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Metabolic Myopathies and Physical Activity

When Fatigue Is More Than Simple Exertion

Mark A. Tarnopolsky, MD, PhD


In Brief: Fatigue can have many causes in active people. A metabolic myopathy—though uncommonly identified as a cause of fatigue during sporting events—must be considered in certain circumstances, and the diagnosis may be helpful for preventive and genetic counseling. In general, symptoms of disorders of glycogen breakdown and glucose utilization (glycogen storage diseases) occur during high-intensity exercise. Symptoms of disorders of fatty acid transport or oxidation and mitochondrial disorders occur after endurance exercise. Important investigations include forearm ischemic testing, electromyographic and nerve conduction studies, muscle biopsy (histology, enzyme, and DNA testing), and exercise testing. Most patients with metabolic myopathies can participate in sports with appropriate exercise adaptations and dietary manipulation.

All athletes and most individuals have experienced muscle fatigue and pains. Muscle cramps, pain, and a feeling of fatigue are expected consequences of unaccustomed exercise or activities. With repeated activities, the body usually adapts to the training, and these symptoms abate. In some individuals, however, these symptoms can be persistent or extreme and may represent an underlying neuromuscular or neurometabolic disorder. By definition, metabolic myopathies are disorders of substrate energy provision in skeletal muscle.

Determining whether patients have an underlying metabolic disorder or have just overexerted themselves is not always easy. The history, physical exam, and laboratory studies help determine who needs further investigation.

Muscle Fatigue and Myalgias

Fatigue can be defined as a failure of the muscle to produce the expected force. The causes of fatigue are multifactorial, and entire careers have been dedicated to unraveling its mechanisms.1,2 Fatigue can occur anywhere in the neurologic and muscular systems, from central fatigue (an inability to centrally activate motor neurons), to muscle adenosine triphosphate (ATP) generation, to numerous other loci.

The ongoing cycling between actin and myosin in muscle requires ATP from several pathways. A failure to generate ATP can ultimately lead to contractile dysfunction and fatigue. The oxygen-independent pathways for energy transduction include glycolysis, the phosphocreatine-creatine pathway, and the adenylate-kinase pathway. The oxygen-dependent sources of ATP include carbohydrate oxidation pathways such as aerobic glycolysis and glycogenolysis, utilization of pyruvate through the tricarboxylic acid cycle, and ultimately, electron transport; electron transport; and oxidation of fatty acids derived from intramuscular triglycerides, plasma free fatty acids (FFAs), and very low-density lipoproteins. FFAs are oxidized through beta-oxidation in the mitochondria, yielding acetyl-CoA, which is ultimately oxidized through the tricarboxylic acid cycle and oxidative phosphorylation. Protein, primarily the branched-chain amino acids, can also be oxidized for energy; however, it represents only a minor component of the total energy needs during exercise.3 Although fatigue can occur at any of these loci, this review will focus predominantly on metabolic disorders that affect the generation of ATP.

Myalgias are a sense of discomfort within the muscle. Transient myalgias during and after high-intensity exercise result from the accumulation of metabolic byproducts and activation of unmyelinated metaboreceptors and nociceptors within the muscle. These myalgias usually resolve rapidly if activity ceases. In severe ATP depletion, such as with metabolic myopathies, a failure to sequester calcium in the sarcoplasmic reticulum can cause muscle contracture and membrane damage. After unaccustomed exercise, ultrastructural disruptions in sarcomeric proteins lead to inflammation and delayed-onset muscle soreness within 24 to 48 hours. After exercise, increased creatine kinase and other sarcomeric enzymes can persist for up to 1 week.4,5

Sorting out the cause of the discomfort from potential mechanisms is not always clinically possible. The skilled diagnostician keeps a wide differential diagnosis after the first patient encounter because many neurologic and nonneurologic disorders can mimic metabolic myopathies, including muscular dystrophy, channelopathies, electrolyte abnormalities, neuropathy, radiculopathy, myasthenia gravis, and multiple sclerosis.

General Causes of Fatigue

Numerous causes of fatigue and myalgias exist, and the vast majority of patients seeking treatment from their primary care physicians will not have metabolic myopathies. Some of the more common conditions that mimic fatigue include depression, hypothyroidism, vitamin B12 deficiency, anemia, asthma (especially exercise-induced bronchospasm), infectious processes, and deconditioning. It is not always easy to determine whether fatigue or myalgias are due simply to overexertion prior to adaptation, or whether the patient has an underlying neurometabolic disorder. Most often the disorders will be revealed with a careful history, physical examination, and simple blood tests.

