficiency, myoglobinuria, rhabdomyolysis, motor neuron diseases, A. thaliana A. thaliana 2S2 seed storage protein SP + 0.02-0.4% TSP of fresh leaf extract (10-12% TSP of intercellular fluid) 52... 

Chariot, P. et al. (1999) Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. Journal of Hepatology, 30 (1), 156-160. 

Patients with mitochondrial disorders may present at any age and show variation in both the severity and kind of symptoms associated with a single genetic abnormality. For example, the tRNA mutation is predominantly associated with the neurological syndrome MELAS but may also be manifested as CPEO, myopathy, diabetes, and deafness. 

Chabrol B, Mancini J, Chretien D, Rustin P, Munnich A, Pinsard N (1994) Valproate-induced hepatic failure in a case of cytochrome c oxidase deficiency. Eur J Pediatr 153 133-135 Chariot P, Drogou I, de Lacroix-Szmania I, Ehezer-Vanerot MC, Chazaud B, Lombes A, Schaeffer A, Zafrani ES (2000) Zidovudine-indueed mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. J Hepatol 32 364-365 Chen CH, Cheng YC (1989) Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti-human immunodeflcieney vims compound 2, 3 -dideoxycytidine. J Biol Chem 264 11934-11937... 

Metabolic Myopathies Glycogen Storage Disease Disorders of Lipid Metabolism Respiratory Chain Disorders Mitochondrial DNA Abnormalities Myotonias, Periodic Paralyses, and Malignant Hyperpyrexia Myotonias... 

Corticosteroids a chronic painless myopathy associated with the long-term use of corticosteroids is a particularly common example of drug-induced muscle disorder. It is almost certain that mild cases are overlooked because steroids are so frequently used to treat inflammatory myopathies such as polymyositis. Fluorinated steroids are particularly frequently implicated, and the incidence of drug-induced muscle disease is dose and time-related. The presence of muscle weakness can even complicate topical steroid therapy. Corticosteroid-induced myopathy is mediated via intramuscular cytosolic steroid receptors. The steroid-receptor complexes inhibit protein synthesis and interfere with oxidative phosphorylation. The myopathy is associated with vacuolar changes in muscle, and the accumulation of cytoplasmic glycogen and mitochondrial aggregations. 

HPPD hallucinogen persisting perception disorder MF.l.AS mitochondrial myopathy, encephalopathy, lactic... 

Mitochondrial Myopathy. A general deticiency of iron may ho implicated in mitochondrial myopathy, which is a complex disorder that affects muscular activity. It lias been suspected for a number of years that the disorder is caused hy a delect of mitochondrial-protein transport. H.H.V. Sdiarpa and a team of researchers (Royal Free Hospital. London) postulate that a deficiency of an iron-sulfur protein in muscle dehydrogenase may be the specific cause. 

Although DNA mutations in nuclear DNA may cause mitochondrial dysfunction, the majority of genetically defined mitochondrial diseases are caused by mutations in mtDNA (M15, PI, S4). Point mutations and deletions of mtDNA have been reported to be associated with or responsible for mitochondrial myopathies and/or encephalomyopathies (M15, PI, S4). Patients with such diseases usually manifest major clinical symptoms early in life and at a later stage may develop additional multisystem disorders such as encephalopathy and/or peripheral neuropathy. Most of the mitochondrial myopathies occur sporadically and are often caused by large-scale mtDNA deletions (PI). However, there are several reports on maternally inherited mitochondrial myopathy and familial mitochondrial myopathy. These patients usually harbor a specific mtDNA mutation and often exhibit defects in NADH-CoQ reductase and/or cytochrome c oxidase. 

Several inherited disorders are associated with faulty operation of the electron transport pathway. ATP production is diminished in such cases. These disorders are known as mitochondrial myopathies, and they are associated with the absence of specific polypeptide chains found in complexes I, III, or IV. In many cases, the problem may be traced to specific lesions in mitochondrial DNA, which codes for at least 13 polypeptide chains found in these complexes. Myopathies are tissue specific some affect the heart, others the skeletal muscle. Many are accompanied by lactic acidosis, because the inability to reduce NADH normally results in its accumulation and the channeling of pyruvate toward lactic acid production. In complex I disorders, the oxidation of FADH2 is not impeded. In complex III lesions, neither NADH nor FADH2 can be oxidized. However, use has been made by B. Chance and colleagues of menadione (Chapter 6) and ascorbic acid in such cases. The former can oxidize UQH2, whereas ascorbate can oxidize menadione and reduce cytochrome c. Marked clinical improvement in affected patients follows such treatment. 

Acylcamitine then moves across the mitochondrial membrane via an antiport, which also transports carnitine in the opposite direction. In the mitochondria, carnitine is once more exchanged with CoA, which is a reversal of Equation (19.6), yielding acyl-CoA. Free carnitine is then returned to the extramitochondrial space by the antiport. The carnitine shuttle is shown in Figure 19.5. Carnitine is synthesized in the organism from lysine. The symptoms of carnitine deficiency are muscle weakness, cardiac myopathy, and hypertriglyceridemia. These are observed in certain genetic disorders, alcoholism, hemo-... 

Mitochondrial DNA (mtDNA) is present in mitochondria as a circular molecule and in most species codes for 13 or 14 proteins involved in the electron transfer chain, 2 rRNA subunits and 22 tRNA molecules (all necessary for protein synthesis) (Table 16.1). Given that 80% of mtDNA codes for functional mitochondrial proteins involved in energy production, it is not surprising that mtDNA mutations commonly lead to functional problems that manifest as muscle disorders (myopathies). 

A slowly progressive congenital neuromuscular disorder was reported in which the respiratory chain-linked energy transfer at a level common to all three energy coupling sites of respiratory chain was defective.52 Uncouplers of mitochondrial oxidative phosphorylation (2,4-dinitrophenol and carbonylcyanide-m-chlorophenylhydrazone) (5) produced mitochondrial myopathy in rats.53... 

Storage of energy thermodynamics free energy chemical equilibria and group transfer potential, acid-base balance, disorders of energy metabolism, e.g., mitochondrial myopathies, diabetic ketoacidosis 107-108, 230-268, 318, 412... 

The inherited defects of mitochondrial fatty acid -oxidation are considered an important - and frequent - cause of disturbed energy homeostasis throughout all ages. Unfortunately, the clinical spectrum of this group of disorders is extremely variable from a lethal neonatal presentation via relatively mild lipid storage myopathy to completely symptom-free subjects. 

Respiratory-chain disorders (with mitochondrial myopathy) Lactic Various, including cytochromes b, aa, cytochrome c oxidase, NADH-coenzyme Q reductase 15.6... 

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