Metabolic myopathies
Introduction
Metabolic myopathies refer to genetic skeletal muscle disorders that impact enzymes and proteins involved in the intermediary metabolism of glucose and free fatty acids. Although some drugs and hormones can affect metabolism in skeletal muscle, the disorders reviewed here relate to genetic defects in skeletal muscle substrate oxidation.
Classification: Impairments in glycogenolysis/glycolysis (glycogen storage disease), fatty acid transport/oxidation (fatty acid oxidation defects), and mitochondrial metabolism (mitochondrial myopathies) represent most metabolic myopathies. Mitochondrial encephalomyelopathies do not cause defects in a specific biochemical pathway and are technically not considered as metabolic myopathies.
Physiological basis: The immediate source of energy for muscles is derived from the hydrolysis of ATP. At rest, the major substrate for muscle in terms of ATP production comes from the metabolism of long-chain fatty acids. Therefore, any disorder impairing beta oxidation of long-chain fatty acids in the mitochondria can lead to a myopathy. During exercise, ATP is derived from the metabolism of carbohydrates, fatty acids, and ketones. Early in the course of exercise (up to 45 minutes), energy is derived mainly from free glucose or glucose made available through glycogenolysis. Subsequently, there is a shift toward the metabolism of fatty acids such that after a few hours, 70% of energy is derived from lipid breakdown.
Overview of skeletal muscle metabolism:
The continual supply of ATP to the fundamental cellular processes that underpin skeletal muscle contraction during exercise is essential for physical exercise in events lasting seconds to several hours. Because the muscle stores of ATP are small, metabolic pathways must be activated to maintain the required rates of ATP synthesis. These pathways include phosphocreatine and muscle glycogen breakdown, thus enabling substrate-level phosphorylation (‘anaerobic’) and oxidative phosphorylation by reducing equivalents from carbohydrate and fat metabolism (‘aerobic’). The relative contribution of these metabolic pathways is primarily determined by the intensity and duration of exercise.
At the onset of exercise, an immediate drop in adenosine triphosphate (ATP) occurs; this leads to an increased flux through the adenylate kinase (AK) enzyme (ADP + ADP > AK > ATP + AMP), which is maintained by the adenosine monophosphate deaminase 1 (AMPD1) pathway. The AMPD1 enzyme catalyzes the deamination of adenosine monophosphate (AMP) to inosine monophosphate which, after several enzymatic steps, leads to the conversion of xanthine to uric acid. This pathway is active in muscle contraction in healthy people but is enhanced in those with glycogen storage diseases and can lead to gout through increased uric acid production (myogenic hyperuricemia). Traditionally, myoadenylate deaminase deficiency was considered to be a metabolic myopathy; however, the AMPD1 enzyme is not directly involved in substrate metabolism and its role in metabolic myopathies has been called into question for several reasons: (1) the prevalence of the most commonly reported “pathogenic” stop gain variant in AMPD1 (c.34C>T;p.Gln12Ter) was present in 8.7% of a random sample of 282,334 healthy people (gnomad.broadinstitute.org/gene/ENSG00000116748?dataset=gnomad_r2_1) with approximately 2% being homozygous; (2) muscle blood flow is increased with no significant power reduction in skeletal muscle; homozygous patients who are AMPD1 deficient do not have exercise impairment or any of the predicted deleterious metabolic consequences in skeletal muscle. Thus, AMPD1 deficiency is not a metabolic myopathy and humans appear to compensate well for complete AMPD1 deficiency.
The creatine-phosphocreatine system is also activated at the onset of exercise, and adenosine diphosphate (ADP) is rephosphorylated by phosphocreatine to produce ATP and free creatine (Cr) via the cytosolic CK enzyme. A proton (H+) is also part of the reaction (ADP + PCr + H+ > CK > ATP + Cr) and this reaction is driven by the H+ produced by anaerobic glycolysis and glycogenolysis. Skeletal muscle phosphocreatine stores are depleted after approximately 10 seconds of muscle contraction and are restored about 2 minutes after stopping exercise by mitochondrially derived ATP. The activation of the creatine-phosphocreatine system is also important in stimulating mitochondrial respiration. Genetic defects occur in the creatine-phosphocreatine system, including creatine synthesis defects (eg, arginine: glycine aminotransferase deficiency) and creatine transporter defects; however, the impact on exercise is unclear as these disorders lead to severe infantile and childhood encephalopathic symptoms. At the onset of exercise, glycogenolysis and glycolysis are activated and [lactate- + H +] are formed by lactate dehydrogenase. After the first few minutes of muscle contraction, an increase in aerobic respiration occurs through the tricarboxylic acid (TCA) cycle and the mitochondria. The generation of pyruvate increases the flux of acetyl coenzyme A (CoA) into the TCA cycle via the pyruvate dehydrogenase pathway to form citrate and increase TCA cycle flux/content via anaplerosis. Reducing equivalents (NADH + H+ and FADH2) from the TCA cycle and fatty acid β-oxidation enter the mitochondria at complex I and II, respectively, and drive protons to the intermembrane space and build up the proton motive force. The electrons from the oxidation ofNADH+H+ and FADH2 are used to reduce molecular oxygen to water at complex IV. The proton motive force is used to drive ATP synthesis at complex V.
Exercise-mediated substrate fuel selection is determined by a number of factors, including exercise intensity and duration, training status, habitual dietary intake, and biological sex. Aerobic exercise intensity is usually measured as a percentage of maximal oxygen consumption (VO2max). Most people will oxidize free fatty acids at exercise intensities less than 50% VO2max, with the carbohydrate contribution increasing at higher exercise intensities and free fatty acids being predominant with longer-duration endurance exercise. Women oxidize proportionately more lipid at any relative exercise intensity as compared to men.
