Approach to the metabolic myopathies.pdf

Official reprint from UpToDatewww.uptodate.com 2016 UpToDate

AuthorBasil T Darras, MD

Section EditorMarc C Patterson, MD, FRACP

Deputy EditorJohn F Dashe, MD, PhD

Approach to the metabolic myopathies

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Dec 2015. | This topic last updated: May 21, 2015.INTRODUCTION This topic review will provide an overview of the evaluation of the patient with a suspectedmetabolic myopathy. Detailed descriptions of the different disorders are presented separately. (See "Overview ofinherited disorders of glucose and glycogen metabolism" and "Metabolic myopathies caused by disorders of lipid andpurine metabolism" and "Mitochondrial myopathies: Clinical features and diagnosis".)An overview of the biochemistry of energy metabolism in muscle is also discussed elsewhere. (See "Energymetabolism in muscle".)OVERVIEW OF CLINICAL MANIFESTATIONS The symptoms, signs, and laboratory abnormalities resulting from ametabolic myopathy vary with the underlying defect. Most patients with a metabolic myopathy (eg, glycogen storagediseases, carnitine palmitoyltransferase deficiency) have dynamic rather than static symptoms, and therefore usuallycomplain of exercise intolerance or muscle pain and cramps with exercise. Nevertheless, other patients may developprogressive muscular weakness that is usually proximal (mimicking inflammatory myopathy or limb girdle musculardystrophy), but is sometimes 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 asglycogen storage diseases. These disorders have largely been categorized by number according to the chronology ofrecognition of the responsible enzyme defect (table 2). The age of onset varies from birth to adulthood. (See "Overviewof 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, orrunning. 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, cardiacinvolvement, hemolytic anemia with jaundice, splenomegaly, and myoglobinuria. Mental retardation, upper and lowermotor 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 subsequentlyresult in improved exercise tolerance, referred to as the spontaneous "second wind" [3]. This occurs because ofincreased blood glucose levels related to mobilization of hepatic glucose [3]. "Second wind" also can be induced by theinfusion of carbohydrate fuel (eg, glucose) or lipids [4].Patients with certain glycolytic defects (eg, muscle phosphofructokinase deficiency), however, are unable to achieve aspontaneous second wind [5] or have worsening of symptoms after the administration of glucose (the "out of wind"phenomenon") [6] due to decreased availability of free fatty acids and ketones [3]. (See "Overview of inheriteddisorders 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 thefollowing conditions (see "Metabolic myopathies caused by disorders of lipid and purine metabolism"):

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With disorders of lipid metabolism affecting muscle, symptoms are usually induced by infections, fever, prolonged orintense exercise, and prolonged fasting. These patients, in contrast to those with glycogen metabolism defects, do notdevelop 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 oxidationdisorder [7]:

Other conditions that can lead to metabolic decompensation among patients with fatty acid oxidation defects includecold-induced shivering thermogenesis and infection with vomiting:

Skeletal muscle, heart, and liver are highly dependent upon efficient fatty acid utilization. Fatty acids are a major sourceof energy for the heart and liver, particularly during fasting when glycogen and glucose stores have been depleted. Inaddition, resting muscle and exercising muscle during mild to moderate prolonged exercise derive most of the requiredenergy 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 theexisting metabolic block; as a result, they are stored in the cytoplasm as triglycerides, thereby resulting in progressivelipid storage myopathy with weakness, hypertrophic and/or dilated cardiomyopathy, and fatty liver. In addition, withfasting, glucose and glycogen stores are depleted and ketone bodies are not generated because of the existingmetabolic block. As a result, the ratio of serum free fatty acids to ketones increases from the normal ratio of 1:1 tomore than 2:1, which is highly suggestive of a block in beta-oxidation [1].Serum carnitine levels vary with the different defects of lipid metabolism. With carnitine transport defects, for example,total serum carnitine is significantly reduced (eg,

fatigue syndrome or fibromyalgia [3]. (See "Mitochondrial myopathies: Clinical features and diagnosis".)Myoglobinuria and rhabdomyolysis Patients with metabolic myopathies, such as those with inherited disorders ofglycogenolysis, glycolysis, lipid metabolism, or purine metabolism (table 3), are at increased risk for developingmyoglobinuria and rhabdomyolysis. The manifestations and complications of rhabdomyolysis result from muscle celldeath, 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 commoncauses among patients with recurrent episodes of rhabdomyolysis after exertion.

