(4). In primary care diagnosis of metabolic myopathies has commonly been missed, as it is difficult to distinguish against conditions with a ‘pseudo metabolic’ presentation (5) This paper will outline the pathophysiology and symptoms of the disease, to enhance understanding and diagnosis in primary healthcare settings.

FATTY ACID OXIDATION DEFECTS

PATHOPHYSIOLOGY

Fatty acids are the main source of energy for the cardiovascular and musculoskeletal system at rest and low intensity exercise (4). Inside the mitochondrial matrix of a cell, fatty acids undergo beta oxidation to form acetyl coenzyme A. This substrate is then processed by the Krebs cycle and converted into adenosine triphosphate, creating energy (6). Short chain fatty acids enter the mitochondrial matrix freely, however, long chain fatty acids are transported by carnitine (7). The enzyme carnitine palmitoyl transferase (CPT1) forms an ester bond between carnitine and a long chain fatty acid creating acylcarnitine, in the inner facet of the outer mitochondrial membrane (8). Once Acylcarnitine is transported by carnitine acylcarnitine translocase (CACT) into the inner facet of the inner mitochondrial membrane, enzyme CPT-2 splits the bond (9). Thus, fatty acid oxidation defects arise as a result of a deficiency in the carnitine or CPT1 and CPT2 (4).

Carnitine myopathies are very rare, each defect is a result of an autosomal recessive disorder (9). Carnitine myopathies include CACT deficiency, CPT 1 deficiency and CPT 2 deficiency.
The most common is the CPT2 defect (9) which is caused by a mutation most frequently in the CPT2 gene S113L, other mutations include P50H and Q413fs-F448L (10). Due to this mutation long chain fatty acids cannot be split from the carnitine and therefore cannot undergo beta oxidation. Studies have demonstrated that patients with this diagnosis have reduced carnitine levels and an increase in long-chain acylcarnitine (7). Therefore, it is not possible to produce sufficient energy at rest and low intensity exercise.

SIGNS AND SYMPTOMS

There are three forms of CPT2 deficiency which are categorised into neonatal, infantile hepatocardiomuscular, and myopathic (10).

The neonatal form has been described in 18 families (11) and presents a few days after birth. The common symptoms are liver failure with hypoketotic hypoglycaemia, cardiac arrhythmias and seizures, this condition is rapidly fatal, life expectancy is a few months (9). The infantile form of which there have been 30 cases (11) presents in the first 12 months of life. The symptoms include liver failure, hypoketotic hypoglycaemia, seizures, cardiomyopathy and peripheral myopathy, leading to death in the first year (9).

The final myopathic form identified in 300 people (11), has a variable onset, 23 individuals with the disease have an onset age from 1 to 61 years (9). Symptoms include attacks of myalgia with 60% of people also experiencing muscle weakness during the attacks, however between attacks there is no noted muscle weakness and patients remain asymptomatic (9). Additional symptoms in severe attacks include rhabdomyolysis and myoglobinuria (6). Exercise is the most common cause of attacks followed by fasting and infections (9). Rhabdomyolysis occurs when reduced ATP causes an increase in cytosolic ionized calcium, which activates several proteases, magnifies muscle cell contractions, and instigates mitochondrial dysfunction. The myocyte therefore becomes more permeable, undergoes necrosis, and its contents leak into the surrounding muscle fluid (12). In severe cases myoglobinuria occurs, myoglobin leaks into the surrounding muscle fluid and passes into the glomerular filtrate in the kidney. The high concentrations of myoglobin in the glomerular filtrate increase tubular necrosis and can lead renal failure (13).

DIFFERENTIAL DIAGNOSIS BETWEEN FATTY ACID DEFECTS

There are pronounced similar symptoms between the CPT 2 and CACT myopathies. Physiologically both myopathies show an elevation of acylcarnitine’s in the plasma (14). Additionally, the clinically features of hypoketotic hypoglycaemia, cardiomyopathy, arrhythmias, and skeletal muscle damage are exhibited in CACT and the severe neonatal and infant CPT 2 myopathy (15). Direct testing of enzymatic activity is a necessity to differentiate between the two metabolic defects in this instance (14). However, there is a profound difference in variability of the symptoms. Patients with the CACT deficiency will only experience severe symptoms which are fatal. However, patients with the myopathic CPT 2 form exhibit mild symptoms which can be controlled (9).

TREATMENT

CPT 2 cannot be cured, treatment aims to manage the symptoms as they arise and to ensure the patient as comfortable as possible, neonates with the condition live for an average of five days, infants with the disease live up to a year (11). The Myopathic form can be managed by eating a diet rich with carbohydrates, reducing body fat utilisation and limited long-chain dietary fats. Carnitine supplements are also provided to convert potentially toxic long-chain fats to acylcarnitine’s. Prolonged exercise is to be avoided to ensure glycogen stores are not completed depleted and fasting is inhibited (9).

GLYCOGEN STORAGE DISEASE

PATHOPHYSIOLOGY

Glucose is the main energy source for the musculoskeletal system in moderate to high intensity exercise (6). Glucose cannot be stored in the body due to its water-soluble nature, therefore it is converted and contained in the liver and muscles as glycogen (16). To start the aerobic metabolic process glycogen is broken down back into glucose through glycogenolysis, regulated by the enzyme phosphorylase. Glucose then undergoes glycolysis forming the substrate pyruvate, which enters the mitochondria and is converted by pyruvate dehydrogenase to acetyl co-enzyme A. Acetyl Co-A then enters the Krebs cycle and undergoes beta oxidation to produce ATP (6). At very high intensity exercise the concentration of oxygen cannot meet the demands of energy required, and therefore the anaerobic metabolic system occurs. Glucose is broken down into pyruvate and is then catalysed by the enzyme lactate dehydrogenase into lactic acid and ATP. (17).

