CPT deficiency 101 - an overview of CPT 2 deficiency


 

  1. Introduction
  2. The role of long chain fatty acids
  3. Symptoms of CPT 2 deficiency
  4. Rhabdomyolysis
  5. Biochemical features and basis for diagnosis of rhabdomyolysis
  6. Clinical manifestations of rhabdomyolysis
  7. Complications of rhabdomyolysis
  8. Summary

 

 

1. Introduction

Carnitine Palmityl Transferase II Deficiency (hereafter referred to as CPT 2 deficiency) is a medical condition consisting of a deficiency of the CPT 2 enzymes in the patient. These CPT enzymes play an important role in the transport of fatty acids into the mitochondria, so that energy in the form of ATP can be formed, which is necessary for the functioning of the cells in question.

There are different forms of the CPT enzyme encoded by different genes, and located on different membrane surfaces of the mitochondria. These forms are called CPT I and CPT II. CPT 2 deficiency is the most common disorder, resulting in the inability of muscle cells especially to metabolize long chain fatty acids. CPT I deficiency basically causes the same problems, but then in liver cells. The most common disorder of CPT 2 deficiency is the Ďadult onsetí form, but there are also two rare infantile forms of CPT 2 deficiency.

CPT deficiency is a genetic defect of (probably) a compound heterozygosity nature, leading to a clinically heterogenous autosomal recessive disorder.

Approximately 150 patient cases have been described worldwide in the medical literature until 1995. This may at first glance imply that CPT 2 deficiency is a very rare disease. However, suspicions are mounting that CPT 2 deficiency is a vastly underdiagnosed medical condition. An explanation for this could be that a lot of CPT 2 deficient people may never find themselves in a situation in which symptoms of the disease are triggered (see later).

 

2. The role of long chain fatty acids

The long chain fatty acid metabolism is an important energy source in the human body, especially for muscle cells.This is true for muscles at rest, during fasting, in the post-absorptive state and on prolonged exercise.

During the early phase of exercise, muscle cells rely on readily available sources of energy, such as phosphocreatinine (an energy molecule similar to ATP) and glycogen. However, when exercise is prolonged, a gradual shift occurs to fuel sources that are brought in from serum, beginning with glucose. When this energy source is also (temporarily) depleted, a shift occurs towards fatty acids as the energy source. For people with reduced (deficient) CPT 2 activity compared to normal, this shift towards the fatty acid metabolism can result in a shortage of energy that can be acquired from fatty acids, resulting in rhabdomyolysis.

Another state of the body in which muscle cells rely heavily on the fatty acid metabolism occurs during fasting. In this situation, because there is no supply of glucose coming from food absorption, the available blood glucose is spared for erythrocytes and brain functioning. This causes free fatty acids in the serum to function as the main energy source for muscles. Again, in the case of reduced CPT 2 activity, in which energy requirements cannot be met due to the impaired fatty acid metabolism, rhabdomyolysis may result.

Studies have shown that CPT activity is significantly influenced by fasting, diabetes and hyperthyroidism. Furthermore, the increased dependence on lipid metabolism in the case of severe injury, infections and the like may explain why these conditions can provoke rhabdomyolysis in CPT 2 deficient patients. Other conditions, which may result in a higher dependance on lipid metabolism (and, therefore, the triggering of rhabdomyolysis in a CPT 2 deficient individual), can include hormonal and metabolic influences. The same triggering influence in CPT 2 deficient patients can occur from changes in the phospholipid membrane compositions from nutritional factors, most (general) anesthetics, drugs and physical exercise.

It is therefore paramount that CPT 2 deficient patients try to avoid the abovementioned conditions and situations, and any others in which the energy that would be required from the fatty acids metabolism would exceed the available CPT 2 activity and capacity.

It should be noted that patients with CPT 2 deficiency also have lower levels of these enzymes in liver, leukocytes, platelets and fibroblasts.

 

3. Symptoms of CPT 2 deficiency

Symptoms of CPT 2 deficiency consist of attacks of myalgia, cramps, muscle stiffness, painful muscles or muscle weakness. In case of a severe attack, these symptoms progress to myoglobinuria, caused by rhabdomyolisis.

In the majority of cases of CPT 2 deficiency (2 out of 3), the intermittent symptoms began in the first or second decade of life. Depending on the patient, the frequency of the attacks ranges from one or two during a lifespan to several attacks per week. During the attack, there is usually no muscle weakness, and there are no neurological symptoms. The severity of attacks may vary from mild myalgias lasting for only a few hours, or mild pigmenturia with no other symptoms, to rhabdomyolysis lasting for several days, with the possibility of renal failure and other severe conditions. Involvement of the respiratory muscles may require assisted respiration.