Although exercise intolerance, often dating back to childhood, is common in patients with mitochondrial defects,rhabdomyolysis with resultant myoglobinuria is rare [13]. However, myoglobinuria has been reported in patients withmutations involving cytochrome b, cytochrome c oxidase, and the MELAS A3260G mutation [14-16]. (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 ofchildren with recurrent myoglobinuria, an enzyme abnormality could be detected in only 24 percent of the cases [17]; bycomparison, a similar adult series of 77 patients found a biochemical abnormality in 47 percent [18].

The clinical features of rhabdomyolysis include myalgias, weakness, and elevated serum muscle enzymes (including

In a series of 475 hospitalized adults with rhabdomyolysis, the most frequent etiology was an exogenous toxin (46percent), a category that included alcohol, illicit drugs, and prescribed drugs (eg, antipsychotics, statins,zidovudine, colchicine, selective serotonin reuptake inhibitors, and lithium) [11]. Less common causes includedtrauma, seizures, immobility, critical illness myopathy, exercise, heat/dehydration, and hypothermia. Multiplefactors could be identified in 60 percent of cases. An underlying myopathy or metabolic muscle defect wasdiagnosed in only 10 percent of the patients [11]. In this group, recurrences were common, the incidence of acuterenal failure was low, and typically only one etiologic factor could be identified. Myoglobinuria was detected bydipstick/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 mostcommon causes of rhabdomyolysis were viral myositis, trauma, and connective tissue diseases, found in 38, 26,and 5 percent, respectively [12]. Among children with creatine kinase (CK) values 6000 int. units/L, a geneticallydetermined metabolic myopathy or undiagnosed dermatomyositis was present in 6 of 37 (16 percent), while inchildren with CK levels of 1000 to 5999 int. units/L, the proportion was 10 of 154 (6 percent). The incidence ofacute renal failure in children in this study (5 percent) [12] was much lower than that reported in the adult series(46 percent) [11] discussed above.

The most common metabolic cause of recurrent myoglobinuria in both adults and children is carnitinepalmitoyltransferase 2 deficiency. (See "Metabolic myopathies caused by disorders of lipid and purinemetabolism", section on 'Carnitine palmitoyltransferase 2 deficiency'.)

In young children, lipin-1 deficiency, caused by mutations in the LPIN1 gene, usually presents with recurrentrhabdomyolysis and myoglobinuria, mostly in the setting of intercurrent infections with fever and less frequentlywith fasting or exercise. Episodes of rhabdomyolysis related to this disorder may be lethal in up to one-third ofpatients. (See "Metabolic myopathies caused by disorders of lipid and purine metabolism", section on 'Lipin-1deficiency'.)

Ryanodine receptor gene (RYR1) mutations are the cause of several types of neuromuscular disease, includingvarious congenital myopathies (see "Congenital myopathies"), rhabdomyolysis with myoglobinuria induced by heatand exercise, and susceptibility to malignant hyperthermia triggered by certain anesthetic agents such asinhalation anesthetics (except nitrous oxide) and succinylcholine [19,20].

Myoglobinuria may occur in patients with dystrophinopathies or caveolinopathies (eg, limb-girdle musculardystrophy type 1C) [21] and Becker muscular dystrophy [22]. (See "Limb-girdle muscular dystrophy" and "Clinicalfeatures and diagnosis of Duchenne and Becker muscular dystrophy".)


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CK). Acute muscle breakdown of sufficient severity can lead to myoglobinemia and myoglobinuria. The urine acquires abrownish, cola-like color, and the supernatant is positive for heme in the absence of red blood cells in the sediment. Thedegree of myalgias and other symptoms varies widely, and some patients are asymptomatic. Fever, malaise,tachycardia, and gastrointestinal symptoms may be present. (See "Clinical manifestations and diagnosis ofrhabdomyolysis", section on 'Clinical manifestations'.)Other manifestations include fluid and electrolyte abnormalities, many of which precede or occur in the absence ofacute kidney injury and hepatic injury. Hypovolemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia,and metabolic acidosis can develop. Hyperkalemia may result in cardiac dysrhythmias. Later complications includeacute kidney injury, hypercalcemia, compartment syndrome, and, rarely, disseminated intravascular coagulation.The diagnostic approach to myoglobinuria and rhabdomyolysis is discussed in detail separately (see "Urinalysis in thediagnosis of kidney disease", section on 'Red to brown urine' and "Clinical manifestations and diagnosis ofrhabdomyolysis"). Briefly, the laboratory findings that characterize rhabdomyolysis include an acute elevation in theserum 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 findingis the reddish-brown urine of myoglobinuria, but this finding is often absent because of the relative rapidity with whichmyoglobin is cleared.

