Diseases of Muscle and the Neuromuscular Junction Part 3

Metabolic Myopathies

Principles of muscle energy

As a group, the metabolic myopathies are characterized by deficiency of energy production caused by disorders of glyco-gen, lipid or mitochondria.

The two major sources of energy for muscle are glycogen and fatty acids whose metabolic pathways converge into acetyl coen-zyme A (acetyl-CoA) for final oxidation within the mitochondria through the Krebs cycle and the respiratory chain.54,55 At rest, muscle energy is mostly derived from oxidation of free fatty acids (FFAs). During high-intensity aerobic exercise, glycogen is the main source of fuel for oxidative phosphorylation. Muscle glycogen stores are depleted after 90 minutes of exercise. If exercise is prolonged, utilization of FFAs and blood glucose increases. Because the availability of FFAs from adipose tissue is almost unlimited, a healthy person can perform moderate exercise for many hours. In patients with metabolic myopathies, symptoms become evident during activities that require increased metabolic demands, such as exercise. Metabolic myopathies result from defects in the metabolism and utilization of glycogen, glucose, or lipid by the muscle. The myopathies caused by glycogen and glucose utilization are categorized according to the sequence of the enzyme defects along the glycogenolytic or glycolytic pathways [see Figure 2] and characterized by two main presentations: (1) exercise intolerance, myalgia, cramps, and, finally, myoglo-binuria; and (2) fixed, progressive weakness.


Muscle Phosphorylase Deficiency

Muscle phosphorylase deficiency (also known as McArdle disease) is the prototypical glycogenosis: glycogen breakdown is inhibited, which leads to pyruvate shortage and impaired energy output [see Figure 2]. It is the second most common cause of recurrent myoglobinuria after carnitine palmitoyl-transferase (CPT) deficiency.

Diagnosis This autosomal recessive disease presents as exercise intolerance and myoglobinuria in patients older than 15 years. If patients rest briefly after exercise-induced myalgia and stiffness, they can resume activity with better endurance (second-wind phenomenon), owing to increased mobilization and utilization of FFAs and glucose. Fixed muscle weakness may develop later in life. The resting serum CK level is often elevated. The inability to produce venous lactate after exercise has been traditionally examined with the ischemic forearm exercise test. This test, however, is falling out of favor as a diagnostic tool because it produces false positive results, is not specific, can be painful, and may result in focal muscle damage. A nonischemic exercise test is of equal diagnostic value and does not have the drawbacks of the ischemic test. Muscle biopsy shows an absence of phosphorylase, the presence of subsarcolemmal vacuoles, and increased glycogen accumulation. The diagnosis is confirmed by biochemical analysis of muscle and molecular analysis of blood cells. The defect is caused by mutations in the muscle isoform of phosphorylase on chromosome 11q13 and can be detected in the leukocytes in more than 90% of patients.

Treatment No treatment is available for McArdle disease, but aerobic exercise training and a high-protein diet can be helpful. Vitamin B6 supplementation has also been reported to be helpful. The results of a controlled trial indicate that creatine supplementation may improve muscle function.56 Most encouraging was the result from a recent study showing that 75 g of sucrose before exercise markedly improved exercise tolerance and may protect against exercise-induced rhabdomyolysis.57 Experimentations with gene therapy are ongoing.

Phosphofructokinase Deficiency

Phosphofructokinase (PFK) is an enzyme with three genetically distinct structural subunits: M, expressed in muscle, heart, and brain; L, expressed in liver and erythrocytes; and P, expressed in platelets. PFK deficiency is an autosomal recessive disease. Distinct mutations in the M subunit, localized to chromosome 1, cause myopathic symptoms and chronic hemolysis and an increased serum bilirubin level and reticulocyte count.

Diagnosis Because PFK deficiency is a glycolytic defect [see Figure 2], the functional consequences of PFK deficiency are similar to those observed in McArdle disease. PFK deficiency should be suspected in patients who experience exercise intolerance, nausea, and myoglobinuria. Fixed muscle weakness may develop later in life. A long history of mild, compensated hemolysis, a high reticulocyte count, a high bilirubin level, and hyperuricemia also indicate PFK deficiency, especially in certain ethnic groups, such as Japanese and Ashkenazi Jews. The diagnosis is confirmed by biochemical studies on muscle and molecular analysis of blood cells.

Treatment There is no specific treatment for PFK deficiency. Patients should avoid high-carbohydrate meals. Recently, a ke-togenic diet has been advocated.