Neurometabolic Disorders

Neurometabolic diseases that affect skeletal muscle during sport include glycogen storage disease (GSD), myoadenylate deaminase deficiency (AMPD), fatty acid oxidation defects (FAOD), and mitochondrial myopathy. AMPD is present in about 1% to 2% of the population; disorders such as McArdle's disease (GSD type 5), and carnitine palmitoyltransferase deficiency, type 2 (CPT-2) affect many hundreds to perhaps thousands of patients worldwide. Rarer conditions such as phosphoglycerate kinase deficiency have been reported in only a few dozen patients.6

Malignant hyperthermia, a defect of excitation-contraction coupling, can also produce nearly identical symptoms of myalgia, fatigue, and muscle cramps. Amino acid oxidation supplies only a small percentage of energy during exercise; therefore, amino acid oxidation defects are not part of a differential diagnosis of fatigue during exercise.3 These usually result in developmental delay, feeding difficulties, and seizures in infancy.

A number of pseudometabolic disorders have signs and symptoms that are similar to the metabolic disorders (table 1). Exertional myoglobinuria seen in some cases of limb-girdle muscular dystrophy is one example. Interested clinicians should read recent reviews about metabolic myopathies,7,8 mitochondrial disease,9 FAODs,10 and GSDs11 for more details.

TABLE 1. Neuromuscular Diseases That Cause Weakness

Motor Neuropathies
Amyotrophic lateral sclerosis (Lou Gehrig disease)

Spinal muscular atrophy
Hypothyroidism, lead poisoning, diabetes mellitus, Gullain-Barré syndrome

Hereditary motor-sensory neuropathy (eg, Charcot-Marie-Tooth)
Neuromuscular Junction
Myasthenia gravis botulism

Congenital myasthenia gravis (fast + slow channel)
Excitation/Contraction Coupling
Possibly caused by dihydropyridine blockers (eg, nicardipine hydrochloride, amlodipine besylate)

Malignant hyperthermia
Inflammatory: polymyositis, dermatomyositis, inclusion body myositis

Endocrine: hypothyroid, hyperadreno-corticism (Cushing's)

Dystrophy: limb-girdle muscular, fascioscapulohumeral muscular, myotonic, dystrophinopathy (eg, Duchenne's), Emery-Driefuss muscular, congenital

Channelopathy: familial periodic paralysis, paramyotonia congenita, Thomsen's disease

Congenital myopathy (eg, nemaline rod, central core disease)

Metabolic: myoadenylate deaminase deficiency; fatty acid oxidation defects (eg, CPT-2, trifunctional protein deficiency); glycogen storage disease (GSD) including McArdle's (GSD-5), Tarui's (GSD-7), Pompe's (GSD-2); mitochondrial myopathy (eg, MELAS 3243, 3271, cytochrome b mutations)

CPT-2 = carnitine palmitoyltransferase, type 2 deficiency;
MELAS = myopathy, encephalopathy, lactic acidosis, and stroke-like episodes

Focused History

Diagnostic clues from the history and physical exam can help establish subsequent investigations and interventions to prevent serious complications such as myoglobinuria and renal failure.

A careful, chronologic narrative from the patient allows the physician to formulate hypotheses that are strengthened or weakened by further questioning, the physical exam, and subsequent testing. Frequently, the patient recalls aspects of the history after the initial visit.

Important details are often revealed on further reflection and after the patient questions family members. For example, in cases of "cryptogenic neuropathy," detailed questioning of family members reveals a strong autosomal-dominant history of pes cavus and an inability to skate. Subsequent electromyography and genetic testing of the family leads to a diagnosis of hereditary motor and sensory neuropathy.

Family history is particularly important because most metabolic myopathies are autosomal recessive (eg, McArdle's disease), while others are maternally inherited (eg, mitochondrial DNA disorders), or X-linked recessive (eg, phosphorylase b kinase deficiency). The family's ethnic origin is important (eg, phosphofructokinase deficiency is more common in Ashkenazi Jews) as is the potential for consanguinity (eg, autosomal recessive conditions are more common in siblings).