EVALUATION AND DIAGNOSIS The diagnosis of a possible metabolic myopathy should be considered in patientswith 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, andinflammatory) 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 offindings, including the clinical presentation, the type of muscle involvement, specific laboratory abnormalities (particularlyelevations in serum creatine kinase and myoglobinuria), patient age, family history, the results of histologic andpathologic examinations, and, increasingly, genetic testing.

The conventional approach to the diagnosis (algorithm 1) of patients with suspected metabolic myopathies includesserum and urine testing, the forearm semi-ischemic exercise test, electromyography, muscle biopsy, and, in somecases, nuclear magnetic resonance spectroscopy, if available (table 4). The diagnosis is then confirmed by targetedmolecular genetic analysis.

Increasingly, a direct genetic approach to the diagnosis (algorithm 1) using next generation sequencing (eg, targetedgene panel, whole exome, or whole genome analysis) can provide the genetic diagnosis and avoid the need for invasiveprocedures such as electromyography and muscle biopsy.

Symptom assessment When confronted with a patient with a possible metabolic myopathy, the first step is todetermine whether the symptoms are dynamic, static, or both (table 1) [23]:

Both dynamic and static symptoms are common in mitochondrial myopathies related to either mitochondrial DNA

Patients with dynamic symptoms develop acute and recurrent episodes of reversible muscle dysfunction related toexercise intolerance, prolonged fasting, exposure to cold, general anesthesia, intercurrent infection, orlow-carbohydrate, high-fat diet. Some of these patients may develop myoglobinuria. In between episodes, thepatients 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 ofrespiratory muscles or fixed cardiomyopathy (as in acid maltase deficiency). Other static features includeprogressive external ophthalmoplegia, peripheral neuropathies, seizures, developmental delay, failure to thrive,short stature, deafness, and ataxia. The symptoms themselves are not necessarily static since progression ofvarying degree usually occurs depending upon the severity and type of defect.


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defects or specific inborn errors of fatty acid oxidation [1].The second step is targeted at determining the type of the underlying biochemical abnormality as suggested by thepattern of symptoms (algorithm 1). As examples:

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 incombination, 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, livertransaminases, potassium, calcium, phosphate, creatinine, and acylcarnitine, and urinary levels of ketones, myoglobin,dicarboxylic acids, and acylglycines.

Patients who develop symptoms during fasting or after prolonged low-intensity activity such as walking may havea 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 liftingweights) or high-intensity, dynamic exercise (such as sprinting) suggest a defect in glycogen and/or glucosemetabolism; these symptoms tend to occur early, typically within 10 to 20 minutes of activity onset [3].

Defects in glucose, glycogen, or fatty acid metabolism may be observed among patients with symptoms producedby low-intensity, submaximal exercise (eg, running slowly).

Urinary myoglobin excretion can be induced by inborn errors of glycogen/glucose metabolism, fatty acidmetabolism, and some mitochondrial genetic defects. The induction of myoglobinuria by pure exertion or by toxicfactors, such as infection and fever, may suggest a particular disorder. As an example, a clinical presentation withfeatures of a Reye-like syndrome or with myoglobinuria induced by toxic factors suggests a fatty acid oxidationdefect [17]. Myoglobin is released from damaged muscle in parallel with creatine kinase (CK). Myoglobin is amonomer that is not significantly protein-bound and is therefore rapidly excreted in the urine, often resulting in theproduction 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 about 100 to 300 mg/dL, although it can bedetected by the urine (orthotolidine) dipstick at concentrations of only 0.5 to 1 mg/dL. Myoglobin has a half-life ofonly 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 "Clinical manifestations and diagnosis ofrhabdomyolysis", section on 'Urine findings and myoglobinuria'.)

