INTRODUCTION — This topic review will provide an overview of the evaluation of the patient with a suspected metabolic myopathy. Detailed descriptions of the different disorders are presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism" and "Metabolic myopathies caused by disorders of lipid and purine metabolism" and "Mitochondrial myopathies: Clinical features and diagnosis".)
An overview of the biochemistry of energy metabolism in muscle is also discussed elsewhere. (See "Energy metabolism in muscle".)
OVERVIEW OF CLINICAL MANIFESTATIONS — The symptoms, signs, and laboratory abnormalities resulting from a metabolic myopathy vary with the underlying defect. Most patients with a metabolic myopathy (eg, glycogen storage diseases, carnitine palmitoyltransferase deficiency) have dynamic rather than static symptoms, and therefore usually complain of exercise intolerance or muscle pain and cramps with exercise. Nevertheless, other patients may develop progressive muscular weakness that is usually proximal (mimicking inflammatory myopathy or limb girdle muscular dystrophy) but may be distal. In a smaller group of patients, both dynamic and static symptoms predominate (table 1).
Disorders of glycogen metabolism — Inherited disorders that result in abnormal storage of glycogen are known as glycogen storage diseases. These disorders have largely been categorized by number according to the chronology of recognition of the responsible enzyme defect (table 2). The age of onset varies from birth to adulthood. (See "Overview of inherited disorders of glucose and glycogen metabolism".)
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. Intellectual disability, 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 [1,2]. Patients with defects of glycogen metabolism usually complain of easy fatigability upon exertion and, occasionally, of muscle stiffness induced by exercise. In some cases, brief rest when muscle symptoms develop can subsequently result in improved exercise tolerance, referred to as the spontaneous "second wind" . This occurs because of increased blood glucose levels related to mobilization of hepatic glucose  and/or a metabolic switch from glycogen to fatty acid and protein metabolism. "Second wind" also can be induced by the infusion of carbohydrate fuel (eg, glucose) or lipids .
Patients with certain glycolytic defects (eg, muscle phosphofructokinase deficiency), however, are unable to achieve a spontaneous second wind  or have worsening of symptoms after the administration of glucose (the "out of wind phenomenon")  due to inability of muscle to utilize glucose as energy source in the setting of decreased availability of free fatty acids and ketones . (See "Overview of inherited disorders of glucose and glycogen metabolism" and "Phosphofructokinase deficiency (glycogen storage disease VII, Tarui disease)".)
Disorders of lipid metabolism — The metabolic myopathies resulting from disorders of lipid metabolism include the following conditions (see "Metabolic myopathies caused by disorders of lipid and purine metabolism"):
●Carnitine deficiency syndromes
●Fatty acid transport defects
●Defects of beta-oxidation enzymes
●Neutral lipid storage disease
With disorders of lipid metabolism affecting muscle, symptoms are usually induced by infections, fever, prolonged or intense 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."
There are four main clinical and laboratory features that should lead the clinician to suspect a fatty acid oxidation disorder :
●Involvement of tissues dependent on fatty acid oxidation, 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 carnitine
Other conditions that can lead to metabolic decompensation among patients with fatty acid oxidation defects include cold-induced shivering thermogenesis and infection with vomiting:
●With cold exposure, shivering depends heavily upon long-chain fatty acid oxidation 
●After prolonged fasting or during infections, children can become comatose and present with symptoms similar to Reye syndrome
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 "Energy metabolism in muscle".)
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 [1,9].
Serum carnitine levels vary with the different defects of lipid metabolism. With carnitine transport defects, for example, total serum carnitine is significantly reduced (eg, <5 percent of normal) and the esterified fraction is normal . This finding is probably related to both reduced renal carnitine reabsorption, leading to carnitine leak, and defective intestinal carnitine absorption.
By comparison, in the majority of cases of intramitochondrial beta-oxidation defects, the amount of total serum carnitine is reduced to <50 percent of normal, and the esterified carnitine fraction is increased to >50 percent of normal (normal: 10 to 25 percent in the fed state and 30 to 50 percent during fasting) . This occurs because the accumulating longer-chain-length acylcarnitines are reabsorbed much more easily at the renal tubular reabsorptive site than free carnitine. As a result, the free carnitine fraction will be reduced . (See 'Lipid metabolism defects' below.)
Mitochondrial disorders — Exercise intolerance due to premature fatigue is a common manifestation of mitochondrial diseases . The exercise intolerance is usually more severe than muscle weakness. In contrast to those with glycogen metabolism defects, patients with isolated mitochondrial myopathy do not develop true muscle cramps or a "second wind." Resting venous lactic acidosis is common in such patients, who are sometimes misdiagnosed as having chronic fatigue syndrome or fibromyalgia . (See "Mitochondrial myopathies: Clinical features and diagnosis".)