A developmental history including the attainment of gross motor, fine motor, social, cognitive, and verbal milestones is important. Gross motor delays and muscle pains and cramps that started in first grade during gym class are much more likely to indicate an underlying metabolic defect than are myalgias and cramps that began at age 28 after a strenuous recreational football game.

For patients who feel fatigued, the clinician should carefully examine if the following factors are involved: presence of flu or upper respiratory tract infection (see "Muscle Aches With the Flu and Exercise"), dietary and fluid intake before and during the event, environmental conditions, time of day, presence of nausea and vomiting, unaccustomed exercise, type of exercise (sprinting versus endurance), presence of a "second-wind phenomenon," and whether or not these symptoms have occurred before. Second-wind phenomenon occurs when people experience pain and muscle cramps when beginning an exercise, but when they slow down or "push through it," their symptoms diminish. Such a history is almost always pathognomonic for defects in glycogenolysis or glycolysis and should prompt further testing to confirm the diagnosis (see "An Elusive Diagnosis").

Muscle Aches With the Flu and Exercise

A 47-year-old man was referred for evaluation of possible metabolic myopathy. The patient was very active in judo, karate, and recreational swimming, but he experienced muscle pains (usually in the quadriceps) following exercise.

History. He had been given a diagnosis of phosphofructokinase deficiency (glycogen storage disease type 7) in the past. He found that increasing the amount of carbohydrate he consumed before exercise improved his exercise tolerance. In his 20s, he had a flu-like episode and continued to try to do sports but got very sick, had extreme myalgias, and was hospitalized with renal failure. He subsequently recovered. He is now able to swim and jog 6 to 7 km; however, if his carbohydrate intake drops, he experiences increasing leg pain and proximal weakness. Family history revealed an Ashkenazi Jewish origin and a sister with similar symptoms.

Physical exam and lab tests. Neurologic and musculoskeletal examinations were normal. Testing revealed that his muscle creatine kinase fluctuated from normal to approximately 800 U/L without excessive exercise (normal is <230 U/L).

Forearm ischemic testing showed normal lactate and ammonia responses with normal uric acid. A muscle biopsy was normal with light and electron microscopy. Biochemical analysis revealed his carnitine palmitoyltransferase (CPT) activity was 0.421 nmol/min/mg (normal is 15.68 nmol ± 0.03).

Final diagnosis. The diagnosis, made by enzyme assay, was high-grade carnitine palmitoyl transferase type 2 deficiency (fatty acid oxidation defect). DNA analysis confirmed genetic homozygosity for the S113L mutation.


A history of consuming carbohydrates prior to exercise to improve symptoms is common in patients who have fatty acid oxidation defects. Carbohydrates provide an alternative energy source and delay the time until fatty acids represent the greater proportion of energy-yielding substrates. Common symptoms are myalgias and pigmenturia that occur during periods of fasting and with superimposed colds and flus. During these times, fatty acid oxidation is proportionately increased.

An Elusive Diagnosis

For more than 20 years, a 53-year-old man experienced severe muscle cramps in his limbs whenever he participated in recreational baseball or football or pushed his lawnmower uphill.

History. The patient had seen his family physician, a cardiologist, an internist, and a rheumatologist for assessment of symptoms. He was mildly overweight and had severe gout. Because of his persistent complaints with no clear diagnosis, two final referrals were made—one to a neuromuscular-neurometabolic disease clinic and the other to psychiatry to assess a possible psychogenic component.

The additional history obtained in our clinic noted that if he slowed down and tried to "push through" and ignore the cramps, they would eventually get better and he would feel that he had renewed energy ("second-wind phenomenon"). He also reported that his urine had occasionally been tea-colored (pigmenturia). Family history was unremarkable.

Exams and lab tests. His neurologic examination was normal. He had a right knee effusion. A forearm ischemic test demonstrated complete absence of a lactate response and an exaggerated ammonia response to exercise. He experienced a contracture at about 50 seconds, and the cuff was released. He recovered without any problems. His baseline creatine kinase level was elevated at 546 U/L; persistent elevations had prompted the earlier referral to cardiology. Muscle biopsy demonstrated some variation in fiber size, with some subsarcolemmic vacuolation that was periodic-acid-Schiff-stain positive. Phosphorylase activity was absent. Histochemical staining revealed strongly positive phosphofructokinase activity. Electron microscopy showed subsarcolemmic accumulations of nonmembrane-bound glycogen. The finding of histochemical phosphorylase deficiency was confirmed with biochemical and genetic testing.