Phosphoglycerate Kinase Deficiency

Phosphoglycerate kinase (PGK) deficiency is a rare X-linked recessive disorder that presents with exercise intolerance, episodes of myoglobinuria, hemolytic anemia, myopathy, and, occasionally, mild mental retardation54,55 [see Figure 2].

Phosphoglycerate Mutase Deficiency

Phosphoglycerate mutase (PGAM) deficiency is a very rare disease that affects only muscle. In the United States it has only been identified in African Americans [see Figure 2].

Acid Maltase Deficiency

Acid maltase deficiency (AMD) is an autosomal recessive glycogen storage disease caused by deficiency of a-glycosidase, an enzyme encoded in a gene localized to chromosome 17q23.55 Mutations or small deletions that cause abnormal splicing affect a-glycosidase expression.

There are three clinical forms of AMD: infantile, childhood, and adult.59,60 The infantile form (Pompe disease) presents within the first few months of life as hypotonia, weakness, and enlargement of the heart, tongue, and liver; respiratory and cardiovascular changes lead to death before 2 years of age.

In the childhood form of AMD, patients present with a my-opathy characterized by delayed motor milestones, proximal muscle weakness, respiratory muscle involvement, and calf enlargement. The disease leads to death by the second decade of life.

The adult form of AMD manifests in persons older than 20 years as a proximal muscle weakness that resembles polymyosi-tis or limb-girdle dystrophy. Respiratory muscle weakness may be the presenting symptom in one third of AMD cases in adults. Accumulation of glycogen occurs predominantly in the muscle. However, the enzyme is deficient in muscle, liver, heart, and cultured fibroblasts. Patients have elevated serum CK levels; EMG shows prominent myotonic discharges (without clinical myoto-nia), especially in the paraspinal muscles; and the muscle biopsy shows multiple vacuoles with high glycogen concentrations that react strongly with acid phosphatase, indicative of increased lysosomal activity. Because the utilization of glycogen and glucose is not compromised [see Figure 2], AMD causes fixed weakness but not exercise intolerance or myoglobinuria. The muscle fiber undergoes an autophagic process because of abnormalities in the lysosomes.

Scheme of glycogen metabolism, glycolysis, and utilization of fatty acids. Some of the most common myopathies are those that result from deficiencies in the enzymes acid maltase, muscle phosphorylase, phosphofructokinase, and carnitine palmitoyltransferase.

Figure 2 Scheme of glycogen metabolism, glycolysis, and utilization of fatty acids. Some of the most common myopathies are those that result from deficiencies in the enzymes acid maltase, muscle phosphorylase, phosphofructokinase, and carnitine palmitoyltransferase.

The diagnosis is confirmed by biochemical assay of the enzyme level in the muscle, cultured fibroblasts, lymphocytes, or urine. Molecular genetic analysis is now available. There is no specific treatment.

Other Rare Glycogenoses

Rare muscle glycogenoses include disorders caused by a deficiency of specific muscle enzymes; these include lactate dehy-drogenase (LDH), |-enolase deficiency, debrancher enzyme deficiency, brancher enzyme deficiency, and aldolase deficiency.55,56

Lipid storage myopathies

During sustained exercise, long-chain fatty acids (LCFAs) are the main energy source for the muscle. LCFAs are derived from food or, during fasting conditions, from adipose tissue. LCFAs first need to be transported to the mitochondria for oxidation; their transfer across the inner mitochondrial membrane requires L-car-nitine and two enzymes, the carnitine palmitoyltransferases (CPT I and CPT II), which are located in the outer and the inner mito-chondrial membranes, respectively. Inside the mitochondria, a-ox-idation is facilitated first by the acyl coenzyme A (acyl-CoA) dehy-drogenases and then by the transfer of electrons through flavopro-teins to the respiratory chain proteins.54,55 Lipid storage myopathies are caused by impaired fatty acid oxidation by the mitochondria, which results from defects in (1) carnitine and CPT, impairing the transport of fatty acids across the mitochondrial membrane, (2) the enzymes associated with |-oxidation, and (3) the respiratory chain proteins and electron-transferring flavoproteins.

Carnitine Deficiency

Carnitine is mostly derived from the diet, but 25% is synthesized in the liver from lysine and methionine. Carnitine is crucial for the oxidation of LCFAs.54 The burden of carnitine deficiency is dysfunction of the liver, heart, and muscle tissues, which are highly dependent on LCFA oxidation.