Myoglobinuria and rhabdomyolysis — Patients with metabolic myopathies, such as those with inherited disorders of glycogenolysis, glycolysis, lipid metabolism, or purine metabolism (table 3), are at increased risk for developing myoglobinuria and rhabdomyolysis. The manifestations and complications of rhabdomyolysis result from muscle cell death, with the release of intracellular muscle constituents into the circulation.
The metabolic myopathies represent a small percentage of all cases of rhabdomyolysis but are relatively common causes among patients with recurrent episodes of rhabdomyolysis after exertion.
●In a series of 475 hospitalized adults with rhabdomyolysis, the most frequent etiology was an exogenous toxin (46 percent), a category that included alcohol, illicit drugs, and prescribed drugs (eg, antipsychotics, statins, zidovudine, colchicine, selective serotonin reuptake inhibitors, and lithium) . 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 . 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 . Among children with creatine kinase (CK) values ≥6000 int. units/L, a genetically determined metabolic myopathy or undiagnosed dermatomyositis was present in 6 of 37 (16 percent), while in children with CK levels of 1000 to 5999 int. units/L, the proportion was 10 of 154 (6 percent). The incidence of acute renal failure in children in this study (5 percent)  was much lower than that reported in the adult series (46 percent)  discussed above.
Although exercise intolerance, often dating back to childhood, is common in patients with mitochondrial defects, rhabdomyolysis with resultant myoglobinuria is rare . However, myoglobinuria has been reported in patients with mutations involving cytochrome b, cytochrome c oxidase, and the MELAS A3260G mutation [15-17]. (See "Mitochondrial myopathies: Clinical features and diagnosis".)
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 ; by comparison, a similar adult series of 77 patients found a biochemical abnormality in 47 percent .
●The most common metabolic cause of recurrent myoglobinuria in both adults and children is carnitine palmitoyltransferase 2 deficiency. (See "Specific fatty acid oxidation disorders", section on 'Carnitine palmitoyltransferase type 2 deficiency'.)
●In young children, lipin-1 deficiency, caused by mutations in the LPIN1 gene, usually presents with recurrent rhabdomyolysis and myoglobinuria, mostly in the setting of intercurrent infections with fever and less frequently with fasting or exercise. Episodes of rhabdomyolysis related to this disorder may be lethal in up to one-third of patients. (See "Metabolic myopathies caused by disorders of lipid and purine metabolism", section on 'Lipin-1 deficiency'.)
●Ryanodine receptor gene (RYR1) mutations are the cause of several types of neuromuscular disease, including various congenital myopathies (see "Congenital myopathies"), rhabdomyolysis with myoglobinuria induced by heat and exercise, and susceptibility to malignant hyperthermia triggered by certain anesthetic agents such as inhalation anesthetics (except nitrous oxide) and succinylcholine [20,21].
●Myoglobinuria may occur in patients with dystrophinopathies or caveolinopathies (eg, limb-girdle muscular dystrophy type 1C)  and Becker muscular dystrophy . (See "Limb-girdle muscular dystrophy" and "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis".)
The clinical features of rhabdomyolysis include myalgias, weakness, and elevated serum muscle enzymes (including CK). Acute muscle breakdown of sufficient severity can lead to myoglobinemia and myoglobinuria. The urine acquires a brownish, cola-like color, and the supernatant is positive for heme in the absence of red blood cells in the sediment. The degree of myalgias and other symptoms varies widely, and some patients are asymptomatic. Fever, malaise, tachycardia, and gastrointestinal symptoms may be present. (See "Rhabdomyolysis: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)
Other manifestations include fluid and electrolyte abnormalities, many of which precede or occur in the absence of acute kidney injury and hepatic injury. Hypovolemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, and metabolic acidosis can develop. Significant hyperkalemia may result in life-threatening cardiac dysrhythmias. Later complications include acute kidney injury, hypercalcemia, compartment syndrome, and, rarely, disseminated intravascular coagulation.
The diagnostic approach to myoglobinuria and rhabdomyolysis is discussed in detail separately (see "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Urinalysis in the diagnosis of kidney disease", section on 'Red to brown urine'). Briefly, the laboratory findings that characterize rhabdomyolysis include an acute elevation in the serum CK level (typically at least five times the upper limit of normal at presentation) and other muscle enzymes, followed by a decline in these values three to five days after cessation of muscle injury. The other characteristic finding is the reddish-brown urine of myoglobinuria, but this finding is often absent because of the relative rapidity with which myoglobin is cleared.
