Exercise intolerance

This complex consists of at least 25 separate polypeptides, seven of which are encoded by mtDNA. Its catalytic action is to transfer electrons from NADH to ubiquinone, thus replenishing NAD concentrations. Complex I deficiency has been described in myopathic syndromes, characterized by exercise intolerance and lactic acidemia. In at least some patients it has been demonstrated that the defect is tissue specific and a defect in nuclear DNA is assumed. Muscle biopsy findings in these patients are typical of those in many respiratory chain abnormalities. Instead of the even distribution of mitochondria seen in normal muscle fibers, mitochondria are seen in dense clusters, especially at the fiber periphery, giving rise to the ragged-red fiber (Figure 10). This appearance is a hallmark of many mitochondrial myopathies. 

Hypoperfusion of skeletal muscles leads to fatigue, weakness, and exercise intolerance. Decreased perfusion of the central nervous system (CNS) is related to confusion, hallucinations, insomnia, and lethargy. Peripheral vasoconstriction due to SNS activity causes pallor, cool extremities, and cyanosis of the digits. Tachycardia is also common in these patients and may reflect increased SNS activity. Patients will often exhibit polyuria and nocturia. Polyuria is a result of increased release of natriuretic peptides caused by volume overload. Nocturia occurs due to increased renal perfusion as a consequence of reduced SNS renal vasoconstrictive effects at night. In chronic severe HF, unintentional weight loss can occur which leads to a syndrome of cardiac cachexia. This results from several factors, including loss of appetite, malabsorption due to gastrointestinal edema, elevated metabolic rate, and elevated levels of proinflammatory cytokines. 

Beta-enolase deficiency (type XIII, Fig. 42-1) has been identified in a 47-year-old man with late-onset but rapidly progressive exercise intolerance and exercise-triggered myalgia. He did not complain of cramps, never experienced pigmenturia, but had chronically elevated serum CK. The patient was a compound heterozygote for two mutations in the EN03 gene, which is located on chromosome 17 [1],... 

Glutaric aciduria type II, which is a defect of P-oxida-tion, may affect muscle exclusively or in conjunction with other tissues. Glutaric aciduria type II, also termed multiple acyl-CoA dehydrogenase deficiency (Fig. 42-2), usually causes respiratory distress, hypoglycemia, hyperammonemia, systemic carnitine deficiency, nonketotic metabolic acidosis in the neonatal period and death within the first week. A few patients with onset in childhood or adult life showed lipid-storage myopathy, with weakness or premature fatigue [4]. Short-chain acyl-CoA deficiency (Fig. 42-2) was described in one woman with proximal limb weakness and exercise intolerance. Muscle biopsy showed marked accumulation of lipid droplets. Although... 

Coenzyme Q10 (CoQlO) deficiency. This mitochondrial encephalomyopathy has three main clinical presentations. A predominantly myopathic form is characterized by the triad of exercise intolerance, recurrent myoglobinuria, and CNS involvement. A more frequent ataxic form is dominated by ataxia and cerebellar atrophy, variously associated with weakness, developmental delay, seizures, pyramidal signs, and peripheral neuropathy, often simulating spinocerebellar atrophy. A third presentation with fatal infantile encephalomyopathy and renal involvement, has been described in two families. The biochemical defect (or defects) presumably involve different steps in the biosynthesis of CoQlO, but are still unknown, as are the molecular defects. Diagnosis, however, is important because all patients - and especially those with the myopathic and infantile forms - benefit from CoQlO supplementation [13,14]. 

Mutations in the only mtDNA-encoded subunit of complex III (cytochrome b) can cause multisystem disorders or - more commonly - isolated myopathies, manifested by exercise intolerance with or without exercise-related myoglobinuria. Patients with myopathy are almost invariably sporadic, suggesting that the cytochrome b mutations are... 

The primary symptoms are dyspnea (particularly on exertion) and fatigue, which lead to exercise intolerance. Other pulmonary symptoms include orthopnea, paroxysmal nocturnal dyspnea, tachypnea, and cough. 

Type IV/Andersen failure to thrive, hypotonia, hepatomegaly, splenomegaly, progressive liver cirrhosis and failure (death usually before fifth year) some without progression Type V/McArdle exercise intolerance, muscle cramps, myoglobinuria on strenuous exercise, increased creatine kinase (predominantly in male)... 