Patients with acute myoglobinuria may have concurrent elevations of serum creatinine, potassium, phosphate, uricacid, liver enzymes, and even amino acids (particularly taurine). The serum calcium is usually low, buthypercalcemia 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 levelmay be elevated at rest, particularly in patients with static symptoms. By comparison, the CK level in patients withcarnitine palmitoyltransferase 2 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 escapedetection [24]. (See "Clinical manifestations and diagnosis of rhabdomyolysis", section on 'Creatine kinase'.)

Dicarboxylic acids are detected in the urine of all patients with intramitochondrial beta-oxidation defects andrespiratory chain enzyme defects (due to secondary inhibition of fatty acid oxidation) [25]. This change is not seenwith 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 infantsand for patients with cholestatic hepatopathy.


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Lipid metabolism defects In the patient with a suspected lipid metabolism defect, the determination of plasmatotal and free carnitine, serum acylcarnitines, urine acylglycines, and organic acids preferably should be performedduring episodes of acute catabolic crises or periods of fasting. This is important because normal values may beobserved when the patient is metabolically stable and not fasting. A fasting study is not recommended given thepossibility of precipitating an acute catabolic crisis leading to death. (See "Metabolic myopathies caused by disordersof lipid and purine metabolism".)The presence of a fatty acid metabolism disorder is supported by the following findings:

Electromyography In patients with fixed weakness, electromyography may be useful in excluding a neuropathicprocess and providing evidence for a myopathic condition. Myotonic discharges may be observed in patients withmyophosphorylase, acid maltase, and debrancher enzyme deficiency. In patients with excessive fatigability, repetitivenerve stimulation may be instrumental in excluding a defect in neuromuscular transmission [23]. (See "Neuromuscularjunction disorders in newborns and infants" and "Electrodiagnostic evaluation of the neuromuscular junction", section on'Repetitive nerve stimulation (RNS)'.)

Serum and/or urine levels of lactate and pyruvate may be elevated in patients with mitochondrial myopathies. Thelactate/pyruvate ratio (normally

Semi-ischemic exercise test The forearm semi-ischemic exercise test should be performed if the clinical evaluationand laboratory findings suggest an enzymatic defect in the nonlysosomal glycogenolytic pathway and in glycolysis. Thistest may be useful in assessing all patients with exercise intolerance [28]. However, children younger than five years ofage 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 beexercised. Resting blood samples are obtained for serum lactate, pyruvate, CK, and ammonia. The blood pressure cuffis inflated to a level just above the diastolic pressure and the patient is asked to perform one per second hand gripswith at least 75 percent of the maximum voluntary hand grip. The duration of this semi-ischemic exercise test is oneminute 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)[29,30]. However, this method may be less specific and sensitive and is not recommended [31]. Most inflate the cuff toa value intermediate between the systolic and diastolic blood pressures to permit systolic blood flow (semi-ischemicexercise test). In certain patients, inflation of the blood pressure cuff above the systolic pressure and, rarely, evenabove the diastolic pressure carries some risk of focal rhabdomyolysis, myoglobinuria, and acute compartmentsyndrome [32]. Therefore, this test should be conducted with caution, and never under total ischemic conditions. Itshould 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 oflactate, pyruvate, and ammonia are obtained at 1, 2, 3, 5, and 10 minutes. In normal individuals after a good effort, a3- to 5-fold rise in lactate is noted within the first 1 to 3 minutes. The rise in serum ammonia is similar, but somewhatslower and more robust (5- to 10-fold over baseline); ammonia reaches a peak at 3 to 4 minutes.Various abnormalities in the forearm semi-ischemic exercise test may be observed with different metabolic disorders(table 6) [33]:

Muscle biopsy A muscle biopsy should be performed only after obtaining preliminary blood and urine tests, and, insome patients, electromyography, a forearm semi-ischemic exercise test, and/or molecular genetic testing. Given theimpracticality of testing muscle biopsy tissue for all known metabolic defects, the initial clinical and laboratoryassessment helps target subsequent immunohistochemical and biochemical testing of muscle tissue.

Microscopic examination of the muscle sample should include electron microscopy and immunohistochemical stainingfor phosphorylase, phosphofructokinase, and myoadenylate deaminase, if deficiencies in these enzymes are diagnosticpossibilities. Microscopic examination will determine the presence or absence of glycogen or lipid storage, or

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 lastcondition, 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 [1],probably related to differential activation mechanisms for muscle phosphorylase [34,35].

