Metabolic Myopathies

Updated: Sep 14, 2021
  • Author: Elanagan Nagarajan, MD, MS; Chief Editor: Nicholas Lorenzo, MD, CPE, MHCM, FAAPL  more...
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Metabolic myopathies refer to a group of hereditary muscle disorders caused by specific enzymatic defects due to defective genes. Metabolic myopathies are heterogeneous conditions that have common abnormalities of muscle energy metabolism that result in skeletal muscle dysfunction. Most recognized metabolic myopathies are considered primary inborn errors of metabolism and are associated with known or postulated enzymatic defects that affect the ability of muscle fibers to maintain adequate energy and adenosine triphosphate (ATP) concentrations. Traditionally, these diseases are grouped into abnormalities of glycogen, lipid, purine, or mitochondrial metabolism. 

Metabolic myopathies are rare but potentially treatable disorders. They are sometimes misdiagnosed as muscular dystrophies or inflammatory myopathies. Metabolic myopathies are the most clearly defined and etiologically understood muscle disorders because their fundamental biochemical defects are known through recent molecular biology and biochemistry developments. Also, many of the genetic defects have been characterized, and genetic counseling is now possible. [1, 2, 3]

Metabolic myopathies are important disorders since they mimic other more commonly encountered neurologic diseases. The diagnosis depends on a high index of suspicion and involves correlating certain clinical manifestations to specific metabolic defects. Finally, understanding these muscle disorders enables a better understanding of the dynamics of muscle and body metabolism.


Understanding energy metabolism in exercising muscles is a prerequisite to the study of metabolic myopathies. Muscle contraction depends on the chemical energy of ATP and several biochemical processes within the muscle cell maintain a supply of ATP to support muscle contraction. [4, 5] The 3 major pathways that supply ATP to meet the energy demands of exercising muscle are as follows:

  • Glycogen metabolism: Aerobic exercise is essential for intermittent or submaximal contraction. Anaerobic exercise may be substituted for high-intensity muscular activity, particularly when blood flow is reduced and oxygen availability is limited.

  • Lipid metabolism: Lipid is an important source of energy in sustained submaximal exercise (i.e., exercise lasting longer than 40 min).

  • Phosphocreatine stores: These stores, consumed in the purine nucleotide cycle, are vital for very high-intensity exercise of short duration, as other stores are depleted early.

The pathophysiological principles of metabolic myopathies may be simplified into a logical biochemical cascade. For example, presume that a series of reactions proceed forward (from substrate A to H) through stepwise enzymatic reactions (i.e., enzymes 1-7) as follows:

-(1) - -(2)- -(3)- -(4)- -(5)- -(6)- -(7)- H

If enzyme 3 is absent (or deficient), some possible results may be as follows:

  • Accumulation of substrate C

  • Absence (or decrease) in the subsequent substrates (i.e., D, E, ....)

  • Potential disruption in the feedback or rate-limiting effect of one or more of the absent (or deficient) substrate products

  • Potential defect in the transportation of substrate into its target destination


The exact incidence and prevalence of metabolic myopathies are uncertain. They are relatively rare and are much less common than most muscular dystrophies. However, increased awareness and improved diagnostic capabilities have resulted in an increased number of metabolic myopathies diagnosed. Additionally, the presence of an abnormal allele in some patients, such as with myoadenylate deaminase deficiency, may not result in a specific muscular disorder.

Acid maltase deficiency (Pompe disease) is seen in approximately 1 in 40,000 people. McArdle disease affects approximately 1 of 100,000 people. Carnitine palmitoyltransferase deficiency is the most commonly identified metabolic cause of recurrent myoglobulinemia in adults and has been reported in more than 150 patients. Other forms of metabolic myopathies are much less common. Approximately 2% of the population is homozygous for mutant alleles of myoadenylate deaminase, although not all have clinical symptoms.

Mortality and morbidity

Mortality and morbidity rates vary depending on the specific disorder and the extent of enzymatic deficiency (i.e., complete or partial).

  • The mortality rate is high in infantile acid maltase deficiency (Pompe disease). Invariably, the disease is progressive, leading to death within 1–2 years.

  • The juvenile form of acid maltase deficiency is less severe, and most children die by the end of the second decade of life from respiratory complications.