The main source of carbohydrates during exercise is intramuscular glycogen and muscle glycogen stores, and mitochondrial and free fatty acid metabolic enzymes are higher following endurance exercise training. In addition, the depletion of glycogen during the same absolute exercise intensity is less than after endurance exercise training. Muscle glycogen can also be manipulated by diet, with the short-term (3-day) consumption of a high-carbohydrate diet resulting in a significant increase in muscle glycogen, especially in men.
In general, the glycogen storage diseases manifest during brief bouts of high-intensity exercise; in contrast, fatty acid oxidation defects and mitochondrial myopathies usually manifest during longer-duration endurance-type activities, often with fasting or other metabolic stressors (eg, surgery, fever).
Metabolic myopathies can also be viewed as static or dynamic disorders. Static myopathies are defined by the presence of fixed or progressive weakness. On the other hand, dynamic myopathies are associated with exercise intolerance (exertional myalgias, cramps, and myoglobinuria) as the dominant clinical features. Some metabolic defects are associated with both dynamic and static myopathy.
There are 16+ recognized glycogen storage diseases also called glycogenoses which is somewhat of a misnomer because some of these glycogenoses do not result in accumulation of glycogen in the tissues. The glycogenoses predominantly affect the liver and muscle. Type I (glucose-6-phosphate deficiency) and type VI (liver phosphorylase deficiency) affect the liver only. Type II (lysosomal alpha-glucosidase deficiency), type V (phosphorylase deficiency), type VII phosphofructokinase deficiency), type X (phosphoglycerate mutase deficiency), and type XI (lactate dehydrogenase deficiency) almost exclusively cause muscle disease.
Glycogen storage diseases:
McArdle (GSD V, myophosphorylase deficiency)
Tarui (GSD VII, phosphofructokinase deficiency)
GSD IX (phosphorylase b kinase deficiency)
GSD X (phosphoglycerate mutase deficiency)
GSD XI (lactate dehydrogenase deficiency)
GSD XII (aldolase A deficiency)
GSD XIII (β-enolase deficiency)
Phosphoglucomutase deficiency
Phosphoglycerate kinase 1 deficiency
Fatty acid oxidation defect:
Carnitine palmitoyl transferase 2 deficiency
Trifunctional protein deficiency
Very-long-chain acyl-CoA dehydrogenase deficiency
Mitochondrial myopathy:
mtDNA mutations (MELAS, cytochrome b, cytochrome c oxidase)
nuclear DNA mutations (POLG, TK2)
The metabolic myopathies can present in the neonatal and infant period as part of more systemic involvement with hypotonia, hypoglycemia, and encephalopathy; however, most cases present in childhood or adulthood with exercise intolerance (often with rhabdomyolysis) and weakness. The glycogen-storage diseases present during brief bouts of high-intensity exercise, whereas fatty acid oxidation defects and mitochondrial myopathies present during a long-duration/low-intensity endurance-type activity or during fasting or another metabolically stressful event (eg, surgery, fever). The clinical examination is often normal between acute events, and evaluation involves exercise testing, blood testing (creatine kinase, acylcarnitine profile, lactate, amino acids), urine organic acids (ketones, dicarboxylic acids, 3-methylglutaconic acid), muscle biopsy (histology, ultrastructure, enzyme testing), MRI/spectroscopy, and targeted or untargeted genetic testing.
Approach to patient with metabolic myopathy:
Determine whether it is a static vs dynamic process. Fixed weakness may be absent in childhood but present in adulthood.
Muscle atrophy or hypertrophy may be seen in cases of muscular dystrophies associated with rhabdomyolysis.
If the patient has fixed or progressive weakness it is a static myopathy, Pompe disease needs to be considered, particularly if there is early respiratory failure. A good test to do is the dried blood spot analysis. A muscle bx may be needed, particularly if tests are negative.
If the patient has exercise intolerance then it suggests a dynamic process. An exercise forearm test can be done to determine if it is a disturbance in glycogen or fatty acid metabolism. If exercise forearm test is abnormal (no rise in lactic acid despite rise in ammonia), then genetic testing for McArdle disease can be performed. If this is negative, then do a muscle bx and metabolic assay to determine which enzyme is deficient.
If the patient has myoglobinuria only after excessive exercise, fasting, or infection, then first step would be genetic testing for CPT2 deficiency. If this is negative, proceed with a muscle biopsy and metabolic analysis.
Disorders of carbohydrate metabolism
McArdle disease (myophosphorylase deficiency) or glycogensosis type V encoded by a gene on chromosome 11q12-q13.1. It is the most common neuromuscular disorder of carbohydrate metabolism. It is the most common glycogen storage disease affecting the skeletal muscle. It is caused by autosomal recessive mutations in PYGM, encoding muscle glycogen phosphorylate which is an enzyme that catalyzes the first step of glycogenolysis to release glucose-1-phosphate (G1P) monomers from the intracellular glycogen polymers.
Enzyme myophosphorylase catalyzes the conversion of glycogen into glucose-6-phosphate. The enzyme is involved in the breakdown of glycogen to glucose for use in muscle. Myophosphorylase removes 1,4 glycosyl residues from outer branches of glycogen and adds inorganic phosphate to form glucose-1 phosphate. Deficiency of the enzyme results in the accumulation of glycogen.
Incidence: 1:100,000
Onset during the first 10 years of life. Although its onset is at birth, it often goes undiagnosed until adulthood and well into the third and fourth decades. History of exercise intolerance through childhood; complain of being tired and unable to keep up with their peers in physical activities and sports.
Classic symptoms appear in the teenage years. Fatigue and pain begin within the first few minutes of exercise (sprint, weight lifting, etc) particularly if it is strenuous and causes the person to slow down the intensity of exercise. The person feels limited by a barrier to exert more and slows down. The symptoms may be more in arms than in legs and can be asymmetric. If exercise is continued, pain develops within the muscle, which at first is deep aching but then gives way to the rapid development of a painful tightening of muscles, becoming hard and contracted. The muscle contracture may last for several hours and can be differentiated from a muscle cramp: EMG is electrically silent, and the duration of the contracture is far longer than that of a physiological cramp, which usually disappears after a few minutes at most or by stretching the muscle.