Diagnosis. The diagnosis was glycogen storage disease type 5 (McArdle's disease). The right knee effusion was gout related.


Patients who have glycogen storage disease may also experience myogenic hyperuricemia from increased flux through myoadenylate deaminase that generates uric acid. High levels of uric acid can precipitate in the joints. This patient had a uric acid level of 900 µmol/L that responded to very high doses of allopurinol (900 mg/day). The high dose was necessary to keep the uric acid level below 500 µmol/L.

Finally, it is important to do a structured functional inquiry. A head-to-toe checklist of body functions can often provide clues to the diagnosis. For example, dementia, migraines, ataxia, stroke-like episodes, visual loss, shortness of breath, abdominal cramps, vomiting, constipation, and pseudo-obstruction suggest mitochondrial DNA defects (table 2). It is particularly important to question patients about tea or red wine pigmenturia, a sign of urine that contains myoglobin.

TABLE 2. Clues in the History Suggestive of a Metabolic Myopathy
CluePossible Disorder

Myalgias with endurance sports
Myalgias with power or sprint sports
Symptoms triggered by fasting or superimposed illness
Gouty arthritis
Nausea or vomiting with exercise
Multiple system involvement
Family history
    autosomal recessive
CPT-2, FAODs, mtDNA defects, possible AMPD deficiency
GSDs, possible AMPD deficiency
CPT-2, FAODs, mtDNA defect
GSD type 7 (Tarui disease), mtDNA defect
mtDNA defect

phosphorylase b kinase deficiency
CPT-2, most GSDs, AMPD deficiency
mtDNA deletions
GSD = glycogen storage disease; CPT-2 = carnitine palmitoyltransferase, type 2 deficiency; FAOD = fatty acid oxidation defect;
mtDNA = mitochondrial DNA; AMPD = myoadenylate deaminase deficiency

Key Physical Exam Findings

The physical examination is often normal in patients who have metabolic myopathies, but some findings can be helpful. The physical exam is often organized into the following categories: mental status, cranial nerves, motor attributes (bulk, tone, power), muscle stretch reflexes, pathologic reflexes, sensory exam, gait, coordination, musculoskeletal and joint exam, heart, lungs, and abdomen.

Neurologic. Mental status can be altered in mitochondrial DNA disorders, fatty acid oxidation disorders (severe in childhood), and, rarely, in glycogen storage disorders. Cranial nerve abnormalities include ptosis and diplopia (found in mitochondrial disorders and the nonmetabolic condition, myasthenia gravis), optic atrophy and retinitis pigmentosa (found in mitochondrial disorders), and facial paresis (found in mitochondrial disorders and in myotonic and fascioscapulohumeral dystrophies).

Musculoskeletal. The motor exam includes bulk, tone, and power. Bulk is not usually altered in metabolic myopathies, and a severe reduction should prompt consideration of a neurogenic disorder. Tone (spasticity, rigidity, and paratonia) is rarely altered in metabolic myopathies except in mitochondrial disorders when spasticity (corticospinal), rigidity (basal ganglia), and paratonia (bilateral white matter pathology) can be encountered.

Fixed weakness can be encountered acutely after a metabolic crisis when complete paralysis of the affected muscles can occur (eg, CPT-2 deficiency). In the interictal period, proximal weakness eventually develops in several of the myopathies after repeated bouts of metabolic crisis (eg, McArdle's disease). Fixed proximal weakness early in the course of the disease should prompt consideration of a nonmetabolic myopathy. Weakness developing after repeated contractions (fatigue) can be elicited on the exam and may indicate a glycogen storage disease or the nonmetabolic condition, myasthenia gravis.

Muscle stretch reflexes are usually normal except during an acute metabolic crisis when they may be depressed, or in mitochondrial disorders where corticospinal tract involvement produces brisk, spastic, or other pathologic reflexes (eg, Babinski, Hoffmann's). Gait, coordination, and the sensory exam are usually normal in metabolic myopathies. The joint exam is usually normal in metabolic myopathies; however, gout (myogenic hyperuricemia) can be seen in some of the glycogen storage disorders.