  • In contrast, patients with the adult form of acid maltase deficiency often present with slowly progressive limb-girdle weakness, but some develop early respiratory failure secondary to the involvement of intercostal muscles. The mortality rate of the adult form of acid maltase deficiency is much lower and the morbidity much less severe than those of the other two forms because of a partial deficiency of the enzyme.


Metabolic myopathies have a wide age range of symptom onset. However, most patients present early in life (i.e., infancy, childhood, or young adulthood).


Types of Myopathies

Metabolic myopathies usually manifest as one of the following presentations:

  • Metabolic myopathies presenting with exercise intolerance, cramps, and myoglobinuria

    • Cramps and myalgia may occur after brief exercise or after prolonged physical activity.

    • Glycogen is the main source of energy during brief exercise, while free fatty acids are the most important source of fuel during prolonged exercise. Hence, muscle cramps during strenuous brief exercise are the hallmark of glycogen storage diseases (e.g., McArdle disease). However, in lipid storage disease (e.g., CPT deficiency), muscle cramps and exercise intolerance occur only after prolonged exercise and are worse during fasting.

  • Metabolic myopathies presenting with progressive muscle weakness

    • These metabolic myopathies may mimic limb-girdle muscular dystrophy or polymyositis.

    • They are a common presentation of deficiencies of acid maltase, debrancher enzyme, and carnitine.

Glycogen storage diseases (glycogenoses) are named according to their specific defective enzyme function, an eponym, or by Roman numerals that correlate to the time of their discovery (see Table 1). They are as follows:

  • Glycogenosis type I - Glucose-6-phosphatase deficiency

  • Glycogenosis type II - Acid maltase deficiency (AMD); Pompe disease; autosomal recessive (17q23)

  • Glycogenosis type III - Debrancher enzyme deficiency; Cori-Forbes disease; autosomal recessive (1p21)

  • Glycogenosis type IV - Brancher enzyme deficiency; Andersen disease; autosomal recessive (3p12)

  • Glycogenosis type V - Muscle phosphorylase deficiency; McArdle disease; autosomal recessive (11q13)

  • Glycogenosis type VI - Liver phosphorylase deficiency

  • Glycogenosis type VII - Phosphofructokinase deficiency; Tarui disease; autosomal recessive (12q13.3)

  • Glycogenosis type VIII - Phosphorylase b kinase deficiency; X-linked recessive (Xq12)

  • Glycogenosis type IX - Phosphoglycerate kinase deficiency; X-linked recessive (Xq13)

  • Glycogenosis type X - Phosphoglycerate mutase deficiency; autosomal recessive (7p12-p13)

  • Glycogenosis type XI - Lactate dehydrogenase deficiency; autosomal recessive (11p15.4) (isozyme LDH-M on chromosome 11/ LDH-H on chromosome 12)

  • Glycogenosis type XII - Aldolase A deficiency; autosomal recessive (16q22-q24)



Traditionally, metabolic myopathies are divided into 3 major categories. Note that the mitochondrial myopathies, defined as genetic disorders that encompass abnormalities of the respiratory chain, are usually considered separately and are not discussed in this article.

Glycogen storage diseases

Muscle cells transport glucose from the circulating blood, synthesize glycogen, and then degrade it when energy demands increase. The muscle cell membrane (i.e., sarcolemma) is not freely permeable to glucose; therefore, the use of circulating glucose is limited by its rate of transportation through the sarcolemma. Glycogen is the main form of carbohydrate storage in the muscle. When energy is required for muscle contraction, glycogen is degraded to glucose and provides the energy required for muscle work. Any disturbance in either the synthesis or the degradation of glycogen could result in glycogen storage disease (i.e., glycogenoses). (See Acid Maltase Deficiency and McArdle Disease below.)

Lipid storage diseases

Long-chain fatty acids are the major source of energy for skeletal muscle during sustained exercise or fasting. The passage of these fatty acids through the mitochondrial membrane for beta-oxidation requires their binding with carnitine. Carnitine is synthesized mainly in the liver and actively transported into the muscle against a concentration gradient. Free fatty acids are first converted to acyl-coenzyme A (CoA) compounds by the action of fatty acyl CoA synthetases. Then the long-chain acyl CoA is bound to carnitine by acylcarnitine transferases, such as carnitine palmitoyltransferase I (CPT I). This occurs on the outer mitochondrial membrane.