The symptoms of CPT 2 deficiency are, in most cases, precipitated by prolonged exertion, but there are other causes which can provoke an attack, such as infections (see further).

Note that the ability to perform short, intense exercise is not impaired in people with CPT 2 deficiency. In fact, it is probably healthy for CPT 2 deficient patients to exercise regularly, as long as the fatty acid metabolism is not tested beyond its limit. As a general rule, although the times vary according to the type of exercise and the person involved, a shift towards the lipid metabolism can occur between 30 and 60 minutes after the start of the exercise. Examples of prolonged exertion (which CPT 2 deficient patients would be wise to avoid) are long distance walking, hiking, jogging, mountain climbing, swimming, bodybuilding, and others. The first symptoms may occur some hours later.

However, with the more severe attacks of rhabdomyolysis, a combination of factors is often suspected. It should be mentioned here again that infectious diseases, fasting, high fat intake, the use of certain medicines and drugs (such as ibuprofen, paracetamol, and diazepam) and (volatile) anesthetics can also provoke an attack.Therefore, when one of the triggers is present in a CPT 2 deficient person, it is important to avoid other conditions which may stress the lipid metabolism.

For a list of known and suspected triggers, which should be avoided as much as possible in case of a CPT 2 deficient person, please go to the following section: Attack Triggers.

For treatment options in case of an attack, go to the following page: Attack Treatment.

 

4. Rhabdomyolysis

The underlying defect and cause of various symptoms in CPT 2 deficiency is the lysis of the muscle cells through faulty fat metabolism and (therefore) energy production. The lysis of striated muscle cells is called rhabdomyolysis. Because it is very likely that CPT 2 patients will endure episodes of rhabdomyolysis (ranging from slight to extremely dangerous) at some stage in their lives, this condition is discussed in further detail.

Rhabdomyolysis, in general (i.e. not only looking at CPT 2 deficient patients), is a condition caused by skeletal muscle injury by a variety of causes, and the subsequent release of muscle cell contents into the circulation. Rhabdomyolysis as such has many causes. The most common causes are alcohol, seizures, and trauma (such as a traffic accident in which muscles are 'crushed'). However, many other conditions have been reported to cause rhabdomyolysis; these include hypothyroidism, metabolic myopathies (such as CPT 2 deficiency), an overdose of drugs or medicines, malignant hyperthermia (MH) caused by commonly used general anesthetics in susceptible individuals, electrolyte derangements, plant toxins, extremely strenuous exercise, and viral infections (*). Most cases of exercise-induced rhabdomyolysis have occurred after strenuous activity such as weight lifting, marathon running, or wrestling, usually in untrained individuals.

(*)Viruses reported to cause rhabdomyolysis include influenza virus, echovirus type 9, adenovirus, Epstein-Barr virus, herpes viruses, and, rarely, coxsackieviruses. A case of rhabdomyolysis associated with coxsackie B virus infection occurred in a patient after mild exercise on a treadmill. Recent systemic viral infections may predispose patients to significant rhabdomyolysis, even after non-overly strenuous physical activity.)

Severe rhabdomyolysis is a serious medical condition, which may result in myoglobinuria, progressing towards acute renal failure (ARF), hypovolemia and hyperkalemia, disseminated intravascular coagulation (DIC) and compartment syndrome. As mentioned previously, disruption of muscle cell membranes is caused by a) direct mechanical or toxic insult, b) the inability to maintain ionic gradients across the membrane as seen in ischemia, c) extreme exertion, d) metabolic disturbances such as CPT 2 deficiency.

 

5. Biochemical features and basis for diagnosis of rhabdomyolysis

Injury of the sarcolemma, which is the enveloping membrane of skeletal muscle cells, results in the release of myoglobin, creatinine phosphokinase (CK), as well as other protein and non-protein cellular contents into plasma. Among other things, this leads to an increase of the serum levels of myoglobin, CK, aldolase, lactic dehydrogenase, potassium, phosphates, purines, uric acid, aspartate aminotransferase (AST), carbonic anhydrase III, as well as myosin heavy-chain fragments.