In patients with mitochondrial myopathies, there may be excessive production of lactate at submaximal levels ofeffort, but this is not a universal finding. With the nonischemic forearm exercise test, the production of lactate isnot sufficiently specific or sensitive for the diagnosis of mitochondrial disorders [31].

With myoadenylate deaminase deficiency, there is absence of ammonia production with normal responses ofvenous lactate and pyruvate.

The level of CK may rise in both glycogenolytic/glycolytic and fatty acid oxidation defects. The forearmsemi-ischemic exercise test is normal in defects of fatty acid metabolism as far as the lactate and ammoniacurves are concerned.


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ragged-red fibers in mitochondrial myopathies.

Since all of these evaluations will be normal in a number of metabolic defects, additional biochemical evaluation ofmuscle tissue should be pursued through commercial or research laboratories. In this setting, analysis will need to befocused on specific possible biochemical defects, based upon the results of the preliminary noninvasive evaluation. Insome instances, it may be possible to perform the direct enzymatic assay in cultured skin fibroblasts. This assay will beprofitable 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 frequentlyunrevealing, with diagnostic yield of less than 15 percent. Because of the relatively low yield, a muscle biopsy is oftennot obtained and may become obsolete with advances in molecular diagnostics.

Molecular genetic techniques Specific defects can be characterized at the molecular level either by Westernblotting or by molecular analysis of specific mutations. Western blotting can be used to differentiate between a kineticdeficiency versus a defect in the production of the relevant enzyme. The identification of specific mutations can be usedto 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 [36]. It is advisable to order genetic testing before performing a muscle biopsy if a specificdefect is suspected (eg, myophosphorylase or CPT 2 deficiency) or if large-scale molecular diagnostic testing (ie, nextgeneration sequencing [NGS]) is available at low cost.NGS is appropriate for diagnosing suspected genetic disorders when sequencing of a single gene has failed to or isunlikely to provide a diagnosis. Examples include the following settings (see "Principles and clinical applications ofnext-generation DNA sequencing", section on 'Indications for next-generation sequencing'):

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 5 to 6 grade readinglevel, and they answer the four or five key questions a patient might have about a given condition. These articles arebest for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patienteducation pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 to 12 gradereading 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 topicsto 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.)

SUMMARY AND RECOMMENDATIONS

One of several potential genes may be responsibleObvious candidate genes have been tested and found to be normalThe cost of NGS would be less than that of sequencing individual candidate genes sequentially

th th

th th

Basics topic (see "Patient information: Rhabdomyolysis (The Basics)")

The symptoms, signs, and laboratory abnormalities resulting from a metabolic myopathy vary with the underlyingdefect. Most patients with a metabolic myopathy have dynamic rather than static symptoms, and therefore usuallycomplain of exercise intolerance or muscle pain and cramps. Nevertheless, other patients may developprogressive muscular weakness that is usually proximal (mimicking inflammatory myopathy or limb girdle musculardystrophy), but is sometimes distal. In a smaller group of patients, both dynamic and static symptomspredominate (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 toexercise 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


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because of the existing metabolic block; as a result, they are stored in the cytoplasm as triglycerides, therebyresulting in progressive lipid storage myopathy with weakness, hypertrophic and/or dilated cardiomyopathy, andfatty liver. Symptoms are usually induced by prolonged exercise and prolonged fasting. (See 'Disorders of lipidmetabolism' above.)Exercise intolerance due to premature fatigue is a common manifestation of mitochondrial diseases, and theexercise intolerance is usually more severe than muscle weakness. In contrast to those with glycogen metabolismdefects, 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, lipidmetabolism, or purine metabolism (table 3), are at increased risk for developing myoglobinuria andrhabdomyolysis. The metabolic myopathies represent a small percentage of all cases of rhabdomyolysis but arerelatively common causes among patients with recurrent episodes of rhabdomyolysis after exertion. The mostcommon metabolic cause of recurrent myoglobinuria in both adults and children is carnitine palmitoyltransferase 2deficiency. (See 'Myoglobinuria and rhabdomyolysis' above and "Metabolic myopathies caused by disorders oflipid and purine metabolism", section on 'Carnitine palmitoyltransferase 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- anddrug-related, endocrine, viral, and inflammatory) should be excluded by appropriate testing prior to investigating ametabolic etiology. The evaluation needed to confirm the diagnosis of a metabolic myopathy (algorithm 1) isguided by a constellation of findings including the clinical presentation, the type of muscle involvement, specificlaboratory abnormalities (particularly elevations in serum creatine kinase and myoglobinuria), patient age, familyhistory, the results of histologic and pathologic examinations, and, increasingly, genetic testing. (See 'Evaluationand diagnosis' above.)