The new compound passes through the inner mitochondrial membrane by the action of acylcarnitine translocase. Within the mitochondrial matrix, carnitine palmitoyltransferase II (CPT II) splits the transferred compound to free fatty acids and carnitine. In the mitochondria, beta-oxidation of the long-chain fatty acids is then carried out. Carnitine deficiency, deficiency of carnitine palmitoyltransferases, or a defect in beta-oxidation of these fatty acids may lead to myopathies. (See Carnitine Deficiency and Carnitine Palmitoyltransferase Deficiency below.)

Disorders of purine nucleotide metabolism

Adenylate deaminase is an enzyme that catalyzes the transformation of adenosine monophosphate (AMP) to inosine monophosphate (IMP) and ammonia. This reaction mainly occurs during anaerobic exercise to replenish ATP, which is an essential source of energy for the muscles. Myoadenylate deaminase deficiency is the result of a relatively common mutant allele with a heterogeneous clinical presentation. (See Myoadenylate Deaminase Deficiency below.)


Acid Maltase Deficiency

Acid maltase deficiency (Pompe disease; glycogen storage disease II), one of the two most common glycogen storage diseases, is a rare, autosomal-recessive, progressive disorder that affects skeletal and cardiac muscles. It is caused by a deficiency of the intralysosomal enzyme alpha-glucosidase (GAA) that cleaves 1,4- and 1,6-alpha-glycosidic linkages. The GAA gene is linked on the long arm of chromosome 17, and more than 200 mutations have been identified. These multiple genetic mutations may account for the variability of the age of presentation and mode of expression. Pompe disease is commonly divided into infantile form, juvenile form, and adult form. The level of residual activity of the enzyme seen with biochemical analysis correlates with the severity of the disease. The overall incidence is approximately 1 in 40,000-50,000 live births, with a prevalence of 5,000–10,000 cases worldwide.

Infantile acid maltase deficiency

The infantile form is often subdivided into classic infantile and nonclassic infantile forms. The classic form is more severe and presents before 12 months of age and is fatal by age two years, while the nonclassic form presents between 1–2 years of age and has a more attenuated course with a variable survival.

Infants with classic infantile acid maltase deficiency often present within the first few months of life with hypotonia, weak bulky muscles, macroglossia, hepatomegaly, cardiomegaly, and congestive heart failure. Infantile acid maltase deficiency is a progressive systemic disease leading to respiratory failure and feeding difficulties, and death is usually caused by cardiorespiratory failure before the child reaches age two years.

ECG shows short PR interval, high QRS voltage, and left ventricular hypertrophy. Echocardiography demonstrates marked thickening of the interventricular septum and posterior left ventricular wall, left ventricular outflow obstruction, and trabecular hypertrophy.

Pathological studies reveal a massive accumulation of glycogen in the liver, heart, and skeletal muscles. Microscopic examination shows more glycogen deposition in smooth muscle, endothelial cells, lymphocytes, all cellular components of the eye (except the pigmentary epithelium of the iris and retina), and renal glomerular and interstitial cells (sparing the distal tubular cells). Most cells of the brain and spinal cord are affected, but cerebellar and cortical neurons are spared. Motor neurons of the brain stem and spinal cord are most severely involved. Glycogen also accumulates in Schwann cells in the peripheral nerves.

Appropriate biochemical studies establish the correct diagnosis. Acid maltase is deficient in muscle, liver, heart, leukocytes, and cultured fibroblasts.

The nonclassic infantile acid maltase deficiency is similar but milder than the classic type. The cardiomyopathy and hepatomegaly are mild. The hypotonia and weakness are usually progressive and death is variable.

Juvenile acid maltase deficiency

Juvenile acid maltase deficiency presents in late infancy or early childhood (ages 2-18 y). Motor milestones are delayed, and the weakness is usually greater in proximal than distal muscles. Respiratory muscles tend to be involved selectively early in the course of the disease. Enlargement of calf muscles may occur, thereby confusing the presentation with muscular dystrophies. There is usually no cardiac involvement. Rarely, the liver and tongue are enlarged. Juvenile acid maltase deficiency has been reported to be associated with basilar artery aneurysm, which may lead to subarachnoid hemorrhage.

The disease progresses slowly, and the usual cause of death is usually due to respiratory failure. Death is variable, usually in the second decade of life, but patients surviving longer than 20 years have been reported.