Other systems. The heart and lungs are common sources of "fatigue" during exercise. For example, several children with glycogen storage disease referred to our clinic were initially diagnosed with asthma (see "A Young Hockey Player and 'Asthma'"), and, conversely, we recently evaluated a patient with a history suspicious for a metabolic disease (ie, CPT-2) and found asthma. Finally, abdominal cramps, pain, and nausea during exertion are quite common in metabolic myopathies (eg, mitochondrial myopathy, CPT-2, GSD), yet the exam is usually normal. Some of the GSDs can also cause hepatomegaly (eg, GSD type 2).12

A Young Hockey Player and 'Asthma'
A 9-year-old boy was referred by his family doctor to a pediatric exercise and nutrition clinic to evaluate symptoms of shortness of breath and abdominal pain during exercise that were thought for serveral years to be caused by asthma. Pulmonary function was normal, and the child was sent for evaluation of a possible metabolic myopathy.

History. Since the age of 4 or 5, he had an inability to keep up with the other children during sporting activities. His fatigue was particularly apparent during high-intensity exercise and when playing hockey. His father stated that he would "coast and seemed lazy compared to other kids." At times during exercise he would have leg pain, shortness of breath, and nausea, and, occasionally, he vomited following hockey games. He was able to ride his bike for a long duration on level terrain, but if he had to ride uphill, he would get sick to his stomach and have leg pains. Functional inquiry was otherwise negative, and the patient had no history of pigmenturia. Family history was unremarkable.

Physical exam and lab tests. Complete neurologic and musculoskeletal examinations were normal. Exercise testing revealed a low VO2max for his age, less than 3 standard deviations below age-matched controls (27 mL O2/kg/min). Plasma samples taken before and after this test showed lactate values of 0.7 mmol/L and 1.3 mmol/L, respectively (normal range is < 2.2 mmol/L before and > 6.0 mmol/L after exercise). Ammonia concentrations were 30 µmol/L preexercise and 694 µmol/L postexercise (normal range is < 33 µmol/L preexercise and 60 to 150 µmol/L postexercise).

He was sent to a neuromuscular-neurometabolic disease clinic for evaluation. His neurologic examination was normal. Baseline blood chemistries (Sequential Multiple Analyzer 12) were normal. Forearm ischemic testing demonstrated an exaggerated ammonia response and almost no lactate response with no contracture. Muscle biopsies revealed a mild variation in fiber size, with some subsarcolemmic vacuolations that were periodic-acid-Schiff-stain positive. Phosphorylase activity was normal. Phosphofructokinase activity was completely absent. Electron microscopy demonstrated accumulations of nonmembrane-bound glycogen in the subsarcolemmic region (figure A). Magnetic resonance spectroscopy showed no acidosis with high-intensity exercise.

Diagnosis. The diagnosis was glycogen storage disease type 7, also called Tarui's disease.


The child's symptom's improved after creatine monohydrate (0.1g/kg/day) was prescribed. He was also given instructions to avoid high-intensity exercise.

FIGURE A. Microscopic view (periodic-acid Schiff stain, 4005) view of muscle tissue from a 9-year-old boy shows subsarcolemmic vacuoles with accumulations of nonmembrane-bound glycogen (arrow) characteristic of glycogen storage disease.

Figure courtesy of Mark A. Tarnopolsky, MD, PhD

Laboratory Tests

Selected tests are used to support, confirm, or refute the hypothesis made by the history and physical exam.

Blood tests. Every athlete presenting with fatigue or cramps should have a complete blood cell count (CBC) and electrolyte analysis (sodium, potassium, magnesium, and calcium), because anemia and electrolyte disorders are much more likely than a metabolic disorder. After metabolic stress, serum creatine kinase (CK) activity is invariably elevated in patients who have FAODs and GSDs. Hypercreatinemia is also found in the interictal period in many of the GSDs, but it should also prompt consideration of a nonmetabolic myopathy. Hypercreatinemia is often seen after unaccustomed exercise and may take up to 10 days to return to baseline. Thus, for athletes who have significant symptoms of neuromuscular dysfunction, we usually request that at least one CK level be tested after a 10-day rest.

Thyroid and vitamin B12 testing have been helpful in selected athletes who report fatigue. Hypothyroidism can cause very significant weakness, fatigue, and hypercreatinemia and, statistically, will be encountered more frequently than a metabolic myopathy. Vitamin B12 deficiency should be considered in vegans, particularly when vibration sensation is reduced on the physical exam, or in a patient who has macrocytosis or anemia on the CBC. In the absence of specific symptoms and signs, other screening tests during the lab workup are not time- or cost-effective.

