Знакомьтесь, - Metabolic Muscle Diseases. Походу мой случай. Либо метаболик, либо аутоиммюн. У меня всегда с детства была слабая выносливость, и в 10 лет, когда в футбол играл и в 19 в каратэ. Очень слабая, сколько ни тренировался, не улудшалась. Походу у меня, что-то типа denosine monophosphate deaminase deficiency type 1.
Они могут протекать бессимптомно. Походу всегда была такая штука, может генетическая, а веганская диета была триггером. Теперь надо понять, что у меня конкретно. Мало времени осталось, надеюсь, успею.
Похоже когда у меня давление было, пострадала http://en.wikipedia.org/wiki/Pituitary_
Пришлос 20 баксов отдать за доступ к статьям. Хороший сайт, но платный.
Approach to the metabolic myopathies http://www.uptodate.com/contents/approa
Basil T Darras, MD
Marc C Patterson, MD, FRACP
John F Dashe, MD, PhD
Last literature review version 19.2:
This topic last updated: February 17, 2011
INTRODUCTION Most patients with a metabolic myopathy (eg, glycogen storage diseases, http://www.uptodate.com/contents/l-carn
In a smaller group of patients, both dynamic and static symptoms predominate http://www.uptodate.com/contents/im
This topic review will provide an overview of the evaluation of the patient with a suspected metabolic myopathy. A general approach to the diagnosis of metabolic myopathies is presented in Figure 1 (http://www.uptodate.com/contents/im
Detailed descriptions of the different disorders are presented separately. (See http://www.uptodate.com/contents/overvi
An overview of the biochemistry of energy metabolism in muscle is also discussed elsewhere. (See http://www.uptodate.com/contents/en
OVERVIEW OF CLINICAL MANIFESTATIONS: The symptoms, signs, and laboratory abnormalities resulting from a metabolic myopathy vary with the underlying defect. The diagnosis of these disorders depends upon a constellation of findings, including the type of muscle involvement, specific laboratory abnormalities (particularly elevations in serum creatine kinase and myoglobinuria), patient age, family history, and the results of histologic and pathologic examinations.
Glycolytic/glycogenolytic disorders. In patients with defects of carbohydrate metabolism, muscle symptoms are induced by either brief isometric exercise, such as lifting heavy weights, or by less intense but sustained dynamic exercise, such as swimming, climbing stairs, or running. Acute muscle breakdown may lead to myoglobinuria, cramps, and muscle swelling.
In young children, defects in glycogenolysis may present with liver dysfunction, hepatomegaly, failure to thrive, hypoglycemia (sometimes with associated hypoglycemic seizures), gross motor delay, peripheral neuropathy, cardiac involvement, hemolytic anemia with jaundice, splenomegaly, and myoglobinuria. Mental retardation, upper and lower motor neuron involvement with sensory loss, sphincter problems, and neurogenic bladder may also be observed.