Pathological studies reveal that glycogen excess in muscle is relatively less marked than in infantile acid maltase deficiency. Autopsy studies show little, if any, increase in glycogen in the liver, heart, skin, and nervous system. Autopsies of patients who died of subarachnoid hemorrhage show abnormal lysosomal storage material in the smooth muscle fibers of the arterial vessel wall.

Biochemical testing confirms deficiency of acid maltase enzyme in skeletal muscle, heart, liver, and cultured fibroblasts. Sometimes, residual enzyme activity is detected.

Adult acid maltase deficiency

Adult acid maltase deficiency presents after age 20 years, either as a slowly progressive myopathy, which clinically mimics polymyositis or limb-girdle muscular dystrophy, or with symptoms of respiratory failure, or both. The weakness affects the proximal muscles more than the distal muscles. Selective muscle weakness is not uncommon, e.g., the sternal head of the pectoralis major often is affected more than the clavicular head and the thigh adductors are affected more severely than other lower limb muscles. Scoliosis affects about 10% of patients. Atrophy of muscles, when present, is proportionate to weakness. The deep tendon reflexes diminish and disappear with the progression of weakness. About 30% of patients present with respiratory failure. An increased association with basilar artery aneurysms exists.

Diagnosis of acid maltase deficiency

Laboratory values of creatine kinase (CK) are elevated in 95% of patients, highest in the infantile form, usually 10 times normal. Abnormal liver function tests (mostly AST and ALT) are seen in most patients but may be absent in the adult form.

ECG and echocardiography abnormalities are most common in the infantile forms; they can occasionally be seen in the juvenile form but are rare in the adult form. High QRS complex voltage and short PR interval are the most common findings. Echocardiography demonstrates marked thickening of the interventricular septum and posterior left ventricular wall, left ventricular outflow obstruction, and trabecular hypertrophy.

Usually, nerve conduction study findings are normal. Needle electromyography (EMG) may reveal increased insertional activity and/or myotonic discharges without clinical myotonia. Short-duration, low-amplitude motor unit potentials may be detected in proximal muscles.

Muscle imaging, using CT and MRI, are useful adjunctive studies in acid maltase deficiency. Selective atrophy and fatty degeneration of the hamstrings and paraspinal muscles are useful findings.

Magnetic resonance spectroscopy (MRS) studies the differences in chemical shifts of water, glycogen, and lipids in the proton (1H) spectra or lipids and glycogen in the carbon (13C) spectra. Even though MRS is highly sensitive and is an alternative to MRI, it is limited in spatial resolution compared to MRI. [6, 7]

Short-tau inversion recovery (STIR) imaging was reported in some studies to have shown hyperintensities in late-onset Pompe disease patients, particularly in juvenile presymptomatic and symptomatic patients. [8, 9]

Diffusion tensor imaging (DTI) is highly sensitive to the changes in water diffusion and could detect changes in the disease progression earlier than the muscles are replaced by fat. [10]

Magnetization transfer (MT) imaging is a different technique that can be used to attain contrast between tissues when 1H protons are present at different levels. MT imaging can provide a quantitative assessment of tissue pathology, enhancing the contrast between the healthy and pathologic tissue, e.g., inflammation, infarction, ischemia, white matter edema, and demyelination. MT ratio is sensitive to any changes in muscle water distribution and lipid content in neuromuscular disorder patients, and hence it can be used to assess muscle fiber loss in Pompe disease. [11, 12]

Muscle biopsy shows a vacuolar myopathy in all 3 forms of acid maltase deficiency. In the infantile form, all muscles and fibers contain many, often confluent, vacuoles, which result in a lacework appearance. In juvenile and adult acid maltase deficiency, vacuoles are less numerous and tend to be smaller, and may only be present in clinically affected muscles. The vacuoles contain PAS-positive material and stain intensely for acid phosphatase, another lysosomal enzyme. Electron microscopy shows that much of the glycogen is contained within single membrane-limited lysosomal sacs. On biochemical analysis, glycogen content is massively increased in muscle with infantile acid maltase deficiency, often reaching a level 10 times higher than normal. Muscle glycogen concentrations are generally only slightly increased in juvenile acid maltase deficiency and may be normal in adult acid maltase deficiency.

Pathologic examination reveals vacuolar myopathy with an increased amount of glycogen and increased activity of acid phosphatase within these vacuoles. However, a normal muscle biopsy has been reported in up 1/4 of cases with Pompe disease.