It is a dynamic myopathy but with recurrent attacks of rhabdomyolysis, can result in a fixed weakness (static myopathy). Myoglobulinuria occurs only about 50% of the time during physically strenuous exertional activity. It may not be seen until the 2nd or 3rd decade of life. ~10% of attacks are accompanied by renal failure. Most patients have a normal motor exam in between (interictal) attacks. Fixed contractures can develop with recurrent bouts of rhabdomyolysis and the condition turns from a dynamic to a static myopathy. Rarely, do patients develop proximal muscle atrophy and weakness in late adult life rather than exercise intolerance. Fixed weakness when it occurs has been described to involve proximal muscles of upper and lower limbs and can be asymmetric. Isolated paraspinal involvement has rarely been reported. MRI of skeletal muscles can reveal the involvement of paraspinal, semimembranosus, long-head of biceps femoris, moderate to severe fat replacement of subscapularis muscle, and involvement of tongue. Some cases are reported with congenital weakness leading to rapidly progressive ventilatory failure within the first year of life.
The second-wind phenomenon is seen as another aspect of the condition. If, with the onset of fatigue, the patient slows down exercise but does not stop, the abnormal sensation of fatigue may disappear, 7 - 10 minutes later, and thereafter, the muscle may function more normally. By gradually increasing the level of exercise, the patient may be able to break through the barrier and then may be able to perform exercise at an adequate level for longer periods. The second-wind phenomenon is associated with a rise in fatty acid use as a substrate. It is, however, the result of mobilization and use of blood-borne glucose. Cardiac, neuronal, and metabolic adaptation occurs, presumably. It results in a change in blood supply in the muscle from mobilization of blood-borne glucose. There is an associated switch to fatty acid oxidation as the fuel substrate required for aerobic metabolism (usually after 10 minutes of exercise).
The second-wind phenomenon is not seen in patients with other disorders associated with exercise intolerance, such as glycogenosis types VII (phosphofructokinase deficiency, Tarui disease), VIII (phosphorylase b kinase deficiency), and X (phosphoglycerate mutase deficiency); acid maltase deficiency; mitochondrial myopathies; and disorders of lipid metabolism.
Pathological: Subsarcolemmal glycogen deposits (blebs) which are PAS positive. Intermyofibrillar vacuoles. Immunostain show absent staining for phosphorylase.
In patients with myophosphorylase deficiency (McArdle disease), serum CK is usually elevated even between episodes of myoglobinuria,
Exercise forearm test:
Given the very high sensitivity and specificity of the forearm ischemic test and nonischemic forearm exercise test, a normal test rules out every glycolytic and glycogenolytic defect with the possible exception of phosphorylase b kinase deficiency, which can be further evaluated with the aerobic cycling exercise test. There are many examples of aerobic cycling tests; however, a standard Bruce protocol test used for cardiac evaluation where the intensity/speed of either a cycle ergometer or treadmill is progressively increased until voluntary exhaustion with measurement of lactate and ammonia pre/post is sufficient.
A simple diagnostic clinical test is the non-ischemic exercise forearm test.
A butterfly needle is inserted in the antecubital fossa, and baseline plasma lactate and ammonia are collected into wet ice-chilled tubes, followed by 1 minute of maximal handgrip dynamometry with a 9-second on, 1-second off ratio, and then blood samples after 1 minute.
Before the test used to have more blood draws. Blood draws are obtained immediately, 1, 2, 4, 6, and 10 minutes post-exercise (serum lactic acid and ammonia and pyruvate concentrations should be measured). A single post exercise sample at 1 minute may be as sensitive as a standard 10-minute test.
The normal response is a three- to fourfold rise in lactic acid and ammonia.
Sr. lactate is raised >20 mg/dL, and Sr. ammonia is raised >100 mcg/dL.
If neither lactate nor ammmonia conc. increases during the test, the subject is not exercising strenuously and the test should be repeated.
In patients with glycolytic pathway disorders: myophosphorylase (McArdle disease), phosphorylase b kinase, phosphoglycerate mutase, phosphoglycerate kinase, phosphofructokinase, debranching enzyme, LDH, and enolase deficiencies, there in no rise in lactate. but there is normal rise in ammonia concentration.
In myoadenylate deaminase deficiency there is a rise in lactate with no rise in ammonia concentration.
MRI of paraspinal and subscapularis muscles and tongue.
EDX: Usually normal. Cramps/contracture is electrically silent. Occasional myotonic discharges, fibrillation potentials, and PSW in some patients. Early recruitment and myopathic potentials can also be seen.
Management:
Diet: CHO diet, 75 gm of oral sucrose before exercise showed an improvement in exercise performance. Benefits is short lasting, and repeated use may lead to weight gain. High-protein diet may be beneficial.
Creatine: Low-dose creatine (60 mg/kg/d) showed an increase in exercise capacity. High-dose creatine (150 mg/kg/d) resulted in worsening of symptoms.
Vit B6, 50 mg/day can enhance exercise tolerance.
Ramipril 2.5 mg daily in ACE D/D genotype patients.
Exercise: Avoid intense isometric exercises – e.g., weight-lifting. Avoid maximum aerobic exercises – e.g., sprinting. Warm-up for 15 minutes with low-level activity prior to moderate exercise promotes transition to 2nd wind phenomenon. Initial training done in Exercise Physiology Laboratory
Tarui disease (glycogenosis type VII) is caused by phosophofructokinase deficiency in muscle and erythrocytes. PFK catalyzes the ATPase-dependent conversion of fructose 6 phosphate to fructose 1,6-diphosphate. Human PFK comprises 3 distinct isoenzyme subunits (M-muscle, L-liver, and P-platelet). Skeletal muscles have only the M isoform, while erythrocytes have a hybrid of M and L subunits. PFK-M (muscle) is the gene on 12q13. The symptoms in the disease are due to the inactivation of PFK on muscle and partial inactivation of PFK in RBC.