Primary carnitine deficiency (PCD) is an autosomal recessive disorder caused by mutations in the SLC22A5 gene, which encodes the sodium ion-dependent cation transporter-2 (OCTN2). These mutations cause a deficiency in the number of functional high-affinity carnitine receptors, which results in defects in carni-tine transport across cell membranes.54 PCD is an uncommon disorder seen more often in childhood.

The most common causes of carnitine deficiency are secondary. They result from (1) defective p-oxidation, which is associated with organic acidurias; (2) mitochondrial dysfunction and defects in the respiratory chain proteins; (3) renal disease, such as Fanconi syndrome, nephropathic cystinosis, or chronic he-modialysis; and (4) treatment with drugs, especially zidovudine (AZT) and valproate.

Diagnosis Patients with PCD experience progressive car-diomyopathy, episodes of hypoketotic hypoglycemia (because of hepatic dysfunction), and proximal myopathic weakness. Lipids accumulate in the muscle, forming small lipid droplets.

Treatment Carnitine supplementation has produced variable treatment results.

Carnitine Palmitoyltransferase Deficiency

In infants, CPT I deficiency manifests as Reye syndrome, with hepatic encephalopathy, hypoketotic hypoglycemia, and hyper-ammonemia. In adults, carnitine deficiency syndrome most often results from CPT II deficiency, caused by mutations in the gene for CPT II, located on chromosome 11p11-p13.55 CPT deficiency represents the most common cause of myoglobinuria in young adults. Patients present with attacks of muscle stiffness, cramps, myalgia, and myoglobinuria hours after prolonged or sustained exercise, especially after fasting or when muscle energy depends on utilization of LCFAs and not on the utilization of glycogen or glucose. CPT II-deficient patients do not have reduced exercise tolerance, second-wind phenomena, or warning signs of myalgia that prevent them from further exercise. Between attacks, muscle strength and the serum CK level are normal. Diagnosis is established by measuring CPT II enzyme activity in the muscle or by genetic testing.

It is unclear why CPT deficiency causes intermittent attacks of myoglobinuria and why lipid does not accumulate in the muscle. There is no therapy to prevent myoglobinuric attacks. However, a high-carbohydrate and low-fat diet, frequent meals, and extra carbohydrate intake before and during sustained exercise are recommended.

Mitochondrial Myopathies and Encephalopathies

Mitochondrial myopathies and encephalopathies constitute a diverse group of disorders that affect not only muscle and the nervous system but also other organs. These disorders are characterized by a primary defect in mitochondrial energy output. Genetic defects of mitochondrial energy enzymes may be caused by either nuclear DNA genetic mutations or mitochondrial DNA (mtDNA) mutations. Three types of mutation are responsible for this varied group of diseases: (1) sporadic mtDNA mutations, which cause large-scale deletions of mtDNA, are responsible for multisystem disorders (e.g., Kearns-Sayre syndrome) that can affect the heart, brain, endocrine system, and gastrointestinal tract; (2) maternally inherited mtDNA point mutations, which affect the brain and muscle, cause such disorders as MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes), MERRF syndrome (myoclonic epilepsy and my-opathy with ragged-red fibers), and Leber hereditary optic neuropathy; and (3) tissue-specific depletion of mtDNA causes a mul-tiorgan syndrome that can affect muscle, liver, kidney, and brain.


The main function of mitochondria is to generate energy for the cell by producing adenosine triphosphate (ATP) through ox-idative phosphorylation (OXPHOS). OXPHOS relies on five enzymatic complexes, which include coenzymes and transition metal components (iron, copper), located in the inner mitochon-drial membrane. These complexes (designated as I, II, III, IV [cy-tochrome-c oxidase], and V) sequentially collect and transfer electrons, derived from the catabolism of fats, proteins, and carbohydrates, to O2. The coupling of oxidation and phosphoryla-tion, which occurs via a proton gradient across the inner mito-chondrial membrane, enables the phosphorylation of adenosine diphosphate (ADP) to produce ATP.