The diagnosis is confirmed through biochemical analysis of GAA enzyme activity. [13] This could be performed on lymphocytes, skin fibroblasts, muscle tissue, or dried blood spots (DBS). DBS is relatively simple, quick, and convenient testing readily available for screening newborns. If GAA is reduced on DBS, the criterion standard test should be performed for confirmation. This is a GAA assay in cultured skin fibroblasts.

Important clinical clues that direct attention to the diagnosis of acid maltase deficiency are as follows:

  • Muscle weakness with firm consistency of the muscle on palpation

  • Selective involvement of the respiratory muscles and diaphragm

  • Myotonic discharges on needle EMG without clinical myotonia

  • Organomegaly, especially in children

  • Selective atrophy and fatty degeneration of the hamstrings and paraspinal muscles


The management of acid maltase deficiency requires a multidisciplinary team that includes, at least, a neurologist, cardiologist, pulmonologist, metabolic disease specialist, dietitian, and genetic counselor. [14]

  • Dietary management: A high-protein diet has been suggested based on the rationale that muscle damage is caused partially by muscle proteolysis. A high-protein diet counteracts muscle protein depletion by supplying increased amino acid substrates. A proposed diet consists of 25-30% protein, 30-35% carbohydrates, and 35-40% fat. Compliance with this diet has been historically poor, mostly because of weight gain.

  • Physical training: Dietary management offers better results when combined with physical training, which helps in decreasing glycogen deposition, increasing fat use, and assists in weight management. A daily aerobic exercise program, supervised by a physical therapist, is recommended.

  • Enzyme replacement therapy (ERT) [15, 16, 17, 18, 19] : Intravenous recombinant acid alpha-glucosidase (rhGAA) was obtained from the milk of transgenic rabbits and delivered intravenously. The rhGAA (Myozyme) is a novel and effective therapy in the infantile form of acid maltase deficiency. Most infants treated lived beyond the critical age of 1 year. Myozyme not only improves cardiac disease and motor development but also prolongs survival. An improvement in left ventricular mass, cardiac function, skeletal muscle function, and histological appearance of skeletal muscle was noted. [20] The recommended dose is 20 mg/kg infusion biweekly. Adverse effects include fever and anaphylactic reactions. With the approval of ERT, and the success of immunomodulation to prevent the antibody responses to ERT, along with newborn screening (NBS) and a multidisciplinary management approach, patients with infantile Pompe disease are living longer and a new phenotype of survivors is emerging. [15, 21, 22]

  • The US Food and Drug Administration has now designated rhGAA (Myozyme) as an orphan drug. Ongoing studies evaluating the efficacy and safety of Myozyme in the adult form of acid maltase deficiency can be found at


McArdle Disease

McArdle disease (myophosphorylase deficiency; glycogenosis type V), the other most common glycogen storage disease, is a pure myopathy caused by a genetic defect of the skeletal muscle isoform of glycogen phosphorylase. It is usually inherited as an autosomal recessive disorder but sometimes as a dominant trait. It is encoded by a gene on chromosome band 11q13. More than 30 different mutations have been identified to date.

McArdle disease usually begins in childhood or early adolescence, typically with attacks of muscle cramps and pain and, in 50% of patients, rhabdomyolysis and myoglobinuria. Many patients with exercise-induced muscular pain or cramps are able to continue with their activities after 10 minutes of exercise (ie, second-wind phenomenon). Fixed muscle weakness, usually mild, is common in older patients. Rarely, McArdle disease may present in adulthood with muscle weakness.

CK levels at rest are almost always elevated in McArdle disease. Patients may have an elevated potassium level during exercise. However, a key diagnostic feature is the absence of a rise in serum venous lactate during the Forearm ischemic exercise test in Workup. Also, the cramp, when recorded by needle EMG, is silent (contracture). Definitive diagnosis requires histochemical and biochemical testing showing the enzyme deficiency in muscle.

McArdle disease is a common cause of recurrent rhabdomyolysis and myoglobinuria, second only to CPT deficiency. However, differentiating these two disorders requires a detailed history of the characteristics of exercise intolerance (see Table 2).

Specific effective treatment is not available. Situations that precipitate myoglobinuria, such as vigorous exercise, should be avoided.