EVALUATION AND DIAGNOSIS — The diagnosis of a possible metabolic myopathy should be considered in patients with dynamic symptoms (eg, exercise intolerance, acute reversible weakness, rhabdomyolysis) or static symptoms (eg, fixed weakness, cardiomyopathy, neuropathy) .
Other, more common etiologies of myopathy (eg, toxic, traumatic, alcohol- and drug-related, endocrine, viral, and inflammatory) should be excluded by appropriate testing prior to investigating a metabolic etiology.
The evaluation needed to confirm the diagnosis of a metabolic myopathy (algorithm 1) is guided by a constellation of findings, including the clinical presentation, the type of muscle involvement, specific laboratory abnormalities (particularly elevations in serum creatine kinase and myoglobinuria), patient age, family history, the results of histologic and pathologic examinations, and, increasingly, genetic testing .
The conventional approach to the diagnosis (algorithm 1) of patients with suspected metabolic myopathies includes serum and urine metabolic testing, the forearm semi-ischemic exercise test, electromyography, muscle biopsy, and, in some cases, nuclear magnetic resonance spectroscopy, if available (table 4). The diagnosis is then confirmed by targeted molecular genetic analysis .
Increasingly, a direct genetic approach to the diagnosis (algorithm 1) using next generation sequencing (eg, targeted gene panel, whole exome, or whole genome analysis) can provide the genetic diagnosis and avoid the need for invasive procedures such as electromyography and muscle biopsy. The diagnostic yield is probably higher than the yield of conventional approaches .
●Patients with dynamic symptoms develop acute and recurrent episodes of reversible 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 .
The second step is targeted at determining the type of the underlying biochemical abnormality as suggested by the pattern of symptoms (algorithm 1). As examples:
●Patients who develop symptoms during fasting or after prolonged low-intensity activity such as walking may have a defect in fatty acid oxidation (especially if the symptoms occur after 30 to 60 minutes).
●Symptoms developing during or after high-intensity isometric exercise (such as pushing a stalled car or lifting weights) or high-intensity, dynamic exercise (such as sprinting) suggest a defect in glycogen and/or glucose metabolism; these symptoms tend to occur early, typically within 10 to 20 minutes of activity onset .
●Defects in glucose, glycogen, or fatty acid metabolism may be observed among patients with symptoms produced by low-intensity, submaximal exercise (eg, running slowly).
Various biochemical defects can be categorized on the basis of the symptoms they produce (table 1).
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 carnitine, ketones, glucose, ammonia, myoglobin, liver transaminases, potassium, calcium, phosphate, creatinine, and acylcarnitine, and urinary levels of ketones, myoglobin, dicarboxylic acids, and acylglycines.
●Urinary myoglobin excretion can be induced by inborn errors of glycogen/glucose metabolism, fatty acid metabolism, and some mitochondrial genetic 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 . Myoglobin is released from damaged muscle in parallel with creatine kinase (CK). Myoglobin is a monomer that is not significantly protein-bound and is therefore rapidly excreted in the urine, often resulting in the production of red to brown urine. It appears in the urine when the plasma concentration exceeds 1.5 mg/dL. Visible changes in the urine only occur once urine levels exceed approximately 100 to 300 mg/dL, although it can be detected by the urine (orthotolidine) dipstick at concentrations of only 0.5 to 1 mg/dL. Myoglobin has a half-life of only two to three hours, much shorter than that of CK. Because of its rapid excretion and metabolism to bilirubin, serum levels may return to normal within six to eight hours. (See "Rhabdomyolysis: Clinical manifestations and diagnosis", section on 'Urine findings and myoglobinuria'.)
●Patients with acute myoglobinuria may have concurrent elevations of serum creatinine, potassium, phosphate, uric acid, liver enzymes, and even amino acids (particularly taurine). The serum calcium is usually low, but hypercalcemia may develop after recovery from renal failure.
●The serum CK concentration should be tested at rest and during episodes of acute recurrent muscle dysfunction, whether or not the episodes are accompanied by 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 carnitine palmitoyltransferase 2 (CPT2) deficiency may be normal between acute episodes.
●During an episode of rhabdomyolysis, serum CK increases within 2 to 12 hours after the onset of muscle injury, reaches a peak level at 24 to 72 hours and then decreases gradually to baseline levels within three to five days. Compared with myoglobin, CK has a longer half-life of approximately 1.5 days and thus it usually does not escape detection . (See "Rhabdomyolysis: Clinical manifestations and diagnosis", section on 'Creatine kinase elevation'.)