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Kazemi-Esfarjani P, Skomorowska E, Jensen TD, et al. A nonischemic forearm exercise test for McArdledisease. Ann Neurol 2002; 52:153.

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Lindner A, Reichert N, Eichhorn M, Zierz S. Acute compartment syndrome after forearm ischemic work test in apatient with McArdle's disease. Neurology 2001; 56:1779.

32.

Bruno C, Hays AP, DiMauro S. Glycogen storage diseases of muscle. In: Neuromuscular Disorders of Infancy,Childhood, and Adolescence: A Clinician's Approach, Jones HR Jr, De Vivo DC, Darras BT (Eds), ButterworthHeinemann, Philadelphia 2003. p.813.

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rngreen MC, Schelhaas HJ, Jeppesen TD, et al. Is muscle glycogenolysis impaired in X-linked phosphorylase bkinase deficiency? Neurology 2008; 70:1876.

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DiMauro S, Garone C, Naini A. Metabolic myopathies. Curr Rheumatol Rep 2010; 12:386.36.

Topic 6193 Version 10.0


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GRAPHICS

Correlation of metabolic myopathy symptoms and signs with specificbiochemical defects

Static symptoms and signs

Acid maltase deficiency

Branching enzyme deficiency

Debranching enzyme deficiency

Carnitine transport defect

LCAD, VLCAD deficiencies

Trifunctional enzyme deficiency

Mitochondrial disorders

Dynamic symptoms and signs

Phosphorylase b kinase deficiency

Myophosphorylase (PPL) deficiency

Phosphofructokinase (PFK) deficiency

Phosphoglycerate kinase (PGK) deficiency

Lactate dehydrogenase (LDH) deficiency

Carnitine palmitoyltransferase II (CPT II) deficiency

Fatty acid oxidation/mitochondrial defects

Static and dynamic symptoms and signs

Myophosphorylase deficiency

PFK, PPL b kinase deficiencies (plus fixed weakness)

Debranching enzyme deficiency (plus dynamic symptoms)

LCAD, VLCAD, SCHAD deficiencies

Trifunctional enzyme deficiency

Multiple mitochondrial DNA deletions

LCAD: long-chain acyl-CoA dehydrogenase; VLCAD: very long-chain acyl-CoA dehydrogenase; SCHAD:short-chain 3-hydroxyacyl-CoA dehydrogenase.

Graphic 59733 Version 3.0


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Disorders of glycogen/glucose metabolism

ClassificationKey clinical

findingsDiagnosis Therapy

GSD 0a (MIM #240600, glycogensynthase 2 deficiency in liver)

Ketotichypoglycemia, nohepatomegaly

Liver biopsy andenzyme testing;DNA testing

Uncookedcornstarch

GSD 0b (MIM #611556, muscleglycogen synthase deficiency)

Cardiomyopathy,exerciseintolerance,weakness

Muscle biopsy(glycogendepletion),enzyme assay,DNA testing

No specifictreatment

GSD I (MIM #232200; GSD Ia, vonGierke disease, glucose-6-phosphatasedeficiency; GSD Ib, c, and d due totransport defects)

Ketotichypoglycemia,hepatomegaly

DNA testing, liverbiopsy, andenzyme assay

Cornstarch,allopurinol,granulocytecolony-stimulatingfactor (G-CSF)

Lysosomal acid maltase deficiency(MIM #232300, Pompe disease, GSDII*)

Hypotonia, muscleweakness,hypertrophiccardiomyopathy

Fibroblast,leukocyte,muscle, or liverenzyme assay;DNA testing

Enzymereplacementtherapy

Lysosome-associated membraneprotein 2 (LAMP2) deficiency (MIM#300257, Danon disease, GSD IIb )