There are numerous carbohydrate myopathies due to the vast number of enzymes involved in the reactions, each defect is caused due to an autosomal recessive gene. The myopathies include myo-phosphorylase deficiency, muscle phosphofructokinase deficiency, phosphoglycerate mutase deficiency and lactate dehydrogenase deficiency (6).

Myo-phosphorylase deficiency is the most common of all the carbohydrate deficiencies (4) the prevalence has been estimated at 1 in 100,000 people, and more than 100 mutations have been found in the phosphorylase gene (18). The myopathy was discovered by McArdle in 1951 after studying a gentleman with exercise intolerance at moderate to high intensities. More recent biochemical testing on a 19-year old male patient with intense pain in his forearms developed after heavy lifting, showed the absence of muscle phosphorylase activity, causing a high concentration of glycogen in the muscles, and significantly reduced lactic acid produced after exercise (19).

SIGNS AND SYMPTOMS 

Signs of McArdle’s disease include muscle cramps and stiffness and an intolerance to strong isometric contractions (4). Moreover, symptoms include rapid fatigue in frequently exercised muscles. Extreme exercise and high intensity isometric contractions will cause rhabdomyolysis and, in some cases, myoglobinuria (20). An important sign of Mc Ardle’s disease is the experience of the ‘second wind’. Patients with the myopathy will experience near to complete exhaustion after exercising moderately for several minutes (20). However, before hitting absolute exhaustion the patients encounter a ‘second wind’ in which they are suddenly able to continue exercising comfortably again (19). Evidence suggests that this is caused by a change in metabolic pathway from the use of glucose to fatty acids, additionally there is increased cardiac output supplying more nutrients to the muscles, and enhanced activation of motor unites to compensate for failure of other muscle fibres (21).

Differential diagnosis within glucose storage disease

There are many similarities between each carbohydrate myopathy therefore diagnosis requires intricate testing. Similarly to Mc Ardle’s disease, patients with a deficiency in phosphofructokinase activity have symptoms of muscle cramping, exercise intolerance and episodes of rhabdomyolysis and myoglobinuria (22). However, a significant difference between the myopathies is the inability for those with phosphofructokinase deficiency to experience the ‘second wind’ (23). An additional difference is the effect of glucose and sucrose supplements. Patients with Mc Ardle’s disease experience reduced symptoms when taking supplements because glycolysis is not affected in this myopathy. However, those with phosphofructokinase deficiency experience an increase in symptoms (4), as the enzyme catalyses fructose-6-phosphate to fructose – 6-diphosphate, an important step in the break-down of glucose (22).

TREATMENT

McArdle’s disease cannot be cured, treatment is centralised around symptom control. Patients are advised to adapt their lifestyles to prevent any strenuous activity. Additionally, creatine sucrose and glucose supplements are prescribed (24). It has been evidenced that a strictly monitored aerobic exercise regime can enhance patient’s health by improving VO2 max and increase gross muscle efficiency (25).

Differential diagnosis – metabolic myopathies VS ‘pseudo-metabolic’ diseases

In primary care patients may present with similar muscular symptoms, it is important to distinguish between these symptoms in order to establish whether a patient will need further investigations, and by what methods (5). The clinical features of metabolic myopathies are difficult to differentiate between those of inflammatory myopathies (myositis), particularly polymyositis (26). The similar symptoms are, myalgia, muscle weakness and stiffness (27) however, the biggest differential factor is that polymyositis has an inflammatory component which would be picked up on an EMG, MRI or muscle histology (26). Hypothyroidism also share symptoms with metabolic myopathies which include, fatigue, and exercise induced myalgia and rhabdomyolysis (28), however additional symptoms of hypothyroidism are large thyroid glands, raised cholesterol, heavy periods and hair thinning (29). Becker’s disease can provide confusion in the diagnostic process of metabolic myopathies due to similar symptoms of calf pain on exertion (due to replacement with connective tissue and fat (30) and proximal arm and leg weakness (5), however differential symptoms of Becker’s disease include, bone abnormalities leading to scoliosis (31).

IMPACT FOR PHYSIOTHERAPY

Physiotherapists must adapt their treatment plans for patients with metabolic myopathies as their exercise tolerance is reduced. Therefore, when treating a patient with Mc Ardell’s disease for any injury, anaerobic activity patterns should be avoided especially with exercises that involve frequent eccentric or isometric muscle contractions (5). However, it has been evidenced that carefully monitored aerobic exercise can be beneficial in improving and cardiovascular fitness without weakening the muscles (32). Guidelines state that 30 minutes of light anaerobic activity 3-5 times a week is beneficial (33). Physiotherapists must also adapt their treatment for those with CPT 2 deficiency as they must avoid prolonged aerobic exercise and it is imperative that they are not fasting and eat a high carbohydrate diet before exercising (5).

CONCLUSION

Metabolic myopathy is a term encompassing a variety of conditions whereby an enzyme involved in a biochemical reaction is deficient. Symptoms are variable to the specific condition and differentiate in severity. However, the profuse communality between each myopathy is the intolerance to exercise. Physical activity depends entirely on copious amounts of energy. Therefore, a defect reducing the energy supply prevents the musculoskeletal and cardiorespiratory systems from keeping up with the demand required, this can be fatal if not treated. Each myopathy requires intricate understanding of the different causes and symptoms behind the disease, in order to create the best treatment plan to control symptoms. Therefore, it is imperative to diagnose persons with metabolic myopathies at an early stage, to ensure they are able to adapt their lifestyle accordingly.

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