A diet high in complex carbohydrates [23] (65%), such as rice; bread; pasta; cereals; vegetables; and fruit, and low in fat (20%) is effective by ensuring sufficient and constant blood glucose derived from liver glycogen stores. [24] A high-protein diet was thought to be helpful, based on the theory that branched-chain amino acids may be used as a fuel alternative to glycogen. However, this diet has shown no benefit and, in some patients, expresses exercise impairment rather than improvement, possibly since the branched amino acids lower the levels of free fatty acids. Low-dose creatine [25] (60 g/kg/d) is useful, but high-dose (150 mg/kg/d) may exacerbates the muscle crisis. Dietary supplement carnitine has shown a significant increase in ischemic, isometric forearm exercise capacity. However, no improvement occurred in the nonischemic isometric exercise or in cycle exercise. These results are encouraging for those studying other possible treatments.

Paradoxically, regular aerobic, dynamic exercise [26, 27] at low or moderate intensities is safe and has been proposed to prevent deconditioning and to promote overall cardiorespiratory health and circulatory capacity of blood-borne fuels that may promote an increase in mitochondrial biogenesis.


Other Less Common Glycogenoses

Table 1. Other Less Common Glycogenoses (Open Table in a new window)


Clinical Features

Laboratory Findings


Phosphofructokinase (PFK) deficiency (glycogenosis VII, Tarui disease)

Exercise intolerance


Mild hemolytic anemia

Indistinguishable clinically from McArdle disease, except that glucose intake prior to exercise does not improve (or worsens symptoms)

Normal muscle strength, except in old age

Hemolytic anemia

CK elevated

Forearm exercise test - No rise in lactate

PFK absent in muscles

Autosomal recessive trait

Gene location - Band 1cenq32

Male predominance (unexplained) in Ashkenazi Jews

Phosphoglycerate mutase deficiency (glycogenosis X)

Exercise intolerance


Normal muscle strength

CK level elevated

Forearm ischemic exercise test - Reduced (not absent) rise in lactate

Enzyme - Reduced in muscles

Autosomal recessive trait

Gene location - Band 7p12-13

Predominantly African American

Lactate dehydrogenase deficiency (LDH) (glycogenosis XI)

Excessive fatigue and exercise intolerance, especially for maximal exercise


Normal muscle strength

CK level elevated (with normal serum LDH)

Forearm ischemic exercise test - No rise in lactate

A normal rise in pyruvate

Absent or reduced LDH in muscles and RBCs

Autosomal recessive trait

Gene location - Band 11p15.4

Phosphoglycerate kinase (glycogenosis IX)

Two forms: (1) seizure, mental retardation, and (2) exercise intolerance and myoglobinuria with slowly progressive weakness

Hemolytic anemia

CK level elevated

Forearm ischemic exercise test - No rise in lactate level

EMG usually normal

An absent or reduced enzyme in muscles

X-linked recessive trait

Gene location - Band Xq13


Carnitine Deficiency

Whether carnitine deficiency, a lipid storage disease, manifests as a spectrum of disorders or is two separate entities remains a matter of debate. However, most clinical cases of the deficiency are ascribed to one of the following two types of carnitine deficiencies.

Myopathic carnitine deficiency

Myopathic carnitine deficiency is attributed to impairment in the active transportation of carnitine from the plasma into muscle cells. Hence, the carnitine level is reduced in muscles and is normal or slightly decreased in plasma and liver.

Clinically, carnitine deficiency manifests during childhood or early adult life as progressive proximal muscle weakness, exertional myalgias, or, rarely, myoglobinuria.

Pathologically, the muscle shows an increased number of lipid droplets, especially in type I muscle fibers. Electron microscopy often confirms the abnormal lipid accumulation with minimal or no increase of mitochondria.

Systemic carnitine deficiency

Systemic carnitine deficiency is attributed to impaired hepatic biosynthesis and/or excessive renal excretion of carnitine. Plasma, liver, and muscle carnitine levels are reduced.

The disorder usually manifests in infancy or childhood as progressive muscle weakness or episodes of hepatic and cerebral dysfunction precipitated by sustained exercise or fasting. This often simulates Reye syndrome. Cardiomyopathy and congestive heart failure are common and may be the direct cause of death.

Pathologically, the muscle shows a marked increase in the number of lipid droplets, mainly in type I muscle fibers.