For the patient seen in an emergency situation who has collapsed after an exhaustive sporting event or has cramps and pigmenturia after exercise, the lab workup will include the above tests plus renal function, liver function, and urine myoglobin tests. Serum and urine samples should be taken and stored for future testing; some of the FAODs will show serum abnormalities only during an acute event.

Urinalysis. Any patient with pigmenturia must have a urine myoglobin test. If this is not available, the presence of myoglobin can be inferred from the finding of a positive hemoglobin test with no red cells. Myoglobinuria is nonspecific, but it indicates significant underlying rhabdomyolysis and should prompt a careful investigation into the underlying cause. The more common neuromuscular diseases that cause myoglobinuria include carnitine palmitoyltransferase deficiency type 2, McArdle's disease (GSD type 5), malignant hyperthermia, viral myositis (eg, influenza A and B), and some muscular dystrophies. Extreme overexertion, especially if the athlete is dehydrated in a hot environment, is also a possibility. The less common causes of myoglobinuria include mitochondrial DNA deletion, mitochondrial cytochrome oxidase defect, familial recurrent myoglobinuria, other GSDs, and other FAODs.

Patients who have GSD should have uric acid tests to detect myogenic hyperuricemia and possible gout formation. Those with phosphofructokinase deficiency (GSD type 7) should have a hemolysis screen. Plasma-free and acyl-carnitine concentrations are frequently low in patients who have FAOD and may provide an important clue to the diagnosis. Specific urine organic acids and acyl-carnitines are often elevated after an acute metabolic crisis in patients who have FAOD.10

Organic acids, such as ethylmalonic acid, can also be elevated in patients who have mitochondrial myopathies. The plasma lactate-to-pyruvate ratio and ammonia concentration are often elevated, and plasma samples must be collected on ice to avoid false positives. Many of these tests are available only in tertiary care centers and should be ordered only when there is a strong probability of a given disorder.

Electromyography and nerve-conduction studies. Most often, these studies are normal in patients who have metabolic myopathies, and the tests are primarily helpful in ruling out alternative or concomitant diagnoses. Electromyography may show fibrillations and positive sharp waves during acute rhabdomyolysis. Acid maltase deficiency is one of the few examples in which a metabolic myopathy will often show abnormalities on resting electromyography.

Spectroscopy. Phosphorus magnetic resonance spectroscopy is a noninvasive technique used to evaluate metabolic myopathies and impaired muscle oxidative metabolism in patients who have exercise intolerances of undetermined causes.13-16 In GSD, no acidification occurs during and after exercise, and the phosphocreatine (PCr):inorganic phosphate (Pi) ratio drops rapidly. The basal PCr:Pi ratio can be low in mitochondrial myopathy; however, a slow rate of PCr recovery is more often seen.14,15

Near-infrared spectroscopy17 is another noninvasive diagnostic test for hemoglobin and myoglobin oxygenation. Characteristic patterns of oxygenation after exercise have been identified in patients with mitochondrial and other metabolic myopathies.18 Considerable operator experience is needed with these methods, and comparison with data from controls is a must.

Exercise Testing

One of the classic tests used for screening suspected GSD and AMPD is the forearm ischemic test. To ensure that individual normal ranges can be established, this test must be performed in a tertiary care center that has experience with the test. After the patient fasts overnight, a plastic catheter is placed into the antecubital vein, a blood sample is taken, placed on ice, and immediately transported to the laboratory to determine the resting lactate and ammonia levels. Then, a sphygmomanometer cuff is inflated to about 20 mm Hg above arterial pressure, and the patient performs rhythmic isometric exercise with a 9-second:1-second exercise-to-rest cycle. The test is immediately terminated if the individual develops a painful muscle contracture. Following the 60-second contraction (six sets of 10-second epochs), the manometer cuff is released, and recovery samples are taken at 1, 3, and 5 minutes postexercise.19

A normal (about 3 to 4 X baseline) to elevated (> 4 X) rise in ammonia levels with no elevation in lactate levels (< 1.5 X baseline) is characteristic of GSD. A normal lactate elevation (about 2.5 to 4 X baseline) without a rise in ammonia levels (< 1.5 X baseline) is characteristic of AMPD. A suboptimal increase in both lactate and ammonia concentrations usually indicates that the patient did not put forth an appropriate effort, although given the high prevalence of AMPD deficiency in Caucasians (about 1% to 2%), it is possible to have both AMPD and GSD.