Mitochondria contain their own extrachromosomal DNA (mtDNA), which is distinct from nuclear DNA. It is a double-stranded, circular molecule that encodes 24 structural RNAs, 2 ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), and 13 mRNAs. The mRNAs encode several polypeptides of the respiratory chain. The remaining subunits of OXPHOS and other mitochondrial proteins are encoded by nuclear genes. The organization of mtDNA is highly compact; it has no introns. As a result, random mutations in mtDNA usually strike a coding sequence and frequently cause disease. In addition, mtDNA is susceptible to oxygen-radical damage because of its proximity to oxygen-radical production by OXPHOS and because of its minimal repair mechanisms.62-65 The entire mtDNA of each person is exclusively maternally inherited (nonmendelian inheritance) because the sperm cell contributes only its nuclear DNA to the zygote during fertilization. Occasionally, diseases of OX-PHOS may occur as the result of mutations in some of the nuclear-encoded OXPHOS genes; such diseases follow a mendelian inheritance pattern.

Muscle biopsy results of patients with OXPHOS defects are abnormal and reveal ragged-red fibers on trichrome stain, or ragged-blue fibers on succinate dehydrogenase stain. These findings result from the accumulation of mitochondria in the periphery of the muscle fibers, and accumulation of fibers that are negative for cytochrome-c oxidase. On electron microscopy, the mitochondria have paracrystalline inclusions or abnormal cristae.44 Specific mutations, deletions, or depletions are detected by study of the mtDNA.

Sporadic mtdna deletions

Kearns-Sayre Syndrome

Kearns-Sayre syndrome presents in patients younger than 20 years as ophthalmoplegia, ptosis, retinitis pigmentosa, and myo-pathic weakness. Short stature, cardiac conduction defects, elevated levels of cerebrospinal fluid protein, cerebellar syndromes, sensorineural hearing loss, and elevated serum lactate levels are common. Muscle biopsy reveals ragged-red fibers. In persons older than 20 years in whom ophthalmoplegia is the predominant phenotype, KSS is classified as chronic progressive external ophthalmoplegia (CPEO).

KSS and the more limited CPEO are characterized by a single, large mtDNA deletion that is between nine and 50 base pairs. Most often, the deletion occurs sporadically and is rarely maternally inherited. OXPHOS is defective, and the levels of activity of complex I and complex IV are reduced. Variants of CPEO, which are characterized by multiple mtDNA deletions in the nuclear DNA-encoded genes of OXPHOS, may be transmitted in an au-tosomal dominant or recessive fashion.

Mitochondrial Neurogastrointestinal Encephalomyopathy

A special form of autosomal recessive CPEO is a multisystem syndrome known as MNGIE (mitochondrial neurogastrointesti-nal encephalomyopathy). Disease can occur in persons 20 to 60 years of age. Patients present with progressive external ophthal-moplegia accompanied by intestinal dysfunction, peripheral neuropathy, and leukoencephalopathy. Patients with MNGIE have increased serum levels of thymidine and decreased activity of thymidine phosphorylase on leukocytes; these findings, along with mutations in the thymidine phosphorylase nuclear gene, which impair the replication and repair of mtDNA, confirm the diagnosis.

Maternally inherited mtdna point mutations

MELAS Syndrome

Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes combine to form the MELAS syndrome. Muscle biopsies in affected patients reveal ragged-red fibers. Patients may also have hearing loss, short stature, cardiomyopathy, diabetes, or pigmentary retinal degenerations resembling KSS or CPEO. As many as 80% of patients have mtDNA point mutations in the tRNA leucine gene. These mutations, like the other mtDNA mutations, are heteroplasmic, meaning that normal and mutant mtDNA coexist in a cell. A cell normally contains between two and 10 mtDNA molecules, which allows an otherwise lethal mutation (i.e., lethal impairment of OXPHOS) to persist in viable organisms.

MERRF Syndrome

The MERRF syndrome consists of myoclonic epilepsy and myopathy with ragged-red fibers. In addition, ataxia, dementia, deafness, weakness, wasting, and cardiac abnormalities are common, although their expression is variable and depends on the degree of heteroplasmy. Approximately 80% of MERRF patients have a mutation in the tRNA lysine gene.48

Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is the most common cause of blindness in young adults (the prevalence is higher in men than in women). Patients present with painless, subacute, and bilateral vision loss. In at least 90% of the families, several mtDNA mutations have been observed. Some patients with LHON and distinct mutations may have other associated conditions, such as encephalopathy, deafness, ataxia, myelopathy, or dystonia.62-65

mtdna depletion syndrome

mtDNA depletion syndrome is an autosomal recessive disorder that is usually fatal by 3 years of age. It affects the muscle, liver, kidneys, and brain; death is caused by encephalopathy or respiratory failure. The mitochondrial defect is quantitative rather than qualitative. The disorder results from imbalances in the mitochondrial nucleotide pool which, in turn, impair mtDNA replication and repair.