Hypotonia,hypertrophiccardiomyopathy

Muscle biopsy,DNA testing


GSD III (MIM #232400, glycogendebrancher deficiency)

Ketotichypoglycemia,hepatomegaly

Fibroblast or liverenzyme assay;DNA testing

Uncookedcornstarch

GSD IV (MIM #232500, glycogenbranching enzyme deficiency)

Hepatomegaly Fibroblast,muscle, or liverbiopsy; DNAtesting

Livertransplantation

GSD V (MIM #232600, McArdledisease, muscle phosphorylasedeficiency)

Fatigability,myoglobinuria

Muscle biopsy,muscle enzymeassay, DNAtesting

Sucrose prior toexercise

GSD VI (MIM #232700, Hers disease,liver phosphorylase deficiency)

Hepatomegaly,mildhypoglycemia

Liver biopsy andenzyme assay;DNA testing


GSD VII (MIM #232800, Tarui disease,phosphofructokinase deficiency inmuscle)


Muscle enzymeassay, DNAtesting


Phosphoglycerate kinase deficiency(MIM #311800)

Hemolysis,fatigability,myoglobinuria,CNS dysfunction

Muscle/RBCenzyme assay;DNA testing

Bone marrowtransplantation

*


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GSD IX (phosphorylase kinasedeficiency; IX a1, MIM #306000,formerly GSD VIII, alpha-2 subunitdefect in liver; IXb, MIM #261750, betasubunit defect in liver; IXc, MIM#613027, gamma subunit defect inliver and muscle; IXd, MIM #300559,alpha subunit defect in muscle)

Hepatomegaly,mildhypoglycemia,fatigability,exerciseintolerance

Liver/musclebiopsy; enzymeassay; DNAtesting


GSD X (MIM #261670,phosphoglycerate mutase deficiency)

Fatigability,myoglobinuria,exerciseintolerance

Muscle biopsy andenzyme assay;DNA testing


GSD XI (MIM #612933; lactatedehydrogenase A [LDHA, MIM#150000] deficiency and lactatedehydrogenase B deficiency [LDHB,MIM #150100])


Muscle or RBCenzyme assay;DNA testing


GLUT2 deficiency (MIM #138160;Fanconi-Bickel syndrome)

Growthretardation, renalFanconisyndrome,galactosemia

Clinical features,DNA testing

Small meals,cornstarch,electrolytes asneeded

GSD XII (MIM #611881, aldolase Adeficiency)

Hemolysis,jaundice,myoglobinuria,muscle weakness,fatigability

Muscle or RBCenzyme assay;DNA testing


GSD XIII (MIM #612932, beta-enolasedeficiency in muscle)

Exerciseintolerance,increased CPK

Muscle biopsy,enzyme assay,DNA testing


GSD XIV (MIM #612934,phosphoglucomutase 1 deficiency inmuscle)

Exerciseintolerance,myoglobinuria,increased CPK

Muscle biopsy,enzyme assay,DNA testing


GSD XV (MIM #613507, glycogenin 1deficiency in muscle)

Muscle weakness,arrhythmias

Muscle biopsy(glycogendepletion), DNAtesting


GSD: glycogen storage disease; MIM: Mendelian inheritance in man; DNA: deoxyribonucleic acid; CNS:central nervous system; RBC: red blood cell; GLUT2: glucose transporter 2; CPK: creatinine phosphokinase.* These diseases were originally classified as glycogen storages diseases. It was subsequentlyrecognized that the accumulation of glycogen in lysosomes seen in these diseases is due to defectivelysosomal metabolism rather than energy deficiency from glycogen/glucose metabolism. Thus, they areconsidered both glycogen storage diseases and lysosomal storage diseases.



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Metabolic myopathies associated with rhabdomyolysis

Disorders of glycogenolysis

Myophosphorylase deficiency (McArdle disease)

Phosphorylase kinase deficiency

Disorders of glycolysis

Phosphofructokinase deficiency

Phosphoglycerate kinase deficiency

Phosphoglycerate mutase deficiency

Lactate dehydrogenase deficiency

Disorders of lipid metabolism

Carnitine palmitoyltransferase deficiency

Carnitine deficiency

Short-chain acyl-CoA dehydrogenase deficiency

Long-chain acyl-CoA dehydrogenase deficiency

Lipin-1 deficiency

Disorders of purine metabolism

Myoadenylate deaminase deficiency

Other defects

Malignant hyperthermia susceptibility caused by RYR1 gene mutations

Alpha-methylacyl-CoA racemase (AMACR) deficiency

Brody myopathy (Calcium adenosine triphosphatase deficiency)



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Algorithm for the diagnosis of metabolic myopathies

In a patient with signs that raise the possibility of a metabolic myopathy, the constellation of clinical and laboratory features anthe underlying biochemical defect and thus narrow down the laboratory investigation.