It is less common than McArdle disease. It has clinical features that are quite similar to McArdle disease: Exercise intolerance, muscle pain, contractures, and relief from discomfort by rest. However, PFK deficiency is not associated with the warm of phenomena and there is a lower incidence of myoglobinuria. An inadequate increase of lactate on forearm exercise testing suggests a glycolytic defect. The hemolytic trait, as indicated by the reticulocytosis and increased bilirubin, and the elevated uric acid distinguish phosphofructokinase deficiency from McArdle disease.
Some individuals who are affected present with only hemolytic anemia without a myopathy.
Positive ischemic exercise test, CK is elevated.
EMG is normal myopathic, or irritative.
Pathological: Subsarcolemmal glycogen deposits (blebs) which are PAS positive. Intermyofibrillar vacuoles. Immunohistochemical stains show absent staining for phosphofructokinase.
Treatment: Patients with PFK rely on free fatty acids as a fuel substrate during exercise. If given glucose infusion or high -CHO meals they will experience increased exercise intolerance. This is because the presence of glucose reduces the blood levels of free fatty acids.
Cori's disease (glycogenosis type III) is caused by a deficiency in the debranching enzyme, leading to glycogen accumulation. It accounts for ~25% of GSD. The debranching enzyme has two separate catalytic functions: oligo-1,4-1,4-glucanotransferase activity and alpha-1,6 glucosidase activity. Both the transferase and glucosidase activities are vital in breaking down glycogen into glucose, and a deficiency in either or both enzymatic functions leads to myopathy.
Forms of GSD III:
GSD IIIa, debranching enzyme is deficient in both liver and muscle.
GSD IIIb, the debranching enzyme is deficient only in the liver.
GSD IIIc, only the glucosidase function of the debranching enzyme is affected.
GSD IIId, only the transferase function of the debranching enzyme is affected.
The onset of muscle weakness may be appreciated in infancy and childhood but usually does not manifest until adulthood, usually in the 3rd or 4th decade of life. It presents often in adulthood with short stature, exercise intolerance, progressive distal weakness, peripheral neuropathy (sensorimotor), mild hepatomegaly, and cardiomyopathy. Severe atrophy and weakness of muscles in the distal extremity (peroneal and calf muscles) occur in ~50% of cases. Tight heel cords are common and patients tend to toe-walk. The distal involvement may be given an appearance of motor neuron disease or peripheral neuropathy. They may be pseudohypertrophy of proximal muscle groups. Some patients develop ventilatory muscle weakness with or without extremity weakness. Ventilatory failure evolves fairly rapidly. Some patients develop cardiomyopathy.
Serum CK levels are elevated (2-20 x ULN). Deficiency of enzyme can be demonstrated with biochemical assay of muscle, fibroblasts, or lymphocytes. Exercise forearm test: increased in ammonia without increase in lactate levels.
PFTs are reduced, with restricted defects.
TTE shows HOCM
ECG: conduction defects and arrhythmias.
Electrodiagnostic studies demonstrate short polyphasic motor unit action potentials and fibrillation potentials.
Muscle biopsy reveals vacuolar myopathy with abnormal accumulation of glycogen in the subsarcolemmal and intermyofibrillar regions of muscle fibers. These vacuoles stain intensely with PAS and are digested by diastase. The do not stain with acid-phosphatase, unlike acid-maltase deficiency, suggesting that the glycogen does not primarily accumulate in lysosomes. On EM, free pools of glycogen are seen. Although some glycogen appear in lysosomes they are not quite to the same extent as seen in acid-maltase deficiency. Glycogen is found in heart, valves, smooth muscle of intramyocardial arteries, skin and peripheral nerves.
Molecular Genetics and Pathogenesis: Mutation in the gene AGL on 1p21.
Treatment: Low -CHO, high-protein diet. Supportive therapy for CHF. Liver transplantation in cirrhosis of liver and hepatocellular carcinoma.
Andersen's disease (glycogenosis type IV) is caused by a deficiency of branching enzyme that helps make the branched glycogen molecule. Several forms exist:
A classic and most common form of GSD IV known as Andersen disease, presents in infancy characterized by failure to thrive, hepatomegaly, and splenomegaly. Muscular weakness and atrophy, hypotonia, hyporeflexia, and contractures may occur until these manifestations are overshadowed by the liver disease.
There is an accumulation of amylopectin-like polysaccharide, also known as polyglucosan, in almost all tissues. Its clinical presentation is variable and involves the liver or the neuromuscular system.
Mutations in the GBE1 gene, located on chromosome 3, have been identified in both phenotypes. Non-progressive hepatic form of the disorder is rarely reported. Neuromuscular forms are primarily seen and reported (3 variants) which should be viewed as a clinical continuum and not separate.
Neuromuscular forms: Either proximal or distal muscle groups are preferentially affected.
Congenital phenotype can be subdivided into two clinical subgroups.
The first is characterized by severe perinatal disorder presenting as fetal akinesia deformation sequence (FADS) with by multiple congenital contractures (arthrogryposis multiplex congenita), hydrops fetalis, and perinatal death.
The second is characterized by severe congenital myopathy, inconsistently associated with cardiopathy, often simulating Werding-Hoffman disease
Juvenile form is dominated by myopathy or by cardiomyopathy.