Carnitine deficiency in muscle and plasma is not specific for carnitine deficiency disorders. It may be encountered in genetic diseases (e.g., mitochondrial myopathies, advanced cases of X-linked muscular dystrophies) or acquired disorders (e.g., patients on hemodialysis or valproate therapy).


Carnitine Palmitoyltransferase Deficiency

Carnitine palmitoyltransferase (CPT) deficiency, a lipid storage disease, is the most commonly identified metabolic cause of recurrent myoglobinuria in adults. Men are affected more than women.

Symptoms start soon after puberty, but often patients come to medical attention following an attack of rhabdomyolysis and myoglobinuria. Patients often have episodes of muscle pain, stiffness, and tenderness, usually without frank cramps. The attacks are triggered by prolonged exercise, especially in fasting conditions.

Patients with CPT deficiency often have a history of recurrent episodes of rhabdomyolysis and myoglobinuria dating back to childhood. When severe, myoglobinuria may result in acute renal failure. Most of the episodes of rhabdomyolysis are precipitated by prolonged exercise, especially when combined with exposure to cold weather or fasting. Some episodes are precipitated by concurrent infection. The patients usually have no warning signs, like cramps, as in glycogenoses. Rhabdomyolysis results in marked elevation of serum CK and the release of myoglobin into the plasma. When myoglobin is excreted through kidneys, it gives the urine a distinct dark color (cola color), which is characteristic of myoglobinuria.

Two CPT enzymes, CPT I and CPT II, exist. [28] Both are essential in the transport of long-chain fatty acids from the cytosol to the mitochondria. CPT II deficiency is more common and is inherited as an autosomal recessive trait (gene is located on band 1p32).

In addition to the adult muscular form, CPT I or CPT II deficiency may cause a rare but severe and fatal disease in the neonatal period and during early infancy. This is characterized by hypoketotic hypoglycemia and multiple organ malformations (eg, microgyria, neuronal heterotopia, renal cystic dysplasia, facial dysmorphism). Another rare disorder linked to CPT II deficiency is manifest in infancy as hypoketotic hypoglycemia, hepatomegaly and hepatic failure, cardiomegaly and arrhythmias, lethargy, seizure, and coma.

A more severe CPT deficiency (CPT I) is related to a separate gene that has been mapped to human chromosome band 1p32 by Gellera et al. [29]

Diagnosis of carnitine palmitoyltransferase deficiency

Usually, the diagnosis is suggested by the typical history of exercise-induced myalgia (the most common symptom), with recurrent myoglobinuria, and is supported by a normal ischemic exercise test result. However, myoglobinuria has been reported to be missing in 21% of patients, so it is not essential for the diagnosis. [30] Usually, CK level is normal between attacks. Plasma carnitine level may be increased in CPT I deficiency, but it is usually normal in CPT II. Patients will have a high ratio of palmitoylcarnitine + oleocarnitine/acetylcarnitine. Findings of electrodiagnostic studies, including needle EMG, as well as the morphological and histochemical studies on muscle biopsy, may be normal, which does not exclude the diagnosis of CPT deficiency. CPT deficiency should be differentiated from glycogen storage diseases, particularly McArdle disease (Table 2).

The final diagnosis usually is established through a biochemical demonstration of CPT deficiency in the muscle or by identification of the genetic defect. Earlier studies suggested that a decrease of CPT level in cultured fibroblasts was a diagnostic test. However, recent advances have discovered that cultured fibroblasts harbor the liver isoform but not the muscle isoform of CPT.


No specific treatment for CPT deficiency exists. However, preventive measures, such as a high-carbohydrate and low-fat diet and frequent small meals, may be helpful in alleviating muscle pain. Carbohydrate supplements also are advised before and during anticipated exercise. Prolonged exercise should be avoided to prevent attacks of rhabdomyolysis. Recently, a diet that is rich in polysaccharides (although not glucose) has been shown to improve exercise intolerance in those with CPT II. [31]


Myoadenylate Deaminase Deficiency

Most patients with myoadenylate deaminase (MAD) deficiency, a disorder of purine nucleotide metabolism, are asymptomatic. The most commonly reported complaints are muscle cramps, exercise intolerance, fatigue, stiffness, and pain after exercise. Whether this deficiency is clinically significant or is an epiphenomenon is not clear; approximately 3% of muscle biopsies studied have an MAD deficiency. Many of these biopsies were performed on patients with specific neuromuscular disorders and symptoms not consistent with MAD deficiency.