Estimation of myoglobin in the serum and urine is useful for the diagnosis of rhabdomyolysis (in CPT 2 deficiency and other causes), particularly in the early phases of the disease. Myoglobin is filtered by the kidney and appears in the urine when the plasma concentration exceeds 1.5 mg/dl. It imparts a dark red, almost brown color to urine when urine concentration exceeds 100 mg/dl.

The presence of myoglobin in the urine establishes the diagnosis of rhabdomyolysis in an early stage (see above). It therefore seems important to make this diagnosis in an early stage of the myoglobinuria, for example by using a urine dipstick (the reagent being ortholuidine). The ortholuidine also reacts to the globine fragment of hemoglobin. However, in the absence of hematuria, a positive reaction with the dipstick is highly suggestive, even more so when hemolysis can be excluded. It should be noted that a radioimmunoassay is more sensitive and accurate than using a urine dipstick, and therefore preferred. However, a dipstick can be used by the patient with known CPT 2 deficiency as well, when a fast and preliminary diagnosis is desirable.

Myoglobin has a short half-life (2-3 hours), and is rapidly cleared by both renal excretion and metabolism to bilirubin. Serum myoglobin levels, therefore, return to normal in about 6-8 hours, following the cessation of muscle injury. Owing to its rapid clearance from plasma, the absence of myoglobin does not exclude the diagnosis of rhabdomyolysis.

Elevated creatinine phosphokinase (CK) is the hallmark of rhabdomyolysis by any cause. In the case of CPT 2 deficient patients, CK elevation above 100,000 has been reported in many patients, in one patient even reaching 516,000. It rises within 12 hours of the onset of muscle injury, peaks in 1-3 days, and declines 3-5 days after the cessation of muscle injury. The half-life of CK is 1.5 days and so it remains elevated much longer than serum myoglobin levels.

Hyperkalemia increases the risk of cardiac dysrrhythmia. The release of organic and inorganic phosphates from the injured muscles causes an increase in serum phosphate levels, which may elevate calcium phosphate product resulting in the deposition of calcium salts in muscle and other tissues. Hypocalcemia then ensues. The combination of hypocalcemia and hyperkalemia makes the likelihood of cardiac dysrhythmia even larger. However, in late stages of the disease, mobilization of calcium from damaged muscle results in hypercalcemia. The released purine precursors are converted to uric acid, thus increasing its levels.

Carbonic anhydrase III is an enzyme present in skeletal muscles but not in myocardium, in contrast to creatinine phosphokinase (CK). An increase in its levels is thus more specific for skeletal muscle injury than CK. However, CK is elevated to such a degree that myocardial infarction can be excluded. Increase in myosin heavy-chain fragments is also more specific in skeletal than myocardial muscle injury. The levels increase in about 4 to 7 days after muscle injury, and remain so even until after day 12.

Measurement of myosin heavy-chain fragments is particularly useful for the late diagnosis of rhabdomyolysis. Unfortunately, these tests are not readily available. Other biochemical abnormalities include increased serum levels of creatinine, hydroxybutyrate and lactic acid, thrombocytopenia, increased fibrinogen degradation products, prolonged prothrombin time and proteinuria.

 

6. Clinical Manifestations of Rhabdomyolysis

There is wide variation in the clinical presentation of rhabdomyolysis (by any cause). The classical triad of symptoms are muscle pain, weakness and dark colored urine. The muscles can be tender and swollen, and there can be skin changes indicating pressure necrosis. However, these classical features are seen in less than 10% of rhabdomyolysis patients. Over 50% of rhabdomyolysis patients may not complain of muscle pain or weakness.

Diagnosis becomes even more difficult in patients with altered mental state or levels of consciousness, who are unable to give a coherent history. Features related to the effects of drug poisoning can also predominate and the possibility of rhabdomyolysis can be missed. A high index of suspicion of rhabdomyolysis is thus necessary for early diagnosis.

Rhabdomyolysis should be suspected in patients presenting with drug poisoning, altered levels of consciousness, severe fluid and electrolyte abnormality, hyperthermia, hypotension, hypoxia, and states of increased muscular activity, such as seizures, agitation, strenuous muscle exercise or dystonia, particularly in patients with alcohol or substance abuse. Patients who have ingested neuroleptic drugs can present initially with dystonia, hyperthermia, or neuroleptic malignant syndrome characterized by fever, muscle rigidity, autonomic dysfunction and altered consciousness.

Some experts are of the opinion that rhabdomyolysis with as underlying cause CPT 2 deficiency should be suspected in at least some of the the above mentioned cases. It should also be noted that patients with CPT 2 deficiency are more prone to develop Malignant Hyperthermia (MH).