Adult form presents with myopathic weakness
The adult form of branching enzyme deficiency can present as isolated myopathy or adult polyglucosan body disease, characterized by a combination of upper and lower motor neuron syndromes, sensory nerve involvement, ataxia, neurogenic bladder, cardiomyopathy and dementia. There is predilection for polyglucosan body neuropathy in the Ashkenazi Jewish population.
Serum CK may ben normal to slightly elevated. EMG shows muscle membrane irritability and myopathic features, axonal sensorimotor neuropathy, ECG shows conduction defects, complete AV block. Echocardiogram shows DCM.
Treatment: Liver transplantation in children has shown some beneficial results.
Phosphoglycerate kinase deficiency. The gene for this disorder is on chromosome Xq13.
Phosphoglycerate mutase deficiency. The responsible gene is located at chromosome 7p12-13.
Lactate dehydrogenase deficiency. 11p15.4.
β-Enolase deficiency
A single patient has been reported with exercise intolerance, myalgias, and episodic hyper-CK-emia caused by a mutation in the gene encoding β-enolase.
Acid maltase deficiency, or Pompe's disease (glucogenosis type II), is an autosomal recessive disorder caused by a deficiency of lysosomal acid α-1,4 glucosidase in lysosomes on 17q21.23. Missense, nonsense, and frame-shift mutations have been identified in the alpha-glucosidase gene.
Lysosomal α-1,4 glucosidase breaks down glycogen to glucose. It does so by cleaving 1,4 and 1,6 linkages in glycogen, maltose, and isomaltose. Glycogen within lysosomes is degraded to glucose by alpa-glucosidase, and the deficiency of the enzyme results in glycogen accumulation. It is hypothesized that the accumulating glycogen accumulates in the lysosomes and eventually rupture, thereby releasing proteases that degrade myofibrils and other important muscle proteins. The accumulated glycogen may also displace or replace important cellular organelles. Patients do not exhibit exercise intolerance or myoglobinuria because metabolism of non-membrane-bound glycogen and glucose for energy metabolism is not impaired.
Glycogen accumulation in tissues resulting in typical histopathologic findings on muscle biopsy, mainly type I muscle fibers, demonstrating vacuolated sarcoplasm with glycogen accumulation that stains strongly with acid phosphatase. These vacuoles are prominent in muscles in infantile form, but not so apparent (25-75%) in childhood and adult forms. The vacuoles stain intensely with PAS stain and are digested by diastase. They stain intensely with acid phosphatase stain, confirming that the vacuoles are secondary lysosomes filled with glycogen. On EM glycogen can be found free in the cytoplasm. There is necrotic and regenerating muscle fibers, variation in fiber size and fiber splitting. In later stages, muscle fiber atrophy and increased endomysial connective tissue may be present. Occasionally fiber type grouping and group atrophy may be seen due to motor neuron degeneration. Glycogen accumulates in the AHC and bulbar nuclei as well as Schwann cells accounting of the superimposed neurogenic findings in some patients.
Forms:
Severe infantile form is called Pompe's disease
Infantile Pompe's disease, the classic form, is characterized by generalized weakness and hypotonia, cardiomegaly, macroglossia and mild to moderate hepatomegaly with onset in the first several months of life. The weakness and cardiomyopathy are progressive, and the disease is invariably fatal by 2 years of age, secondary to cardiorespiratory failure. Feeding difficulties and ventilatory muscle weakness are common.
Incidence: 1:31,000 to 1 in 138,000. CK levels are moderately elevated in infantile onset.
Dried blood spot test if positive > GAA genetic test.
Prenatal diagnosis is possible with amniocentesis or CVS.
Tx: Intravenous recombinant α-glucosidase enzyme appears to be safe and beneficial for infants with Pompe disease
Childhood-onset type
Occurs by 1st decade of life. Mainly myopathic. Manifests with proximal weakness, motor developmental delay, hypotonia, enlarged calves, waddling gait, and rarely with cardiomegaly, hepatomegaly, and mental retardation. Significant lumbar lordosis may be present. Children demonstrate a Gower maneuver to arise from the floor. Affected children are commonly misdiagnosed with Duchenne or some other form of limb-girdle muscular dystrophy. Rarely, acid maltase deficiency presents with rigidity of the spine. Unlike infantile onset acid maltase deficiency, cardiomegaly, hepatomegaly, and macroglossia are uncommon. Patients may die of pulmonary infections and respiratory failure.
Incidence: 1:53,000
Milder adult-onset variant
Mainly myopathic - Limb girdle type weakness.
Occurs in 3rd to 4th decades of life (upto 8th decade).
Manifests with slowly progressive proximal limb girdle weakness more than distal muscle weakness resembling polymyositis or LGMD, some have scapuloperoneal distribution of weakness. Weakness can be sometime asymmetric, may involve face and tongue. Patient complain of muscle pain, mostly in their thighs. Shortness of breath, myalgia, axial weakness, trendelenburg gait, and typically weakness of the diaphragm, leading to neuromuscular respiratory problems. MSR may be reduced. 16% to 33% of patients present with symptoms related to ventilatory insufficiency (dyspnea, frequent nocturnal arousals, morning headaches, and excessive daytime sleepiness).
These patients do not typically have cardiomegaly, hepatomegaly, or mental retardation.
CK is normal, TTE. FVC (seated and supine shows restrictive defect with reduced FVC, reduced MIP and MEP, early fatigue of the diaphragm.) EMG (myotonia)
,GAA enzyme activity (high sensitivity) correlates with disease severity. Infantile onset disease is associated with a severe deficiency of alpha-glucosidase activity, while the less severe adult onset form has residual activity, upto 30% in muscle and 53% in lymphocytes. A direct spot analysis of alpha-glucosidase activity is not the preferred initial screening test. The activity level by this method does not correlate with disease severity. If the dried blood spot test shows reduced enzyme activity, confirmatory testing may be performed using genetic testing of GAA gene.
