Carnitine palmitoyltransferase II (CPT II) deficiency is a genetic condition that prevents the body from effectively using certain fats for energy, especially during fasting periods. This disorder stems from a defect in the carnitine palmitoyltransferase 2 enzyme (CPT2), which normally escorts breakdown products of fats from the main part of the muscle cell into the mitochondria (the cell's "engine"), where they can be further metabolized for energy. It is considered to be an autosomal recessive disorder, so incidence is equal in males and females. Clinical symptoms of the disease occur more frequently during infancy (1-12 years old) than in adolescence (13-22 years old) and adulthood (>22 years old).
Understanding CPT2 Deficiency
CPT II deficiency, also known as carnitine palmitoyltransferase deficiency, is a fatty acid oxidation disorder (FAOD). It is a defect in one of the enzymes involved in the deployment of fats to fuel that can be used by the body. It becomes very important when the body is low on glucose or needs additional fuel such as when the child has not eaten for a period of time, during infections and other illnesses, during operations and when exercising vigorously. Variants in the CPT2 gene reduce the activity of carnitine palmitoyltransferase 2. As a result, there are not enough enzymes available to remove carnitine from long-chain fatty acids. With carnitine still attached, these fatty acids (known as long-chain acylcarnitines) cannot be broken down and used for energy.
Types of CPT2 Deficiency
CPT II deficiency presents in varying degrees of severity:
- Lethal Neonatal Form: This severe form becomes apparent soon after birth. Infants develop respiratory and liver failure, a weakened heart muscle (cardiomyopathy), and an irregular heartbeat (arrhythmia). Brain and kidney abnormalities are also common. Affected individuals experience low blood glucose levels and low ketone levels (hypoketotic hypoglycemia).
- Severe Infantile Hepatocardiomuscular Form: This form affects the liver, heart, and muscles, with signs and symptoms typically appearing within the first year of life. Recurring episodes of hypoketotic hypoglycemia, seizures, liver dysfunction, cardiomyopathy, arrhythmia, and muscle weakness are characteristic. These symptoms can be triggered by fasting or illnesses.
- Myopathic Form: The least severe type, the myopathic form, is characterized by recurrent episodes of muscle pain (myalgia) and occasional weakness associated with muscle tissue breakdown (rhabdomyolysis). Episodes may be triggered by exercise, stress, extreme temperatures, infections, or fasting.
Symptoms of CPT2 Deficiency
Symptoms usually are brought on by prolonged and intense exercise, especially in combination with fasting, but may not appear for several hours after activity stops. Symptoms also can be brought on by illness, cold, stress or menstruation. This disorder causes muscle pain, stiffness and tenderness, while weakness is less common.
The myopathic form of CPT2 deficiency causes milder symptoms. Symptoms may begin any time up to age 60, often triggered by skipping meals, a lot of exercise, or illness. In the hepatocardiomuscular form, symptoms begin in the first year of life, typically within a few days after birth.
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Complications of CPT2 Deficiency
CPT2 deficiency can sometimes cause kidney failure, particularly during exercise, a condition known as rhabdomyolysis. Rhabdomyolysis is the partial rupture of myocytes, followed by a dramatic release of several muscle molecules (e.g., creatine kinase (CK), lactate dehydrogenase (LDH), myoglobin (Mb), aminotransferases) in the extra cellular space and then into the blood stream. The destruction of muscle tissue releases a protein called myoglobin, which may cause urine to be red or brown (myoglobinuria). Kidney injury typically occurs with acute decompensation. Repeated rhabdo could lead to some muscle weakness.
Cardiomyopathy is another potential complication where the heart may not be able to pump blood as well, leading to shortness of breath. Hypoglycemia, often set off by an infection, is also a possible complication.
Diagnosing CPT2 Deficiency
CPT II deficiency is often detected shortly after birth by newborn screening, which identifies abnormal levels of certain compounds in the blood. Diagnosis typically starts with a medical history and a physical exam, including a neurological exam. Doctors will inquire about symptoms, past medical conditions, and family medical history.
Diagnostic tests include:
- Blood tests: To check for acylcarnitine in the blood.
- Urine test.
- Exercise tests.
- Genetic test: Molecular genetic investigation, regarded as the gold standard for the diagnosis, is often performed only after several years of clinical misunderstandings and attempts at treatment.
- Heart tests.
Dietary Management of CPT2 Deficiency
Treatment for CPT deficiency primarily involves dietary modifications. The cornerstone of CPT II deficiency treatment is a high-carbohydrate, fat-modified/decreased diet given at regular, defined intervals around the clock, or even, in some cases, during the initial period by continuous nasogastric feeding. The suggested nutritional regimen results in a short-term increase of the exercise tolerance but recurrent rhabdomyolysis has been also observed in these cases.
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Macronutrient Ratios
The daily diet should be tailored to reach a macronutrient intake of around 65% carbohydrates, 20% fat, and 15% protein, as suggested by previous studies.