The principal symptoms and signs, however, are those related to exercise intolerance and recurrent myoglobinuria [http://www.uptodate.com/contents/appro
"Second wind" also can be induced by the infusion of carbohydrate fuel (eg, glucose) or lipids [http://www.uptodate.com/contents/appro
Patients with certain glycolytic defects (eg, muscle phosphofructokinase deficiency), however, are unable to achieve a spontaneous second wind [http://www.uptodate.com/contents/appro
Disorders of lipid metabolism. The metabolic myopathies resulting from disorders of lipid metabolism include:
- Defects of beta-oxidation enzymes
Carnitine deficiency syndromes
- Fatty acid transport defects
With disorders of lipid metabolism, symptoms are usually induced by prolonged exercise and prolonged fasting. These patients, in contrast to those with glycogen metabolism defects, do not develop true muscle cramps or contractures, and do not experience a "second wind." Their symptoms and signs, such as muscle pain, tightness, or myoglobinuria, are usually induced by infection, general anesthesia, exposure to cold, and a low-carbohydrate, high-fat diet [http://www.uptodate.com/contents/appro
Some investigators have suggested that there are four main clinical and laboratory features that should lead the clinician to suspect a fatty acid oxidation disorder [http://www.uptodate.com/contents/appro
- Involvement of fatty acid oxidation-dependent tissues, such as the heart, muscle, and liver
- Recurrent episodes of hypoketotic hypoglycemia (ketoacidosis does not occur because fatty acids cannot be converted to ketoacids in the liver)
- Acute metabolic decompensation in association with fasting
- Alterations in plasma and tissue concentrations of http://www.uptodate.com/contents/l-carn
Skeletal muscle, heart, and liver are highly dependent upon efficient fatty acid utilization. Fatty acids are a major source of energy for the heart and liver, particularly during fasting when glycogen and glucose stores have been depleted. In addition, resting muscle and exercising muscle during mild to moderate prolonged exercise derive most of the required energy from fatty acid oxidation. (See http://www.uptodate.com/contents/en
Among fasting patients with fatty acid oxidation defects, the free fatty acids cannot be metabolized because of the existing metabolic block; as a result, they are stored in the cytoplasm as triglycerides, thereby resulting in progressive lipid storage myopathy with weakness, hypertrophic and/or dilated cardiomyopathy, and fatty liver. In addition, with fasting, glucose and glycogen stores are depleted and ketone bodies are not generated because of the existing metabolic block. As a result, the ratio of serum free fatty acids to ketones increases from the normal ratio of 1:1 to more than 2:1, which is highly suggestive of a block in beta-oxidation [http://www.uptodate.com/contents/appro
Other conditions that can lead to metabolic decompensation among patients with fatty acid oxidation defects include cold-induced shivering thermogenesis (Закаляйте, бляди, детей больше — H.B.) and infection with vomiting:
- With cold exposure, shivering depends heavily upon long-chain fatty acid oxidation [http://www.uptodate.com/contents/appro
- After prolonged fasting or during infections, children can become comatose and present with Reye-like syndrome symptoms
By comparison, in the majority of cases of intramitochondrial beta-oxidation defects, the amount of total serum http://www.uptodate.com/contents/l-carn
Myoglobinuria and rhabdomyolysis — Acute muscle breakdown of sufficient severity can lead to myoglobinemia and myoglobinuria [http://www.uptodate.com/contents/appro
The diagnostic approach to myoglobinuria and rhabdomyolysis is discussed in detail separately. (See http://www.uptodate.com/contents/re
Rhabdomyolysis may also occur in the absence of overt myoglobinuria, even when myoglobin is undetectable in the urine by qualitative or semiquantitative assay [http://www.uptodate.com/contents/appro
Serum CK is usually highly elevated (more than 5 to 100 times normal), with associated hyperuricemia, hyperphosphatemia, and hypocalcemia. The patient may or may not have any muscle symptoms or signs such as stiffness, cramps, aches, or swelling.
Patients with myoglobinuria may develop acute renal failure. Renal failure may be preventable with aggressive hydration and alkalinization of the urine. Hypercalcemia can occur during recovery of renal function in patients who develop renal failure. (See http://www.uptodate.com/contents/preven
In addition to the risk of acute renal failure, some patients develop respiratory failure, cardiac arrhythmias, or sometimes coma.
The frequency of myoglobinuria due to a metabolic defect may vary among children and adults. In a large series of children with recurrent myoglobinuria, an enzyme abnormality could be detected in only 24 percent of the cases [http://www.uptodate.com/contents/appro
The most common metabolic cause of recurrent myoglobinuria in both adults and children is http://www.uptodate.com/contents/l-carn
In addition to genetically determined muscle metabolic defects, common causes of rhabdomyolysis are toxins, alcohol, drugs, muscle compression, overexertion, or inflammatory processes. Both viral (influenza A and B, Epstein-Barr, HIV, adenovirus, cytomegalovirus, echovirus, coxsackievirus, parainfluenza, herpes simplex) and autoimmune (dermatomyositis, polymyositis) inflammatory etiologies have been implicated. Hypothyroidism may lead to rhabdomyolysis and myoglobinuria, and a few cases related to thyrotoxicosis have also been described [http://www.uptodate.com/contents/appro
Toxins appear to be the most frequent cause of rhabdomyolysis. In a series of 475 hospitalized adults with rhabdomyolysis, the following observations were made [http://www.uptodate.com/contents/appro
- The most frequent etiology was an exogenous toxin (46 percent), a category that included alcohol, illicit drugs, and prescribed drugs (eg, antipsychotics, statins, http://www.uptodate.com/contents/zidovu
dine-drug-information?source=see_link zidovudine, http://www.uptodate.com/contents/colchi cine-drug-information?source=see_link colchicine, selective serotonin reuptake inhibitors and http://www.uptodate.com/contents/lithiu m-drug-information?source=see_link lithium) [http://www.uptodate.com/contents/appro ach-to-the-metabolic-myopathies/abstract/1 4 ].