Graded stress tests are helpful, not only for ruling out cardiorespiratory causes of fatigue, but also because certain disorders have characteristic patterns. For example, a low VO2max and a high respiratory exchange rate are characteristic of mitochondrial myopathy19 (see "An Underachieving Athlete"). A high respiratory exchange rate during submaximal workloads can indicate an FAOD because of the inability to oxidize lipid. (Note: a respiratory exchange rate of 0.7 indicates 100% lipid oxidation; 1.0 indicates 100% carbohydrate oxidation.) In some cases of suspected FAOD, a fasting exercise test at submaximal workloads can reveal a postexercise organic acid or carnitine profile that is characteristic of the disorder.

An Underachieving Athlete

A 22-year-old triathlete volunteered for a study to examine gender differences and intramuscular lipid use in endurance athletes. He had been training for 6 years at 12 to 16 hr/wk but had not achieved the results that he expected for his degree of commitment. Given his training, an exercise test VO2max, performed for the study, revealed a surprisingly low value of 52 mL/kg/min.

In addition, he had an extremely high respiratory exchange ratio during submaximal exercise that was greater than 3 standard deviations above the mean for similarly trained athletes at 60% VO2max. This test was repeated three times to ensure its validity. Because of the abnormal pattern, he came to the neuromuscular-neurometabolic clinic for assessment.

History. The patient's developmental history was normal, and he had not experienced pigmenturia, muscle cramps, or weakness. Family history included a sister who was healthy but not physically active and his mother who had late-onset seizures.

Physical exam and lab tests. His neurologic examination was normal, except for very mild ptosis. Tests for resting lactate and ammonia levels were normal, as was the forearm ischemic test. Muscle biopsy demonstrated slight prominence of mitochondria on trichrome stain but no true ragged-red fibers. Electron microscopy showed that more than 70% of the mitochondria contained paracrystalline inclusions with marked pleomorphism.

DNA sequencing of his entire mitochondrial genome demonstrated a heteroplasmic missense mutation at position 15497 in the cytochrome b gene that resulted in an amino acid substitution of glycine to adenine.

Diagnosis. The diagnosis of G15497A (cytochrome b) mitochondrial DNA mutation was confirmed with polymerase chain reaction amplification and restriction fragment length polymorphism testing in this patient, his mother, and sister.


The patient began taking 0.15 g/kg/day of creatine monohydrate.1 After 2 months, all of the paracrystalline inclusions resolved and his submaximal exercise renal excretion rate decreased.

In our experience, this is the first proven case of a primary mitochondrial DNA defect in an athlete. Electron microscopy of muscle samples from more than 100 elite athletes showed no other cases of a single paracrystalline inclusion in mitochondria.


  1. Tarnopolsky MA, Roy BD, MacDonald JR: A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve 1997;20(12):1502-1509

Muscle Biopsy

The first consideration in muscle biopsy is the method. Earlier studies used a relatively small needle without suction that obtained tissue samples of less than 50 mg, which led to debate about the utility of open versus needle biopsy. This is no longer a concern because a much larger sample is obtained using a suction modification (we routinely obtain 125 to 300 mg), and with newer enzyme and genetic tests, the need for very large samples (> 300 mg) is rare. One exception is when malignant hyperthermia is suspected and an in vitro halothane and caffeine contracture test is required. The biopsy must be performed at an experienced tertiary care center where samples can be frozen for biochemical and DNA analysis and electron microscopy.

A series of tests are done to rule out inflammatory myopathy and dystrophy. Sometimes the biopsy histochemistry provides the diagnosis or gives strong clues for future tests, including absent phosphorylase staining in McArdle's disease, ragged red fibers in mitochondrial myopathy, and increased lipid in FAOD. When a suspected diagnosis is entertained (eg, ragged red fibers suggesting mitochondrial myopathy), the frozen sample can be used for confirmatory genetic (eg, MELAS A3243G transition mutation) or biochemical (eg, complex I deficiency) analysis.