●Dicarboxylic acids are detected in the urine of all patients with intramitochondrial beta-oxidation defects and respiratory chain enzyme defects (due to secondary inhibition of fatty acid oxidation) . This change is not seen with defects involving the transport of long-chain fatty acids into the mitochondria or in carnitine uptake defects. Dicarboxylic aciduria can also result from a diet rich in medium-chain triglycerides, as used for premature infants and for patients with cholestatic hepatopathy.
●Serum and/or urine levels of lactate and pyruvate may be elevated in patients with mitochondrial myopathies. The lactate/pyruvate ratio (normally <20) in blood reflects the intracellular NADH/NAD ratio and, in theory, should be elevated in patients with aerobic energy metabolism defects (eg, respiratory chain complex defects) . In practice, however, the calculation of this ratio in blood is usually not helpful when single organs are affected. In addition, the measurement of pyruvate levels in clinical laboratories is not reliable. Determination of the lactate/pyruvate ratio in skin fibroblast tissue culture is more accurate.
●The ketone body ratio (beta-hydroxybutyrate/acetoacetate) measured in blood reflects the intramitochondrial NADH/NAD ratio and hence may be increased with defects involving the respiratory chain . The finding of elevated blood serum alanine reduces the possibility that concomitant lactate elevation is artifactual. Other biochemical indicators of mitochondrial dysfunction include increased excretion of ethylmalonic acid and 3-methylglutaconic acid and/or elevated excretion of citric acid cycle intermediates such as aconitate and succinate.
Lipid metabolism defects — In the patient with a suspected lipid metabolism defect, the determination of plasma total and free carnitine, serum acylcarnitines, urine acylglycines, and organic acids preferably should be performed during episodes of acute catabolic crises or periods of fasting. This is important because normal values may be observed when the patient is metabolically stable and not fasting. A fasting study is not recommended given the possibility of precipitating an acute catabolic crisis leading to death. (See "Metabolic myopathies caused by disorders of lipid and purine metabolism".)
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 (in mmol/L) to ketone (beta-hydroxybutyrate, in mmol/L) ratio of more than 2:1 (the normal ratio is 1:1). Beta-hydroxybutyrate constitutes approximately 80 percent of serum ketones and is sufficient for calculating this ratio .
●Specific abnormalities in serum carnitine concentrations (table 5). 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 carnitine palmitoyltransferase 1A (CPT1A) 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 CPT1A deficiency in which the ratio is high . If serum acylcarnitines are elevated, the further separation and identification of the individual acylcarnitine profile could prove useful in the diagnosis of specific defects. Acylcarnitines can be measured from dried blood spots using tandem mass spectroscopy, ideally after an overnight fast. (See "Metabolic myopathies caused by disorders of lipid and purine metabolism".)
●An amount of dicarboxylic acids (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 .
●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 .
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 fatigability, repetitive nerve stimulation may be instrumental in excluding a defect in neuromuscular transmission . (See "Neuromuscular junction disorders in newborns and infants" and "Electrodiagnostic evaluation of the neuromuscular junction", section on 'Repetitive nerve stimulation'.)
Semi-ischemic exercise test — The forearm semi-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 . However, children younger than five years of age may not be cooperative with the testing protocol.
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 level just 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 this semi-ischemic exercise test is one minute in the absence of cramping, but the cuff should be immediately deflated if an acute cramp develops.
Some experts use a variation of the test without the blood pressure cuff in place (ie, nonischemic forearm exercise test) [34,35]. However, this method may be less specific and sensitive and is not recommended . Most inflate the cuff to a value intermediate between the systolic and diastolic blood pressures to permit systolic blood flow (semi-ischemic exercise test). In certain patients, inflation of the blood pressure cuff above the systolic pressure and, rarely, even above the diastolic pressure carries some risk of focal rhabdomyolysis, myoglobinuria, and acute compartment syndrome . Therefore, this test should be conducted with caution, and never under total ischemic conditions. It should be aborted immediately if the patient develops any symptoms.
After 1 minute of intermittent handgrip exercise, a single blood sample of CK is obtained, and sequential samples of lactate, pyruvate, and ammonia are obtained at 1, 2, 3, 5, and 10 minutes. In normal individuals after a good effort, a 3- to 5-fold rise in lactate is noted within the first 1 to 3 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 3 to 4 minutes.
●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 lactate dehydrogenase enzyme deficiencies. In the last condition, there is no rise in lactate levels, but pyruvate levels rise normally.
●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 nonischemic forearm exercise test, the production of lactate is not sufficiently specific or sensitive for the diagnosis of mitochondrial disorders .