Less common causes included trauma, seizures, immobility, critical illness myopathy, exercise, heat/dehydration, and hypothermia. Multiple factors could be identified in 60 percent of cases.
- An underlying myopathy or metabolic muscle defect was diagnosed in only 10 percent of the patients [http://www.uptodate.com/contents/appro
ach-to-the-metabolic-myopathies/abstract/1 4 ]. In this group, recurrences were common, the incidence of acute renal failure was low, and typically only one etiologic factor could be identified.
Myoglobinuria was detected by dipstick/ultrafiltration in 19 percent of the patients.
In a series of 191 children treated in the emergency department of a pediatric tertiary care hospital, the most common causes of rhabdomyolysis were viral myositis, trauma, and connective tissue diseases, found in 38, 26, and 5 percent, respectively [http://www.uptodate.com/contents/appro
Myoglobinuria may also occur in patients with dystrophinopathies or caveolinopathies (ie, limb-girdle muscular dystrophy type 1C) [http://www.uptodate.com/contents/appro
Although exercise intolerance, often dating back to childhood, is common in patients with mitochondrial defects, rhabdomyolysis with resultant myoglobinuria is rare [http://www.uptodate.com/contents/appro
However, myoglobinuria has been reported in patients with mutations involving cytochrome b, cytochrome c oxidase (cox), and the MELAS A3260G mutation [http://www.uptodate.com/contents/appro
SYMPTOM ASSESSMENT. When confronted with a patient with a possible metabolic myopathy, the first step is to determine whether the symptoms are dynamic, static, or both (http://www.uptodate.com/contents/im
- Patients with dynamic symptoms develop acute and recurrent episodes of irreversible muscle dysfunction related to exercise intolerance, prolonged fasting, exposure to cold, general anesthesia, intercurrent infection, or low-carbohydrate, high-fat diet. Some of these patients may develop myoglobinuria. In between episodes, the patients are free of symptoms.
- Static symptoms include proximal weakness (which is indistinguishable from limb-girdle muscular dystrophies), occasionally distal weakness, generalized muscle weakness, and respiratory difficulties related to involvement of respiratory muscles or fixed cardiomyopathy (as in acid maltase deficiency).
Other static features include progressive external ophthalmoplegia, peripheral neuropathies, seizures, developmental delay, failure to thrive, short stature, deafness, and ataxia. The symptoms themselves are not necessarily static since progression of varying degree usually occurs depending upon the severity and type of defect.
Both dynamic and static symptoms are common in mitochondrial myopathies related to either mitochondrial DNA defects or specific inborn errors of fatty acid oxidation [http://www.uptodate.com/contents/appro
The second step is targeted at determining the type of the underlying biochemical abnormality as suggested by the pattern of symptoms (http://www.uptodate.com/contents/im
- Patients who develop symptoms after prolonged, mild to moderate, low-intensity activity (such as walking) may have a defect in fatty acid oxidation (especially if the symptoms occur after one hour).
- Symptoms developing during or after high-intensity isometric exercise (such as pushing a stalled car or lifting weights) or high-intensity, sustained, submaximal exercise (such as sprinting) suggest a defect in glycogen and/or glucose metabolism; these symptoms tend to occur early in the course of the activity.
- Defects in glucose, glycogen, or fatty acid metabolism may be observed among patients with symptoms produced by low-intensity, submaximal exercise (eg, running slowly).