 

7. Complications of Rhabdomyolysis

Acute Renal Failure (ARF)

Acute renal failure, oliguric or nonoliguric, is the most common complication of rhabdomyolysis. It occurs in 10%-40% of patients. Rhabdomyolysis also accounts for 5%-25% of all cases of acute renal failure. The causes of the renal injury include direct nephrotoxicity of ferrihemate produced by the dissociation of myoglobin at pH 5.6 or less, tubular obstruction due to protein, uric acid crystals and precipitates of myoglobin (myoglobin casts), and reduction in renal blood flow as a result of renal vasoconstriction.

Intracellular iron is an important mediator of tissue damage. As a transition metal it can donate and accept electrons, and its toxicity is due to its ability to catalyze oxygen- and non-oxygen-based free radical reactions. In rhabdomyolysis, the cytotoxic iron effect is derived from heme, a product of myoglobin metabolism. In the renal tubules the iron so derived catalyzes free radical reactions, which are associated with lipid peroxidation. The major mechanism of renal tubular damage in rhabdomyolysis is the mitochondrial free radical production which induces lipid peroxidation. Procedures which chelate iron, or prevent or reduce the release of free iron, have been shown to have a protective effect, thus demonstrating the important role of iron in tubular damage in rhabdomyolysis.

Acute renal failure is associated in the early phases with hyperkalemia, hyperphosphatemia and a marked rise in uric acid and hypocalcemia. The raised uric acid is due to rapid metabolism of muscle purines. Binding of calcium by damaged muscle and decreased levels of serum 1,25 dihydroxycholecalciferol account for the observed hypocalcemia. The combination of hypocalcemia and hyperkalemia can result in ventricular dysrrhythmia and possible cardiac arrest. Acute renal failure as a complication of rhabdomyolysis is also associated with a disproportionate increase in serum creatinine levels as a result of the release of preformed creatinine from the damaged muscle into plasma. Currently there is no reliable factor of predictive value in those likely to develop acute renal failure.

Dialysis may be required in 50-70 % of patients. As the cases in question are acute and life threatening, hemodialysis in the form of continuous venous venous hemodialysis and hemofiltration (CVVH)) is preferred over regular hemodialysis (and peritoneal dialysis), as CVVH has better filtration rates over a 24-hour period, restores the electrolyte balance more quickly, and is also better for very sick patients in general.

 

Involvement of myocardium and intercostal muscles

Involvement of myocardium and intercostal muscles and diaphragm can lead to acute cardiomyopathy and acute respiratory failure, which warrents artificial respiration.

 

Compartment syndrome

This syndrome is not unusual in rhabdomyolysis. The compartments containing anterior tibial, peroneal, lateral thigh, soleus, gluteal, deltoid and forearm muscles may be affected There is increased swelling and tenderness of the involved muscle, and the increased pressure in the compartment can be associated with decreased pulse and neuropathy in the affected limb. Re-elevation of CK levels can herald the onset of compartment syndrome. This is called the 'second wave' phenomenon and denotes the persistent or rebound elevations of CK levels 48 or 72 hours after the initial onset. Failure of the CK levels to decrease by approximately 50% every 48 hours should raise suspicion of further muscle damage by the compartment syndrome. Immediate fasciotomy is required if intracompartment pressure exceeds 30-50 mm Hg, in order to prevent the sequelae of limb contracture, nerve damage, ischemia and possible amputation.

 

Disseminated Intravascular Coagulation (DIC)

Disseminated intravascular coagulation may complicate rhabdomyolysis. It probably results from the activation of the clotting cascade by components of the damaged muscles. However, little additional information is available on this subject.

 

8. Summary

Rhabdomyolysis is a potentially life threatening condition, caused by a host of triggering factors. One of these is CPT 2 deficiency, a genetic disorder in which the enzyme Carnitine Palmotyl Transferase 2, which is necessary for the transport of long chain fatty acids through the mitochondrial membrane in muscle cells, is deficient. Myalgia, pigmenturia and elevated serum creatinine phosphokinase (CK) are the common features of rhabdomyolysis. Acute renal failure (ARF), cardiac arrest, respiratory insufficiency, compartment syndrome and disseminated intravascular coagulation (DIC) may be complications caused by severe metabolic disturbances. The prevention, or swift and adequate treatment, of these life-threatening complications, warrant an early diagnosis, and an agressive treatment protocol (see Attack treatment ).



Version Revision date Revised by Comment
1.0 14 august 2000 MHN