Echocardiogram (septal hypertrophy). MRI may show increased signal in tongue muscles (genioglossus).
ECG abnormalities and arrhythmias can be seen.
CT and MRI scans confirm the early and severe involvement of the abductor magnus and semimembranosus in the early stage of the disease and later fat infiltration of the long head of the biceps femoris, semitendinosus, and the anterior thigh muscles. In advanced phases, selective sparing of the sartorius, rectus femoris, and gracilis muscles, and peripheral portions of the vastus lateralis are also evident. Skeletal muscle MRI and CT also reveal early involvement of paravertebral and abdominal trunk muscles.
Motor and sensory nerve conduction studies are normal. EMG revealed increased insertional and spontaneous activity in the form of fibrillation potentials, positive sharp waves, CRDs, and even myotonic discharges. In mild forms of the disease these irritative discharges may be evident only in the paraspinal muscles. Myopathic MUP are seen.
Lumizyme 20 mg/kg IV every 2 weeks. A poor prognostic factor among infants is cross-reactive immunologic material (CRIM) status; CRIM-negative is strongly correlated with a poor outcome. Although most CRIM-negative infants initially respond to continuous use of ERT, a resurgence of the natural progression of weakness subsequently ensues. The CRIM negative infants develop antibodies directed against the infused recombinant alpha-glucosidase. Presumably, those infants who do not produce even minute amount of alpha-glucosidase are at increased risk of mounting an antibody response against alpha-glucosidase, as it is seen to be foreign protein by the immune system.
Albuterol (8 mg bid): May improve response to enzyme replacement treatment
Review: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035871/
Danon disease, is an X-linked disorder caused by mutations in the lysosome-associated membrane protein 2 (LAMP2) gene. The disorder is associated with early onset of proximal weakness and is usually associated with a cardiomyopathy and mental intellectual disability. Biopsies show non-rimmed, lysosomal vacuoles that do not immunostain with LAMP1 antibodies.
Glycogneosis type 0 (Glycogen synthase 1 deficiency):
Clinical features: Only few patients have been reported with this rare disorder. Individuals present with childhood onset of exercise intolerance and recurrent attacks of syncope for presumed cardiac origin. Prolonged QT syndrome and sudden cardiac death occurred. Mild proximal weakness may be evident.
Laboratory features: Exercise foreram test shows failure of lactate elevation. MRI of the skeletal muscles show fatty degeneration of the gluteal and flexor muscles of the thigh. CK levels have not been reported.
Muscle biopsy shows depletion of glycogen and skeletal, cardiac muscle as well as skin fibroblasts. Phosphorylase activity may also be deficient of muscle fibers.
Molecular genetics and pathogenesis: Synthesis of glycogen requires glycogen synthase 1 which catalyzes the addition of glucose monomers to the growing glycogen molecule through the formation of alpha-1,4-glycoside linkages. Mutations in the GYS1 gene that encode glycogen synthetase 1 results in deficiency of this enzyme leading to the depletion of glycogen in skeletal and cardiac muscles.
Treatment: No specific medical therapies are available.
Disorders of lipid metabolism
Biochemistry of fatty acid oxidation (Text Video1 Video2)
https://www.youtube.com/watch?v=BtAt1VwRxuY
https://www.youtube.com/watch?v=nBFSz63T1c0
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CPT2 Deficiency: autosomal recessive. 2nd to 3rd decade of life. Muscular pain and myoglobinuria followed by intense or prolonged exertion usually by 2nd or 3rd decade of life. Prolonged fasting and infection are other precipitating factors. Neuromuscular exam is normal in between bouts of rhabdomyolysis.
In adults, carnitine palmitoyltransferase II deficiency is the most common cause of recurrent myoglobinuria
Rare cases of CPT2 deficiency causes a fatal CM in infancy or early childhood.
Lab: CK is normal, except when patient does intense physical activities or fasts. Exercise forearm test is normal, which helps distinguish CPT2 deficiency from the glycogen storage disorders which can also cause exercise-induced rhabdomyolysis. Muscle and serum carnitine levels are normal. EMG is usually unremarkable, although myopathic units may be seen. EKG is also normal.
The most sensitive and specific test for a fatty acid oxidation defect is the acylcarnitine profile performed by liquid chromatography tandem mass spectrometry. This test may be abnormal between acute events; however, a false-negative test can occur in a non-stressed situation. It is preferable that patients come fasting in the morning, which tends to increase the diagnostic yield. Additionally, this test should be sent if a fatty acid oxidation defect is suspected during an acute metabolic crisis.
Acylcarnitine profile by HPLC-TMS: Total and Free plasma carnitine levels are low or normal. Raised long-chain acylcarnitines. Acylcarnitine/Free carnitine (AC/FC) ratio is high. C12, C14, C16, C18, & C18.1 elevations in serum. DDx of C12 to C18 acylcarnitines elevations includes glutaric acidemia type II and carnitine acylcarnitine translocase deficiency, which can be excluded by additional screening of urinary metabolites such as glutaric and 3-OH-glutaric acids.
Muscle biopsy is performed 6 weeks after an episode. It may show mild fiber type 2 predominance, and marked reduction in CPT II activity (less than 10% of normal levels).
Histopathology: No gross abnormality on light microscopy exam of muscle tissue. However, an increase in the lipid content of muscle may be apparent on EM.
Molecular genetics: CP2 mutations located on 1p32. Deficiency of CP2 impairs transport of acylcarnitine across the inner mitochondrial membrane. Thus, the generation of ATP from fatty acid metabolism is diminished.
Tx: High protein, low-fat diet with frequent meals should be advised. Avoid prolonged strenous activity, cold temperatures, and fasting may prevent episodes of rhabdomyolysis. During febrile illness, patients should be instructed to increase the intake of complex carbohydrates and again avoid fasting.