The Table provides a list of the various biochemical defects, categorized on the basis of the symptoms they produce (http://www.uptodate.com/contents/im
The general approach to the patient with and the differential diagnosis of muscle weakness is presented separately. (See http://www.uptodate.com/contents/approa
LABORATORY TESTING. The laboratory investigation of patients with suspected metabolic myopathies includes serum and urine testing, the forearm ischemic exercise test, electromyography, muscle biopsy, and, in some cases, nuclear magnetic resonance spectroscopy, if available (http://www.uptodate.com/contents/im
Other etiologies (eg, toxic, traumatic, alcohol- and drug-related, endocrine, viral and inflammatory) should be considered and appropriate testing should be performed to exclude them prior to investigating a metabolic etiology.
Serum and urine testing. Abnormal levels of specific compounds in the blood and/or urine, either alone or in combination, may help diagnose or suggest a specific metabolic abnormality. These include serum levels of lactate, pyruvate, lactic acid dehydrogenase, uric acid, free and total http://www.uptodate.com/contents/l-carn
- Urinary myoglobin excretion, which should be measured at rest and with exercise, can be induced by inborn errors of glycogen/glucose metabolism, fatty acid metabolism, and some mitochondrial DNA defects. The induction of myoglobinuria by pure exertion or by toxic factors, such as infection and fever, may suggest a particular disorder. As an example, a clinical presentation with features of a Reye-like syndrome or with myoglobinuria induced by toxic factors suggests a fatty acid oxidation defect [http://www.uptodate.com/contents/appro
ach-to-the-metabolic-myopathies/abstract/1 5 ].
Patients with acute myoglobinuria may have concurrent elevations of serum creatinine, potassium, phosphate, uric acid, and even amino acids (particularly taurine). The serum calcium is usually low, but hypercalcemia may develop after recovery from renal failure.
- The serum creatine kinase (CK) concentration should be tested at rest and during episodes of acute recurrent irreversible muscle dysfunction, with or without myoglobinuria. In patients with glycogen defects, the CK level may be elevated at rest, particularly in patients with static symptoms. By comparison, the CK level in patients with CPT II deficiency may be normal between acute episodes.
- Dicarboxylic acids (DCAs) are detected in the urine of all patients with intramitochondrial beta-oxidation defects. This change is not seen with defects involving the transport of long-chain fatty acids into the mitochondria and also in http://www.uptodate.com/contents/l-carn
itine-drug-information?source=see_link carnitine uptake defects.
- Serum levels of lactate and pyruvate may be elevated in patients with mitochondrial myopathies.
- Significant elevation of CK levels with a normal LDH concentration raises the possibility of lactate dehydrogenase deficiency.
- Modest hyperammonemia may be accompanied by elevated liver transaminases among patients with fatty acid oxidation defects who present with a Reye-like syndrome.
Lipid metabolism defects — In the patient with a suspected lipid metabolism defect, the determination of plasma total and free http://www.uptodate.com/contents/l-carn
The presence of a fatty acid metabolism disorder is supported by the following findings:
- The combination of hypoketosis and hypoglycemia.
- A serum free fatty acid to ketone ratio of more than 2:1 (normal ratio is 1:1) [http://www.uptodate.com/contents/appro
- Specific abnormalities in serum http://www.uptodate.com/contents/l-carn
itine-drug-information?source=see_link carnitine concentrations. The value of carnitine determination in suspected fatty acid metabolism defects is illustrated in the Table (http://www.uptodate.com/contents/im age?imageKey=RHEUM%2F26606&topicKey=PEDS%2 F6193&rank=1%7E37&source=see_link&search=m etabolic+myopathy table 2).
In carnitine uptake defects, the total serum carnitine is very low. In comparison, total serum carnitine concentrations are usually normal or low in fatty acid metabolism defects, except for CPT I deficiency, a disorder in which they may be normal or increased due to defective esterification of long-chain fatty acids to carnitine. In addition, the ratio of free carnitine to total carnitine is usually normal or low in most fatty acid metabolism defects, except for CPT I deficiency in which the ratio is high [http://www.uptodate.com/contents/appro
ach-to-the-metabolic-myopathies/abstract/2 5 ].