●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 semi-ischemic exercise test is normal in defects of fatty acid metabolism as far as the lactate and ammonia curves are concerned.
Muscle biopsy — A muscle biopsy should be performed only after obtaining preliminary blood and urine tests, and, in some patients, electromyography, a forearm semi-ischemic exercise test, and/or molecular genetic testing. 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 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 on 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. In the author's clinical experience, extensive investigations including a muscle biopsy for microscopic and biochemical evaluation are frequently unrevealing, with diagnostic yield of less than 15 percent. Because of the relatively low yield, a muscle biopsy is often not obtained and may become obsolete with advances in molecular diagnostics.
Molecular genetic 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, as well as presymptomatic or prenatal diagnosis and carrier detection. Targeted genetic analysis can confirm an enzymatic deficiency detected by biochemical assay in muscle tissue, lymphocytes, or fibroblasts .
It is advisable to order genetic testing before performing a muscle biopsy if a specific defect is suspected (eg, myophosphorylase or CPT2 deficiency) or if large-scale molecular diagnostic testing (ie, next generation sequencing [NGS]) is available at low cost. Metabolic myopathy gene panels are increasingly used alone or in conjunction with whole exome sequencing techniques .
NGS is appropriate for diagnosing suspected genetic disorders when sequencing of a single gene has failed to or is unlikely to provide a diagnosis. Examples include the following settings (see "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Indications for NGS'):
●One of several potential genes may be responsible
●Obvious candidate genes have been tested and found to be normal
●The cost of NGS would be less than that of sequencing individual candidate genes sequentially
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mitochondrial disorders".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Rhabdomyolysis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●The symptoms, signs, and laboratory abnormalities resulting from a metabolic myopathy vary with the underlying defect. Most patients with a metabolic myopathy have dynamic rather than static symptoms, and therefore usually complain of exercise intolerance or muscle pain and cramps. Nevertheless, other patients may develop progressive muscular weakness that is usually proximal (mimicking inflammatory myopathy or limb girdle muscular dystrophy), but is sometimes distal. In a smaller group of patients, both dynamic and static symptoms predominate (table 1). (See 'Overview of clinical manifestations' above.)
●Inherited disorders that result in abnormal storage of glycogen are known as glycogen storage diseases (table 2). The age of onset varies from birth to adulthood. The principal symptoms and signs, however, are those related to exercise intolerance and recurrent myoglobinuria. (See 'Disorders of glycogen metabolism' above.)
●The metabolic myopathies resulting from disorders of lipid metabolism include defects of beta-oxidation enzymes, carnitine deficiency syndromes, and fatty acid transport 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. Symptoms are usually induced by prolonged exercise and prolonged fasting. (See 'Disorders of lipid metabolism' above.)
●Exercise intolerance due to premature fatigue is a common manifestation of mitochondrial diseases, and the exercise intolerance is usually more severe than muscle weakness. In contrast to those with glycogen metabolism defects, patients with isolated mitochondrial myopathy do not develop true muscle cramps or a "second wind." Resting venous lactic acidosis is common in such patients. (See 'Mitochondrial disorders' above.)
●Patients with metabolic myopathies, such as those with inherited disorders of glycogenolysis, glycolysis, lipid metabolism, or purine metabolism (table 3), are at increased risk for developing myoglobinuria and rhabdomyolysis. The metabolic myopathies represent a small percentage of all cases of rhabdomyolysis but are relatively common causes among patients with recurrent episodes of rhabdomyolysis after exertion. The most common metabolic cause of recurrent myoglobinuria in both adults and children is carnitine palmitoyltransferase 2 deficiency. (See 'Myoglobinuria and rhabdomyolysis' above and "Specific fatty acid oxidation disorders", section on 'Carnitine palmitoyltransferase type 2 deficiency'.)
●The diagnosis of a possible metabolic myopathy should be considered in patients with dynamic symptoms (eg, exercise intolerance, acute reversible weakness, myoglobinuria) or static symptoms (eg, fixed weakness, cardiomyopathy, neuropathy). Other, more common etiologies of myopathy (eg, toxic, traumatic, alcohol- and drug-related, endocrine, viral, and inflammatory) should be excluded by appropriate testing prior to investigating a metabolic etiology. The evaluation needed to confirm the diagnosis of a metabolic myopathy (algorithm 1) is guided by a constellation of findings including the clinical presentation, the type of muscle involvement, specific laboratory abnormalities (particularly elevations in serum creatine kinase and myoglobinuria), patient age, family history, the results of histologic and pathologic examinations, and, increasingly, genetic testing. (See 'Evaluation and diagnosis' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