Treatment of manifestations:
Multidisciplinary approach
Dietary restriction of lipid intake
High-carbohydrate (70%) and low-fat (<20%) diet (MCFA) + L-carnitine.
Avoidance of known triggers
Infusions of glucose during intercurrent infections to prevent catabolism
Avoiding extended fasting and prolonged exercise
Avoid: Valproic acid, anesthetic agents, ibuprofen, and diazepam in high doses.
Triheptanoin (anaplerotic) diet
Adequate hydration to prevent renal failure during episodes of myoglobinuria.
Genetic counseling of patient and family members.
CP1 deficiency does not cause a myopathy.
Systemic primary Carnitine Deficiency (CDSP) results and defective fatty acid oxidation. It encompasses a broad clinical spectrum including the following:
Metabolic decompensation in infancy typically presenting between age three months and two years with episodes of hypoketotic hypoglycemia, poor feeding, irritability, lethargy, hepatomegaly, elevated liver transaminases, and hyperammonemia triggered by fasting or common illnesses such as upper respiratory tract infection or gastroenteritis
Childhood myopathy involving heart and skeletal muscle with onset between age two and four years.
Pregnancy-related decreased stamina or exacerbation of cardiac arrhythmia
Fatigability in adulthood
Absence of symptoms
The latter two categories often include mothers diagnosed with CDSP after newborn screening has identified low carnitine levels in their infants
The systemic manifestations tend to overshadow the myopathy. Rhabdomyolysis and respiratory weakness can occur.
Secondary carnitine deficiency can result from a variety of disorders, including respiratory defects, organic aciduria, endocrinopathies, dystrophies, and renal and liver failure, malnutrition and as a toxic effect of certain medications. It is not known if the secondary deficiency of carnitine can in and of itself cause a myopathy.
Diagnosis and testing: Plasma carnitine levels are extremely reduced or absent in CDSP. This differentiates it from CP2 deficiency where carnitine level is normal or low. Plasma and tissue (including muscle) carnitine levels are markedly diminished in primary carnitine deficiency, and the levels are only moderately reduced (25 to 50% of normal) in secondary forms of carnitine deficiency. Serum acylcarnitine levels are also reduced. Serum CK levels are normal in approximately 50% of patients with a myopathic form of the disease but can be elevated to as much as 15 times normal. In primary system accounting deficiency, liver enzymes are also elevated. Fasting individuals with carnitine deficiency may develop hypoglycemia, acidosis, and elevated CK levels and liver function tests. However, ketones are not elevated in the urine during fasting. EMG may reveal increased insertional activity with positive sharp waves, fibrillation potentials, and CRDs. Early recruitment of short duration, small amplitude, and polyphasic motor unit action potentials can be observed. An echocardiogram can demonstrate dilated or hypertrophic cardiomyopathy.
The diagnosis is established by identification of biallelic pathogenic variants in SLC22A5 (a.k.a OCTN2) on 5q33.1 or demonstration of reduced fibroblast carnitine transport.
Management:
Treatment of manifestations: Metabolic decompensation and skeletal and cardiac muscle function improve with 100-200-400 mg/kg/day oral levocarnitine (L-carnitine) if it is started before irreversible organ damage occurs. Hypoglycemic episodes are treated with intravenous dextrose infusion; cardiomyopathy requires management by specialists in cardiology.
Prevention of primary manifestations: Maintain appropriate plasma carnitine concentrations with oral L-carnitine supplementation; prevent hypoglycemia with frequent feeding and avoiding fasting. Hospitalization for intravenous glucose administration for individuals who are required to fast for a procedure or who cannot tolerate oral intake due to illness such as gastroenteritis.
Prevention of secondary complications: Oral metronidazole and/or decreasing the carnitine dose usually results in the resolution of the fishy odor due to L-carnitine supplementation.
Surveillance: Echocardiogram and electrocardiogram: annually during childhood and less frequently in adulthood; monitor plasma carnitine concentration frequently until levels reach the normal range, then, measure three times a year during infancy and early childhood, twice a year in older children, and annually in adults; evaluate serum creatine kinase concentration and liver transaminases during acute illnesses.
Agents/circumstances to avoid: Fasting longer than age-appropriate periods.
Evaluation of relatives at risk: Measure plasma carnitine levels in sibs of an affected individual.
Pregnancy management: Pregnant women with CDSP require close monitoring of plasma carnitine levels and increased carnitine supplementation as needed to maintain normal plasma carnitine levels.
Genetic counseling CDSP is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the SLC22A5 pathogenic variants in the family are known.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331364/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1226127/
https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-015-0199-5
Screening Laboratory Tests for Mitochondrial and Metabolic Myopathies
Blood
Lactic acid: elevated values in resting subjects, best performed without a tourniquet
Amino acids: elevated alanine in fasting sample or alanine-to-lysine ratio greater than 4:1; elevated proline or sarcosine, low arginine, taurine, or citrulline in some mitochondrial myopathies.
Carnitine: low free carnitine (may be low in infants and vegetarians), as well as abnormal acylcarnitine intermediates in some primary mitochondrial diseases and lipid myopathies.