If serum acylcarnitines are elevated, the further separation and identification of the individual acylcarnitines could prove useful in the diagnosis of specific defects. (See http://www.uptodate.com/contents/ca
uses-of-metabolic-myopathies?source=see_ link "Causes of metabolic myopathies".)
- An amount of DCAs which is equal to or higher than the amount of ketones (if the urine specimen was obtained after a period of fasting). However, the absence of DCAs in the urine does not rule out a fatty acid metabolism defect. The type of excreted DCAs may also help in the identification of the specific metabolic defect [http://www.uptodate.com/contents/appro
ach-to-the-metabolic-myopathies/abstract/2 6 ].
- The finding of specific acylglycines in small quantities in the urine with some fatty acid metabolism defects. These include short-chain acyl-CoA dehydrogenase (SCAD), medium-chain acyl-CoA dehydrogenase (MCAD), electron transfer flavoprotein (ETF), and ETF-coenzyme Q oxidoreductase deficiencies [http://www.uptodate.com/contents/appro
Electromyography — In patients with fixed weakness, electromyography may be useful in excluding a neuropathic process and providing evidence for a myopathic condition. Myotonic discharges may be observed in patients with myophosphorylase, acid maltase, and debrancher enzyme deficiency. In patients with excessive fatiguability, repetitive nerve stimulation may be instrumental in excluding a defect in neuromuscular transmission [http://www.uptodate.com/contents/appro
Forearm exercise testing — Both anaerobic (ischemic) and aerobic forearm exercise testing may be helpful in evaluating patients suspected of having some type of metabolic myopathy
Ischemic exercise — The forearm ischemic exercise test should be performed if the clinical evaluation and laboratory findings suggest an enzymatic defect in the nonlysosomal glycogenolytic pathway and in glycolysis. This test may be useful in assessing all patients with exercise intolerance http://www.uptodate.com/contents/approa
The test begins with the placement and stabilization of a needle in a superficial antecubital vein of the arm to be exercised. Resting blood samples are obtained for serum lactate, pyruvate, CK, and ammonia. The blood pressure cuff is inflated to a pressure level above the diastolic pressure and the patient is asked to perform one per second hand grips with at least 75 percent of the maximum voluntary hand grip. The duration of the ischemic exercise test is one minute in the absence of cramping, but the cuff should be immediately deflated if an acute cramp develops.
Some recommend that the test be performed without the blood pressure cuff in place (ie, non-ischemic forearm exercise test) http://www.uptodate.com/contents/approa
If the patient tolerates the test and exercises adequately, a single blood sample of CK and sequential samples of lactate, pyruvate, and ammonia are obtained at intervals of 1, 2, 3, 5, and 10 minutes after one minute of intermittent handgrip exercise. In normal individuals after a good effort, a three- to fivefold rise in lactate is noted within the first one to three minutes. The rise in serum ammonia is similar, but somewhat slower and more robust (5- to 10-fold over baseline); ammonia reaches a peak at three to four minutes.
Various abnormalities in the forearm ischemic exercise test may be observed with different metabolic disorders (http://www.uptodate.com/contents/im
- The rise in lactate is less than twofold among patients with inborn errors of glycolysis/glycogenolysis; however, the increase in ammonia is normal in patients who have made sufficient effort during the test.
- Lactate production may be absent or diminished in phosphorylase, phosphofructokinase, debrancher, phosphoglycerate mutase, phosphoglycerate kinase, and LDH enzyme deficiencies. In the last condition, there is no rise in lactate levels, but pyruvate levels rise normally.
- The lactate curve is normal in acid maltase and in most cases of phosphorylase b kinase deficiencies [http://www.uptodate.com/contents/appro
ach-to-the-metabolic-myopathies/abstract/1 ], probably related to differential activation mechanisms for muscle phosphorylase [http://www.uptodate.com/contents/appro ach-to-the-metabolic-myopathies/abstract/3 2,33 ].