CNS: central nervous system; PNS: peripheral nervous system; NGS: next-generation sequencing.


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Evaluation of the patient with suspected metabolic myopathy

General investigations

Blood

Creatinine kinase blood level (at rest, during episodes)

Lactate, pyruvate, LDH, LFTs, uric acid

CBC, electrolytes, glucose

Lactate, pyruvate, and lactate/pyruvate ratio

ALT, AST, LDH

Carnitine - free, total, and free/total ratio

Ketones

Myoglobin

Ca, K, PO4

Urine

Myoglobin

Ketones

Specific investigations

Cardiac evaluation

Electrocardiography

Echocardiography

Lipid metabolism defects

Plasma carnitine - free, total, free/total ratio

Serum acylcarnitines, free fatty acids

Serum glucose, ammonia, ketones

Serum free fatty acid/ketone ratio

Urine dicarboxylic acids

Urine acylglycines and organic acids

Skin fibroblast culture for enzyme assay

Electromyography and nerve conduction studies

Biochemical and/or molecular studies

Glycolytic/glycogenolytic defects

CBC, reticulocyte count, bilirubin


Muscle and skin biopsies for histology and enzyme assays


Mitochondrial defects

Other system evaluation (eg, endocrine, cardiac)


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Serum lactate, pyruvate, lactate/pyruvate ratio

CSF lactate, pyruvate, and lactate/pyruvate ratio

Urine organic acids

MRI spectroscopy of muscle and brain


Muscle and skin biopsies for histology and enzyme assays


ALT: serum alanine aminotransferase; AST: serum aspartate aminotransferase; CBC: complete blood count;CSF: cerebrospinal fluid; LDH: lactate dehydrogenase; LFT: liver function tests; MRI: magnetic resonanceimaging.



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Plasma carnitine levels in disorders of fatty acid metabolism

Enzyme defect Total carnitine Free carnitineFree:total

carnitine ratio

Carnitine transporter Very low Low Normal

CPT I Normal or high High High

Translocase and CPT II Low Very low Low

VLCAD, LCAD, MCAD,SCAD, LCHAD, SCHADETF and ETFdehydrogenase,2,4-dienoyl-CoAreductase

Normal or low Low Normal or low

CoA: coenzyme A; CPT: carnitine palmitoyl transferase; ETF: electron transfer flavoprotein; LCAD:long-chain acyl-CoA dehydrogenase; LCHAD: long-chain 3-hydroxyacyl-CoA dehydrogenase; MCAD:medium-chain acyl-CoA dehydrogenase; SCAD: short-chain acyl-CoA dehydrogenase; SCHAD: short-chain3-hydroxyacyl-CoA dehydrogenase; VLCAD: very long-chain acyl-CoA dehydrogenase.

Adapted from: Vockley J. Mayo Clin Proc 1994; 69:249.



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Ischemic forearm exercise test

Normal response toischemic exercise

Lactate Pyruvate Ammonia

3- to 5-foldincrease



Glycolytic/glycogenolytic defects No rise or

Disclosures: Basil T Darras, MD Nothing to disclose. Marc C Patterson, MD, FRACP Grant/Research/Clinical Trial Support: Actelion[Lysosomal diseases (Miglustat)]. Consultant/Advisory Boards: Amicus; Agios; Cydan; Genzyme; Orphazyme; Shire HGT [Lysosomal diseases(Arimoclomol, cyclodextrin, glucocerebrosidase)]; Stem Cells, Inc; Vtesse [Lysosomal diseases (Human embryonic stem cells)]. John F Dashe,MD, PhD Nothing to disclose.Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through amulti-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content isrequired of all authors and must conform to UpToDate standards of evidence.Conflict of interest policy

Disclosures


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Approach to the metabolic myopathies.pdf

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