Differential Diagnosis

Differential diagnosis of infantile acid maltase deficiency

Disorders with similar clinical presentations should be considered in the differential diagnosis, including the following:

  • Infantile spinal muscular atrophy (Type I, Werdnig-Hoffman disease)

  • Cytochrome c oxidase enzyme deficiency syndromes

  • Debranching enzyme deficiency

  • Congenital myopathies (nemaline, centronuclear, central core)

  • Congenital muscular dystrophies

  • Inflammatory myopathies (polymyositis)

  • Secondary carnitine deficiency syndromes associated with organic acidurias

  • Fatal infantile cardioskeletal myopathy without acid maltase deficiency

  • Danon disease

Differential diagnosis of juvenile and adult acid maltase deficiency

Late-onset acid maltase deficiency may be confused with the following because of the proximal weakness:

Table 2. Differences Between McArdle Disease and CPT Deficiency (Open Table in a new window)


McArdle Disease (Glycogenosis V)

CPT Deficiency

Metabolic defect

Glycogen storage

Lipid storage


Usually cramps with short strenuous exercise

Usually myalgia and tenderness (without cramps) with prolonged exercise, worse with fasting

Second-wind phenomenon



Recurrent myoglobinuria

Less frequent (50% of patients)


CK at rest



Ischemic forearm exercise test

Absence of a normal increase in lactate level


Muscle biopsy

Usually shows glycogen accumulation

May be normal

Gene location

Band 11q13

Band 1p32 (CPT II)



Lab studies

See the list below:

  • Serum CK level may be elevated modestly in metabolic myopathies, and the level may fluctuate significantly in patients prone to rhabdomyolysis.

  • CBC and reticulocyte count may reveal signs of hemolytic anemia in patients with phosphofructokinase deficiency.


Needle EMG may show myotonic discharges in acid maltase deficiency, a relatively specific finding in patients with suspected metabolic myopathy. In general, needle EMG may reveal short-duration, low-amplitude motor unit action potentials. However, EMG readings may be normal in many metabolic myopathies.

Forearm ischemic exercise test

McArdle introduced the forearm ischemic exercise test [13] in 1951. [32] It is a useful screen to detect a possible enzymatic defect in the glycogenolytic and glycolysis pathways.

  • Technique

    • Insert an indwelling catheter in a superficial antecubital vein.

    • Draw blood for lactate and ammonia as baseline samples.

    • Apply a sphygmomanometer on the arm to be tested and raise its pressure slightly above the systolic blood pressure.

    • Ask the patient to exercise repetitively for 1 minute by using an ergometer or by making a hard fist around a rolled-up sphygmomanometer cuff.

    • Assess the power generated by the patient by checking the ergometer or noting the rise in the mercury column.

    • Stop exercise, deflate the sphygmomanometer, and draw blood samples at 1, 3, 6, and 10 minutes after 1 minute of exercise for lactate and ammonia.

  • Remarks

    • Some clinicians prefer to perform the test without producing ischemia (ie, do not apply sphygmomanometer cuff on the arm). This renders the test less painful with less potential for cramps. Advocates of the test have claimed positive results without producing ischemia in patients with glycogenoses.

    • In a series of patients with suspected glycogenosis, applying pressure almost equal to the systolic pressure resulted in the test being less painful with reliable results in all the tested children except 2 who were younger and less cooperative.

  • Findings

    • In healthy subjects, lactate level should increase to 3-5 times the basal level in the first 2 samples after exercise and then decrease gradually to the baseline.

    • Ammonia levels also should increase after exercise. Ammonia level is useful not only as a monitor of sufficient exercise but also as a test for myoadenylate deaminase deficiency (MAD).

    • In glycogen storage diseases, such as McArdle disease, serum lactate levels do not increase after exercise (ie, flat lactate curve), while in lipid storage diseases, both lactate and ammonia levels increase in a normal fashion.

    • In myoadenylate deaminase deficiency, ammonia does not increase (ie, flat ammonia curve).

    • On rare occasions, 2 enzyme defects are found in the same patient, such as myophosphorylase or phosphofructokinase defect along with adenylate deaminase defect. However, when lactate and ammonia are reduced (ie, flat lactate and ammonia curves), this is usually is due to poor muscular effort during exercise testing.