- In patients with mitochondrial myopathies, there may be excessive production of lactate at submaximal levels of effort, but this is not a universal finding. With the non-ischemic forearm exercise test, the production of lactate is not sufficiently specific or sensitive for the diagnosis of mitochondrial disorders [http://www.uptodate.com/contents/appro
ach-to-the-metabolic-myopathies/abstract/3 4 ].
- With myoadenylate deaminase deficiency, there is absence of ammonia production with normal responses of venous lactate and pyruvate.
- The level of CK may rise in both glycogenolytic/glycolytic and fatty acid oxidation defects. The forearm ischemic exercise test is normal in defects of fatty acid metabolism as far as the lactate and ammonia curves are concerned.
Aerobic exercise — There is less experience with aerobic forearm exercise testing, but it may be a valuable method for differentiating mitochondrial myopathies from muscular dystrophy [http://www.uptodate.com/contents/appro
The aerobic forearm exercise test begins with a determination of a patient's maximal voluntary hand grip or maximal voluntary contraction (MVC), using a dynamometer or a rolled sphygmomanometer cuff. Once an estimate of the MVC is made, the patient is allowed to rest for 30 minutes, meanwhile, a venous cannula is placed in the antecubital vein, and a baseline sample of blood is obtained and refrigerated for later blood gas analysis. After the baseline sample has been obtained, exercise is begun (40 percent of MVC for one second alternating with one second of rest) and continued for three minutes. Additional blood samples are obtained during exercise at one minute intervals for three minutes. The venous blood samples are then analyzed for their oxygen saturation.
Using the technique described above, 12 patients with various forms of mitochondrial myopathy had a mean decrease of only seven percent (range +15 to -32 percent) while 12 healthy subjects and 10 patients with muscular dystrophy had mean decreases in antecubital vein oxygen saturation during exercise of 43 percent and 38 percent, respectively [http://www.uptodate.com/contents/appro
Magnetic resonance spectroscopy — Nuclear magnetic resonance (NMR) spectroscopy is a noninvasive method for the study of muscle metabolism [http://www.uptodate.com/contents/appro
Unlike NMR spectroscopy, proton magnetic resonance spectroscopy (MRS) can be performed with available clinical MR equipment. Limited data suggest that the technique may be useful in the diagnosis and in monitoring of therapy in http://www.uptodate.com/contents/l-carn
Muscle biopsy — A muscle biopsy should be performed only after obtaining preliminary blood and urine tests, and, in some patients, electromyography and a forearm ischemic exercise test. Given the impracticality of testing muscle biopsy tissue for all known metabolic defects, the initial clinical and laboratory assessment helps target subsequent immunohistochemical and biochemical testing of muscle tissue.
Microscopic examination of the muscle sample should include electron microscopy, and immunohistochemical staining for phosphorylase, phosphofructokinase, and myoadenylate deaminase, if deficiencies in these enzymes are diagnostic possibilities. Microscopic examination will determine the presence or absence of glycogen or lipid storage, or the presence of ragged-red fibers in mitochondrial myopathies.
Since all of these evaluations will be normal in a number of metabolic defects, additional biochemical evaluation of muscle tissue should be pursued through commercial or research laboratories. In this setting, analysis will need to be focused upon specific possible biochemical defects, based upon the results of the preliminary noninvasive evaluation. In some instances, it may be possible to perform the direct enzymatic assay in cultured skin fibroblasts. This assay will be profitable diagnostically only if the enzymatic defect is expressed in this cell type.
Molecular techniques — Specific defects can be characterized at the molecular level either by Western blotting or by molecular analysis of specific mutations. Western blotting can be used to differentiate between a kinetic deficiency versus a defect in the production of the relevant enzyme. The identification of specific mutations can be used to precisely and rapidly detect specific defects and also to carry out presymptomatic, or prenatal diagnosis, and carrier detection.
Energy metabolism in muscle http://www.uptodate.com/contents/en
Basil T Darras, MD
Marc C Patterson, MD, FRACP
John F Dashe, MD, PhD
Last literature review version 19.2: May 2011
This topic last updated: July 24, 2009