Carnitine palmitoyltransferase II deficiency

Each cell in our body has an energy powerhouse called the mitochondria. It is the job of CPT2 to take long-chain fatty acids to the mitochondria - in the absence of this process, these fats don’t get metabolized. This, in turn, starves the cells of the energy they need during strenuous exercise and periods of fasting.

CPT 2 deficiency is of three types - two of these occur in infants and very young children, and can be fatal:

Lethal neonatal form: In this form of CPT2 deficiency, symptoms like lethargy and poor feeding start presenting soon after birth. If left untreated, the patient usually survives for a few days to a few months.

Infantile hepatic-cardiovascular form: This form of CPT2 deficiency is mostly seen during the first year of life. However, the disease can also become apparent in late infancy or early childhood. Researchers say that infections could be an important factor for the onset of this condition.

Hepatic in medical terminology refers to the liver, and the term cardiovascular is used to signify the heart as well as the blood vessels of the heart. Infants or children who have a severe infantile hepatic-cardiovascular form of CPT2 deficiency are at high risk for liver failure, nervous system damage, going into a coma, and sudden death during the early stages of life.

Myopathic form or Classic form: This is the least severe form of CPT2 deficiency. At the onset, patients can be as young as under 10 years old and as old as 69 years old. Muscle pain (myalgia), weakness and breakdown of muscle tissue (rhabdomyolysis) are characteristic symptoms of the myopathic type of CPT2 deficiency. 

When the muscle tissue breaks down, it releases myoglobin (a protein). This protein goes through the kidneys, and is flushed out of the body with the urine (myoglobinuria) - often, this gives the patient’s urine a red or brown colour. The passage of myoglobin protein can damage the kidneys. In some cases, it can cause kidney failure - a life-threatening condition. 

Episodes of myalgia and rhabdomyolysis are usually triggered by exercise, stress, exposure to extreme temperatures, infections, or fasting. Symptoms start appearing during childhood or adolescence. Most people with the myopathic form of CPT2 deficiency don’t have any of the symptoms in-between episodic attacks.

All three types of  CPT2 deficiency have slightly different clinical presentation:

Lethal neonatal form: Infants with this form of the disorder usually undergo metabolic crisis which can lead to:

• Respiratory failure
• Liver failure
• Seizure
• Cardiomyopathy (weakened heart muscle)
• Arrhythmia (irregular heartbeat) 
• Muscle weakness
• Structural changes in the brain and kidneys
• Kidney cyst
• Cataract
• Newborn babies also develop hypoglycemia (low blood sugar) and a low level of ketones (a product of fat metabolism, ketones are a source of energy). Both these signs together give rise to an unstable condition known as hypoketotic hypoglycemia. 

Infantile hepatic-cardiovascular form: Patients often experience repeated episodes of metabolic crisis in the form of hypoketotic hypoglycemia.

Following symptoms might occur:

• Muscle weakness
• Liver dysfunction
• Cardiomyopathy (enlarged heart)
• Arrhythmia (irregular heartbeat)
• Kidney dysfunction
• Delayed development of motor skills like walking
• Difficulty in learning

Myopathic form: Myopathic form of CPT2 deficiency does not cause a metabolic crisis in the body or heart problems. Instead, common symptoms include:

• Muscle pain or cramps
• Muscle weakness
• Reddish-brown coloured urine
• Kidney failure (if left untreated)

CPT2 deficiency occurs because of a mutation in the CPT2 gene - this gene tells the body how to make the carnitine palmitoyltransferase 2 enzyme. What this enzyme does is a small but important step in the biological reaction that converts fat into energy. Long-chain fatty acids can’t get entry into the mitochondria unless they are attached to carnitine (a bioactive substance). Once these fatty acids enter the mitochondria, the CPT2 enzyme also helps to remove the carnitine from the fat and initiate fatty acid oxidation. 

Fatty acids are a major source of energy for the heart and muscles. Especially in situations of high energy demand and limited glucose availability, such as during prolonged fasting or exercise. 

Mutations in the CPT2 gene reduce the activity of carnitine palmitoyltransferase 2 enzymes. When the body doesn’t make enough of this enzyme, carnitine does not get removed from long-chain fatty acids. As a result, these fatty acids cannot be metabolized to produce energy. 

Reduced-fat metabolism, as well as energy production, lead to characteristic symptoms of CPT2 deficiency, such as hypoketotic hypoglycemia, myalgia, and weakness. Fatty acids and long-chain acylcarnitines (fatty acids which do not get removed from carnitine) can accumulate in cells over time leading to damage in the liver, heart, and muscles.

Genetic testing and enzyme test are the best tools for confirming or ruling out CPT2 deficiency. 

CPT2 deficiency is still a largely underdiagnosed disorder, possibly due to the varying degrees of symptoms in patients. Another reason could be a lack of awareness among the general public and healthcare providers.