Treatment of all the mitochondrial disorders is supportive and symptomatic. Ubiquinone, creatine, vitamins C and K3, carnitine, and vitamin E are often used. Moderate exercises are recommended.

Ion Channelopathies, Periodic Paralyses, and Nondystrophic Myotonias

Ion channelopathies that affect muscle-fiber excitability produce a range of disorders that include periodic paralysis, myoto-nia, and episodic ataxia-myokymia. These represent a rare group of disorders that usually start in childhood and typically present with attacks of paralysis. During paralytic attacks, alterations in the level of serum potassium are common. Myotonia is also common in some forms. The disorders are suspected when there is a history of similar attacks in family members, especially if attacks are provoked by rest after exercise or certain carbohydrate-enriched meals; the diagnosis is confirmed by genetic analysis of blood DNA.


After excitation at the neuromuscular junction, action potentials are propagated through ion fluxes across the sarcolemmal membrane, which depend on the opening (activation) and closing (in-activation) of the appropriate ion channel. In muscle and nerve cells, opening of the voltage-gated Na+ channel causes a rapid increase in Na+ permeability and hence membrane depolarization. For the membrane to initiate the next action potential, however, the Na+ channels must close.66-68 The voltage-gated K+ channels open and K+ ions flow out of the cell, creating a hyperpolarized voltage across the cell membrane. The Cl- channels contribute to repolarization by stabilizing the membrane potential.

Disturbances in membrane excitability can lead to myotonia with or without periodic paralysis. Myotonia, as a symptom in nondystrophic myotonias, occurs in sodium or chloride channel disorders. Myotonia manifests as painless stiffness after a period of inactivity, which improves after continuous movements (warm-up phenomenon). Myotonia that develops after exposure to cold and worsens with exercise is called paradoxical myotonia. The other manifestation of membrane excitability is periodic paralysis, characterized by paralytic attacks associated with either hyperkalemia caused by mutations in the Na+ channel genes or hypokalemia caused by mutations in the voltage-gated calcium channel gene. Patients with cardiodysrhythmic periodic paralysis (Anderson syndrome) and those with episodic ataxia-myokymia have mutations in the potassium channel gene.

Sodium channel disorders

In the skeletal muscle, sodium channel disorders result from mutations in SCN4A, the sodium channel gene. Mutations in SCN4A can produce the clinical phenotypes of hyperkalemic and normokalemic periodic paralysis (hyperKPP), paramyoto-nia congenita, and potassium-aggravated myotonia (previously called acetazolamide-responsive myotonia or myotonia fluctu-ans). Patients with these allelic disorders demonstrate varying degrees of myotonia of eye closure, chewing, swallowing, and gripping of the hands.

HyperKPP and paramyotonia congenita (also called paradoxical myotonia) are autosomal dominant diseases. They are characterized by attacks of weakness that begin in infancy or early childhood. HyperKPP attacks are precipitated by rest after exercise, stress, administration of K+, cold, and certain foods. Mild myotonia may be present, and paradoxical myotonia of the eyelids is common. Patients with paramyotonia congenita develop paradoxical myotonia, which worsens with repetitive exercise; when exposed to cold, they develop stiffness, especially in the face, tongue, eyelids, and hands. Episodic attacks of weakness are also common, resembling those seen with hyperKPP, and they are accompanied by myotonia. The symptoms in patients with paramyotonia congenita, including the frequency of attacks and the interattack weakness, are treated with carbonic anhydrase inhibitors, such as acetazolamide and dichlorphenamide.69

Potassium channel disorders

Point mutations in the potassium channel gene KCNA1, on chromosome 12, have been associated with episodic ataxia-myokymia. Mutations in other potassium channel genes cause long QT syndrome. Andersen syndrome is caused by mutations in potassium channel gene KCNJ2, which encodes the inward-rectifying K+ channel gene, Kir21, on chromosome 17q. Andersen syndrome is characterized by periodic paralysis, which may be accompanied by fixed weakness; long QT syndrome with cardiac ventricular arrhythmias; and dysmorphic craniofacial features, such as micrognathia, low-set ears, short stature, and syndactyly. Anderson syndrome, as well as the other potassium channel disorders, usually responds to carbonic anhydrase inhibitors.

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