Carbohydrates
Carbohydrate intake should include medium and low glycemic index (GI) foods (e.g., whole grain bread, pasta, oatmeal, selected fruits, etc.), with limitation of high GI foods (e.g., sweets in general), to prevent post-absorptive hyperinsulinemia, which impairs glycogenolysis, which represents a fundamental energy supply process in CPTII-deficient patients.
Protein
To support adequate muscle protein metabolism, the total protein intake, mainly based on high quality protein/low-fat foods (e.g., poultry, low-fat fish, legumes, skim milk, egg whites, etc.), should be distributed in each daily meal (breakfast, lunch, dinner, and snacks).
Fats
Dietary fat intake should be based on the use of extra virgin olive oil (one or two servings per day) as a primary fatty acid source, with a restriction of foods rich in saturated fatty acids and cholesterol (e.g., fatty cheese, fast-foods, low nutrition quality snacks, etc.). The minimum daily recommended intake of long-chain fats is about 10% to prevent essential fatty acid deficiency.
Meal Frequency and Timing
It’s also important to eat often to prevent low blood sugar and prevent the body using fats for energy, which may set off symptoms. Fat-free meals will limit the absorption of fat-soluble vitamins, so it's important not to take vitamin supplements with a fat-free meal. Long-chain fat should be spread throughout the day.
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Medium Chain Triglyceride (MCT) Supplementation
Medium-chain triglyceride supplementation is used to provide fat energy past the enzyme block.
Considerations for Infants
If your baby has CPT II deficiency, he or she will have to be fed regularly on a carbohydrate rich fat modified/decreased diet and can not be allowed to miss a meal. Ensuring that you and the baby awake, initially every 4 hours, can be physically exhausting over time, so support from a spouse or other close contacts is beneficial.
Additional Nutritional Strategies
Essential Fatty Acids
If the DRI for omega-6 is met, omega-3 supplementation can be supplemented with DHA solely and NOT EPA. 250-500 mg of DHA would be plenty to keep your blood DHA within the normal range.
Avoiding Triggering Factors
Fasting, prolonged and intense exercise, exposure to cold, infections, low fluid intake, psychological stress, and lack of sleep can trigger episodes.
Exercise and CPT2 Deficiency
The current recommendations remain those of following a carbohydrates-rich diet with a limited fats intake and reducing, even excluding, physical activity, without, however, taking into account the long-term consequences of this approach.
A specific type of training, based on short duration contractions and resistance exercises, can be beneficial also for CPTII deficient patients. In fact, it is widely known that the energy sources used during exercise strictly depend on the duration and percentage of the maximal sustainable load.
Exercise Recommendations
After getting used to the proposed exercises, the patient was involved in an unsupervised 1 h exercise training session three times per week for 6 months. Each session included interval training and resistance exercise activity. The interval training consisted of a 1 min run and 5 min walk for 15 min progressively increased to 30 min (0° inclination). During the patient’s running, the heart rate, monitored with a cardiofrequenzimeter, was maintained over 70% HRmax (corresponding to a RER of 0.98 measured at the first CPET). Resistance training was based on three sets of eight repetitions with 2 min rest between sets. During training, upper/lower split workouts were carried out. Upper-body exercises included bench press, shoulder press, lat pulldown, dumbbell flies, and dumbbell pull-over and arm curls. Load was fixed at 6-7 of the 0-10 scale for resistance exercise.
Exercise Precautions
Patients with FAODs tolerate resistance exercise/weight training well as the FFA oxidation system is not stressed in these activities; however, Dr. Tarnopolsky advises that patients with FAODs do not do any form of exercise on days when they have a super imposed stress like a flu, cold, fever, or fasting for more than 4 hours.
Other Treatments
Some children also take carnitine, a mild supplemental medicine, but your metabolic physician will be able to let you know if this is appropriate for your child. If he or she becomes ill, it may well be necessary early in the illness (i.e. when it might be considered mild), to provide extra energy in the form of glucose through addition to food or, if necessary, by intravenous drip.
Genetic Counseling and Testing
As CPT II deficiency is an inherited condition it is essential to have your other children tested. Children from the same father and mother as the affected infant have a 1 in 4 (25%) chance of having CPT II deficiency. Your other children can appear healthy and still have CPT II deficiency. If they have CPT II deficiency, successfully having weathered illnesses in the past is No guarantee that an illness in the future will not have serious consequences. If you do have the abnormal gene for the condition, you have choices. With in vitro fertilization, the embryos can be tested for the disease.
The Role of Mitochondria and Peroxisomes
The mitochondrial network and its potential cellular interplay with peroxisomes, which are also involved in the oxidation of fatty acids, may offer new theoretical bases for the management of a CPTII deficiency. The β-oxidation (βOx) of fatty acids (FAs) takes place both in mitochondria and peroxisomes, involving, however, different substrates, respectively.
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