Genetic testing: Diagnosis of CPT2 deficiency is usually confirmed by sequencing the complete genome of the suspected patient. Your doctor will take a blood sample. Your gene analysis can show whether one or both genes for CPT2 are mutated, providing a definitive diagnosis. 

People planning to have children together can also use genetic testing to find out if they are carriers of the disease, and how likely they are to pass it on to their offspring. Prenatal testing can help to determine whether or not an unborn child has the disorder.

Enzyme test: Another diagnostic test for CPT2 deficiency is evaluating the level of CPT2 enzyme in the body. This test is done using a skin sample. 

Note: If one or both parents have this disorder, doctors advise both partners to get tested for the CPT2 gene or enzyme before planning a baby. Diagnostic testing of the child after delivery can help in early detection and is advised if one or both parents have this condition. If both gene changes are found in the child, doctors advise DNA testing for any future pregnancies. The sample required for testing the disease in the foetus is obtained either by Chorionic Villus Sampling (by taking a tissue sample of Chorionic Villi - a part of the placenta) or by amniocentesis (amniotic fluid test).

There is no cure for CPT2 deficiency. The myopathic form is a lifelong condition, and management of the disease requires multi-directional approaches - your doctor may recommend medications, dietary supplements and diet or lifestyle modification. The healthcare provider might also refer you to consult a dietician to keep a check on your diet.

Eating at regular intervals: The best way to prevent symptoms from recurring is to keep eating at regular intervals. Parents are advised to pay attention to the eating patterns of infants and young children with CPT2 deficiency - young patients should be fed frequently to prevent a metabolic crisis. Usually,  infants should eat every four to six hours. It is critically important to make the child eat even during the night. Waking up and eating once or twice during the night prevents episodes of metabolic crisis. Your doctor and dietician will give you an appropriate diet plan for your child. A slightly modified diet plan is also given to the parents or patients and should be followed during active illness.

Diet: CPT2 deficiency is a fat metabolism disorder. As such diet is extremely important in order to avoid disease symptoms. Usually a low fat, high carbohydrate food plan is recommended. Carbohydrates provide several types of sugars to the body and can be used as a source of energy. Sometimes, eating sugar during an episodic attack of symptoms can provide relief.

Patients with CPT2 deficiency can’t consume long-chain fatty acids - these include olive oil, fish, meat and nuts. Most of the fat in their recommended diet consists of medium-chain fatty acids - these include dairy products and coconut oil.

Long-chain fatty acids usually have 13-21 carbon atoms where are medium-chain fatty acids have 6-12 carbon atoms and are easier to break down for energy.

MCT oil and Triheptanoin: Medium Chain Triglyceride oil (MCT oil) is often used as part of the food plan for people with CPT2 deficiency. This special oil supplement has medium-chain fatty acids that can be used in small amounts for energy. 

Triheptanoin is a triglyceride made up of three seven-carbon fatty acids. (The name triglycerides comes from the fact that each molecule contains tri or three molecules of fatty acids. Fatty acids, in turn, can be of several types. Those with seven carbon atoms fall in the medium-chain category.) Triheptanoin is thought to break down and produce ketone bodies and propionyl-CoA. Clinical trials are on, and researchers are looking into the effectiveness of this supplement.

L-carnitine: L-carnitine is an amino acid is found abundantly in heart muscle and skeletal tissue. It is sometimes prescribed as a supplement. It functions primarily as a shuttle for fatty acids, transporting them across mitochondrial membranes into the mitochondria, where they are used for energy production. 

Riboflavin: Riboflavin or vitamin B2 supplements may induce a dramatic improvement of muscle symptoms related to CPT2 deficiency disorder.

Bezafibrate: Bezafibrate is a drug which reduces the lipid level in the body. It is usually prescribed for fatty-acid oxidation disorder. Clinical trials have shown that it can improve muscle function in people living with CPT2 deficiency.

AMP-activated protein kinase (AMPK): Exercise, drugs like metformin, rosiglitazone and hormones such as leptin and adiponectin activate AMPK (an enzyme) in the skeletal muscles and increase fatty-acid oxidation in muscles, thereby providing relief from the symptoms of the disease.

CPT2 can not be prevented as it has a strong genetic association. However, symptoms of the disease can be prevented to a large extent by keeping a few things in mind:

• Avoid prolonged or heavy exercise, as it can trigger symptoms of the disease
• Avoid getting cold exposure, keep your body warm to avoid muscle-related symptoms
• Always eat starchy or sugary food before and during periods of moderate exercise
• Avoid eating fats or fat rich food source but keep eating at regular intervals
• Make sure you eat at regular intervals. For young children, parents are advised to feed the patient twice during the night as well as during the day, to avoid a metabolic crisis