Creatine kinase: nonspecific but elevated in some mitochondrial and metabolic myopathies
Growth differentiating factor-15: elevated in mitochondrial myopathy, false elevation in diabetes mellitus, not elevated in nonmitochondrial myopathies
3-Methylglutaconic acid: elevated in some mitochondrial disease
CSF: Lactic acid: elevated; folate: decreased (not specific)
Urine: Organic acids: elevated lactic acid, pyruvic acid, tricarboxylic acid cycle intermediates, dicarboxylic acids, 3-methylglutaconic acid in some primary mitochondrial diseases and disorders of lipid metabolism
Systemic Evaluation (As Deemed Necessary Based On Clinical Presentation)
Brain: MRI, EEG
Muscle: EMG, polysomnography
Nerve: nerve conduction study
Eyes: ophthalmologic evaluation, electroretinogram
Ears: audiogram
Gastroenterology: consultation, swallowing study, gastric emptying test, stool fat
Heart: ECG, echocardiogram
Lung: pulmonary function test, cardiopulmonary exercise testing
Other Laboratory Tests to Consider for Disease Mimicry
Hemogram, iron, and ferritin
Complete metabolic panel
Vitamin B12 level and methylmalonic acid
Thyroid-stimulating hormone (TSH), free T4
Hemoglobin A1c
Paraneoplastic/autoimmune panel
Selective vitamin levels, vitamin deficiencies, including micronutrient disorders seen in patients who have undergone bariatric surgery, on chronic total parenteral nutrition, self-induced restrictive diets, inflammatory bowel disease, or short bowel syndrome.
Genetics:
Check for DOK-7 mutation (congenital MG)
MD1
PABPN1, MYH2, SLC25A4, TWNK, POLG1, POLG2, TYMP, OPA1, RRM2B, DNA2, MT-TL1, RNASEH1.
The SLC22A5 gene is associated with autosomal recessive primary carnitine deficiency
Pseudometabolic Myopathies
Pseudometabolic myopathies are structural myopathies that mimic metabolic myopathies by initially presenting as exercise-induced rhabdomyolysis. Although energy depletion during exercise is a trigger, these disorders are structural or calcium dysregulation myopathies and are not directly involved in substrate metabolism per se. The most common disorders with a pseudometabolic presentation are limb-girdle muscular dystrophies (TTN, SGCA, SGCB, SGCD, ANO5, and DYS gene mutations) and Becker muscular dystrophy (DMD gene mutation). Exercise induces sarcolemmal damage, excessive calcium influx, or both resulting in rhabdomyolysis in these disorders. Even before fixed proximal weakness occurs, a clue to their existence is a CK elevation persisting for more than 10 days following a bout of rhabdomyolysis.
HyperCKemia has not been seen with the excitation-contraction coupling associated mutations (RYR1 and CACNA1S) seen in malignant hyperthermia susceptibility myopathies. Exercise-induced rhabdomyolysis with autosomal dominant mutations in the RYR1 or CACNA1S gene has been reported. These proteins link depolarization of the transverse tubule (dihydropyridine receptor, CACNA1S gene) to calcium release from the sarcoplasmic reticulum (ryanodine receptor, RYR1 gene) with mutations leading to isolated malignant hyperthermia, core myopathy, or exercise-induced rhabdomyolysis. A correlation between RYR1 mutation phenotype and rhabdomyolysis does not seem to exist, although biallelic RYR1 variants are usually associated with a more severe fixed weakness phenotype/core myopathy. Practically, patients with malignant hyperthermia should avoid exercise in the heat or when dehydrated and should wear a medical alert bracelet. In addition, it is important to recognize that several acquired disorders can lead to exercise-induced rhabdomyolysis.
Statins are one of the most commonly prescribed medications in the world and are a well-known trigger of rhabdomyolysis; they can even trigger an autoimmune process mediated by anti–3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies. Statins result in a higher CK response to standardized exercise, can lead to myalgia in approximately 10% of individuals, and may unmask an underlying genetic metabolic myopathy.
Vitamin D deficiency (<30 nmol/L) can lead to exercise intolerance, rhabdomyolysis, and persistent hyperCKemia, with a good clinical and laboratory response to vitamin D supplementation. A reduction in or resolution of statin-associated myalgia was reported in vitamin D-deficient patients following supplementation. Consequently, it is reasonable to measure vitamin D levels in all cases of exertional rhabdomyolysis or statin-associated myalgia/myopathy and replace them to achieve sufficient levels (typically >75 nmol/L).
Hypothyroidism can lead to a fixed myopathy with hyperCKemia and weakness but predisposes to exertional rhabdomyolysis. Hypothyroidism can lead to mitochondrial dysfunction and carnitine depletion, which likely explains the relationship to exercise-induced rhabdomyolysis. Although less common, hyperthyroidism can also lead to rhabdomyolysis. It is therefore reasonable to check plasma thyroid-stimulating hormone (TSH) and thyroxine levels in cases of exertional rhabdomyolysis.
I usually check CK, serum lactate, pyruvate, total and free plasma carnitine, acylcarnitine/free carnitine ratio, amino acids, urine organic acids. GDF-15 (growth differentiating factor – 15 from Mayo). EMG/NCS, ophthalmologic evaluation, GI (if MNGIE suspected), PFT, ECG, echocardiogram. In my opinion EMG, genetics and muscle biopsy have been helpful.
Case Vignettes
A 23-year-old woman presented to the emergency department with rhabdomyolysis following a 30-minute spin class. Her creatine kinase (CK) peaked at 56,000 U/L (normal <220 U/L) during 2 days of in-hospital IV fluids, and she was discharged home with a requisition to measure CK 2 weeks later. The CK 2 weeks later was still at 1200 U/L and remained at 1100 U/L 4 weeks after the initial event. She was referred to the neuromuscular clinic as her CK did not normalize. Her neurologic examination was normal except for hypertrophic calf muscles. A dystrophin genetic test for deletions and duplications was normal, her DMD gene was sequenced, and a known pathogenic stop codon at c.6118-3C>A in IVS 42 was found.
COMMENT This is a typical case of a pseudo-metabolic myopathy and provided the patient with an accurate diagnosis of manifesting carrier state for Duchenne muscular dystrophy and allowed for appropriate genetic counseling given that she was engaged and planning a family. Echocardiogram was normal, but echocardiography was recommended every 5 years or if she developed any cardiac symptoms. The patient was able to slowly work up to cardiovascular exercise four times a week for 30 to 45 minutes, with no further rise of CK and no further bouts of rhabdomyolysis.