Co-enzyme Q10 concentrations were measured in blood from hypercholesterolemic subjects before and after exposure to atorvastatin 80 mg/day for 14 and 30 days in 34 subjects eligible for statin treatment (11). The mean blood concentration of co-enzyme Q10 was 1.26 pg/ml at baseline, and fell to 0.62 after 30 days of atorvastatin therapy. There was a statistically significant fall detectable after 14 days of treatment. The authors concluded that widespread inhibition of co-enzyme Q10 synthesis could explain the exercise intolerance, myalgia, and myoglobinuria that are observed with statin treatment. 

In 1997, Graham et al. (G6) reported that mice lacking the nuclear gene encoding the heart/muscle isoform of ANTI exhibit a severe defect in mitochondrial respiration, a dramatic proliferation of mitochondria in skeletal muscle, and cardiac hypertrophy. The mutant mice developed mitochondrial myopathy and cardiomyopathy associated with ragged-red muscle fibers, lactic acidosis, and severe exercise intolerance, which are similar to observations in patients with mtDNA diseases (G6, Wl). 

In a second case, a 15-year-old girl presented with a long-standing muscle weakness, exercise intolerance, hypoglycemia, lactic acidosis, and a high anion gap. For 2 subsequent years, she was treated by various methods in an effort to control her acidosis without success. At the age of 17, a muscle biopsy was collected, and her mitochondria were shown not to be able to oxidize reduced CoQ. She was then treated with vitamin K3 and vitamin C with remarkable success. 

Mitochondrial cytopathies can be very varied. Since the distribution of defective mtDNA may vary from organ to organ, a mutation that in one person would cause liver disease might in another cause a brain disorder. The severity of the defect may be great or small some may cause exercise intolerance , with no serious illness or disability other defects can have severe body-wide impacts. 

Multiple mtDNA deletions in skeletal muscle. Clinical features include adult onset of weakness of the external eye muscles (ophthalmoplegia) and exercise intolerance. Both autosomal dominant and autosomal recessive inheritance can occur, but in most cases it appears to be due to a sporadic deletion or duplication within the mtDNA. 

Muscles require a significant amount of energy in the form of ATP. When energy levels become too low, muscle weakness and exercise intolerance with muscle pain or cramps may occur. Metabolic muscle diseases that have their onset in infancy tend to be the most severe, and some forms are fatal. Those that begin in childhood or adulthood tend to be less severe, and changes in diet and lifestyle can help most people with the milder forms adjust. The more common metabolic diseases are summarised below. 

Symptoms include exercise intolerance and episodes of myoglobinuria (rust-coloured urine, indicating breakdown of muscle tissue) a skin rash is common. Inheritance is autosomal recessive. 

Phosphofructokinase deficiency (Tarui s disease) is an inborn error of glycogen metabolism characterised by a phosphofructokinase deficiency in the muscles, and associated with abnormal deposition of glycogen in muscle tissues, occasionally with myoglobinuria. The symptoms are similar to those seen in McArdle s disease. Classic Tarui s disease typically presents in childhood with exercise intolerance and anaemia. The fatal infantile variant presents in the first year of life. All reported patients have died by age four years. A late-onset variant manifests itself during later adulthood with progressive limb weakness without myoglobinuria or cramps. It is an autosomal recessive inheritance. Males are slightly more often affected than females. 

Phosphoglycerate kinase deficiency, the seventh enzyme step of the glycolytic pathway, is an inherited X-linked recessive disorder, meaning it mostly affects males, although females are carriers. Onset is infancy to early adulthood. Symptoms may include anaemia, enlargement of the spleen, mental retardation and epilepsy (seizures) more rarely, weakness, exercise intolerance, muscle cramps and episodes of myoglobinuria occur. 

Phosphoglycerate mutase deficiency, the eighth enzyme step of glycolysis, is inherited autosomal recessive. Onset occurs in childhood to early adulthood. Symptoms include exercise intolerance, cramps, muscle pain and sometimes myoglobinuria. 

Prognosis is directly related to the severity of pulmonary injury. Animals that survive the first 24 to 48 h still have a guarded prognosis. These animals are more susceptible to infectious agents as they have suppressed natural killer cell activity. Infections may become evident 3 to 5 days after exposure. Animals may develop chronic exercise intolerance and abnormal pulmonary function (Borak and Diller, 2001). Working dogs and equines may no longer be able to fulfill their fimctions. 

Blockers Treatment of open-angle glaucoma Decreased cardiac rate, syncope, exercise intolerance, bronchospasm, emotional or psychiatric disorders... 

Karas B, Grubb BP, Boehm K, Kip K. The postural orthostatic tachycardia syndrome a potentially treatable cause of chronic fatigue, exercise intolerance, and cognitive... 

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