Genetic Testing

At opposite ends of the spectrum are malignant hyperthermia, in which several mutations account for a minority of cases, and McArdle's disease, in which a few mutations account for most cases. Many techniques are available, and it is important to know the method employed (eg, polymerase chain reaction, Southern blot, allele-specific oligonucleotide, direct sequencing) and the laboratory's experience with the tests before sending a sample for analysis. A detailed discussion of the tests is beyond the scope of this article and can be found in a recent review.6

Continuing Exercise

Exercise is part of a healthy lifestyle, and not all patients will want to give up exercise after they have been diagnosed with a metabolic myopathy. Some adaptations can be made. For example, most patients who have FAODs can do quite well if they avoid exercise during periods of intercurrent illness, consume carbohydrates before and during exercise, and avoid extreme endurance exercise, particularly in high ambient temperatures when fasted.

Awareness Is Key

Although true cases of metabolic myopathy are very rare, it is important to keep these disorders on the differential diagnostic list. Details from the history and physical exam are the most important factors that can lead to appropriate referral. A thorough investigation of suspected cases has genetic implications for other family members, and timely advice to patients and their families can prevent devastating consequences.


  1. Edwards RH: Muscle fatigue and pain. Acta Med Scand Suppl 1986;711:179-188
  2. Edwards RH, Hill DK, Jones DA, et al: Fatigue of long duration in human skeletal muscle after exercise. J Physiol 1977;272(3):769-778
  3. McKenzie S, Phillips SM, Carter SL, et al: Endurance exercise training attenuates leucine oxidation and BCOAD activation during exercise in humans. Am J Physiol Endocrinol Metab 2000;278(4):E580-E587
  4. Bourgeois J, MacDougall D, MacDonald J, et al: Naproxen does not alter indices of muscle damage in resistance-exercise trained men. Med Sci Sports Exerc 1999;31(1):4-9
  5. Stupka N, Lowther S, Chorneyko K, et al: Gender differences in muscle inflammation after eccentric exercise. J Appl Physiol 2000;89(6):2325-2332
  6. Vladutiu GD: The molecular diagnosis of metabolic myopathies. Neurol Clin 2000;18(1):53-104
  7. Darras BT, Friedman NR: Metabolic myopathies: a clinical approach, part 1. Pediatr Neurol 2000;22(2):87-97
  8. Darras BT, Friedman NR: Metabolic myopathies: a clinical approach, part 2. Pediatr Neurol 2000;22(3):171-181
  9. Simon DK, Johns DR: Mitochondrial disorders: clinical and genetic features. Annu Rev Med 1999;50:111-127
  10. Tein I: Metabolic myopathies. Semin Pediatr Neurol 1996;3(2):59-98
  11. Tein I: Neonatal metabolic myopathies. Semin Perinatol 1999;23(2):125-151
  12. Talente GM, Coleman RA, Alter C, et al: Glycogen storage disease in adults. Ann Intern Med 1994;120(3):218-226
  13. Argov Z, Arnold DL: MR spectroscopy and imaging in metabolic myopathies. Neurol Clin 2000;18(1):35-52
  14. Arnold DL, Taylor DJ, Radda GK: Investigation of human mitochondrial myopathies by phosphorus magnetic resonance spectroscopy. Ann Neurol 1985;18(2):189-196
  15. Matthews PM, Allaire C, Shoubridge EA, et al: In vivo muscle magnetic resonance spectroscopy in the clinical investigation of mitochondrial disease. Neurology 1991;41(1):114-120
  16. Olsen NJ, Park JH: MRS and NIRS for muscle disease evaluation. Bull Rheum Dis 1995;44(5):4-7
  17. Bank W, Park J, Lech G, et al: Near-infrared spectroscopy in the diagnosis of mitochondrial disorders. Biofactors 1998;7(3):243-245
  18. Argov Z, De Stefano N, Taivassalo T, et al: Abnormal oxidative metabolism in exercise intolerance of undetermined origin. Neuromuscul Disord 1997;7(2):99-104
  19. Tarnopolsky MA, Roy BD, MacDonald JR: A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve 1997;20(12):1502-1509

Dr Tarnopolsky is an associate professor in the departments of medicine and kinesiology at McMaster University Medical Centre in Hamilton, Ontario. Address correspondence to Mark A. Tarnopolsky, MD, PhD, McMaster University Medical Center, 4U4-Division of Neurology, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada; e-mail to [email protected].

Disclosure information: Dr Tarnopolsky discloses no significant relationship with any manufacturer of any commercial product mentioned in this article. No drug is mentioned in this article for an unlabeled use.