Carnitine Palmitoyltransferas... Health Article

Definition

Carnitine palmitoyltransferase (CPT) deficiency refers to two separate, hereditary diseases of lipid metabolism, CPT-I deficiency and CPT-II deficiency. CPT-I deficiency affects lipid metabolism in the liver, with serious physical symptoms including coma and seizures. Two types of CPT-II deficiency are similar in age of onset and type of symptoms to CPT-I deficiency. The third, most common type of CPT-II deficiency involves intermittent muscle disease in adults, with a potential for myoglobinuria, a serious complication affecting the kidneys. Preventive measures and treatments are available for CPT-I deficiency, and the muscle form of CPT-II deficiency.

Description

Carnitine palmitoyltransferase (CPT) is an important enzyme required by the body to use (metabolize) lipids (fats). CPT speeds up the transport of long-chain fatty acids across the inner mitochondria membrane. This transport also depends on carnitine, also called vitamin B7.

Until the 1990s, discussion centered on whether defects in a single CPT enzyme were responsible for all the conditions resulting from CPT deficiency. Careful chemical and genetic analysis eventually pointed to two different enzymes: CPT-I and CPT-II. Both CPT-I and CPT-II were shown to play an important role in the metabolism of lipids. CPT deficiency of any type affects the muscles, so these disorders are considered to be metabolic myopathies (muscle diseases), or more specifically, mitochondrial myopathies, meaning myopathies that result from abnormal changes occurring in the mitochondria of the cells as a result of excessive lipid build-up.

Understanding the symptoms of CPT requires some familiarity with the basics of lipid metabolism in muscle cells. Fatty acids (FA) are the major component of lipids. FAs contain a chain of carbon atoms of varying length. Long-chain fatty acids (LCFAs) are the most abundant type, and have at least 12 carbon atoms. Lipids and glucose (sugar) are the primary sources of energy for the body. Both are converted into energy (oxidized) inside mitochondria, structures within each cell where numerous energy-producing chemical reactions take place. Each cell contains many mitochondria.

A single mitochondrion is enclosed by a double-layer membrane. LCFAs are unable to pass through the inner portion of this membrane without first being bound to carnitine, a type of amino acid. CPT-I chemically binds carnitine to LCFAs, allowing transfer through the inner membrane. However, LCFAs cannot be oxidized inside the mitochondrion while still attached to carnitine, so CPT-II reverses the action of CPT-I and removes carnitine. Once accomplished, LCFAs can proceed to be metabolized. Therefore, deficiency of either CPT-I or CPT-II results in improper transfer and utilization of LCFAs in the mitochondria.

CPT-I is involved in lipid metabolism in several tissues, most importantly the liver. There, LCFAs are broken down and ketone bodies are produced. Like lipids and glucose, ketone bodies are used by the body as fuel, especially in the brain and muscles. Deficiency of CPT-I in the liver results in decreased levels of ketone bodies (hypoketosis), as well as low blood-sugar levels (hypoglycemia). Hypoketosis combined with hypoglycemia in a child can lead to weakness, seizures, and coma. Symptoms can be reversed by glucose infusions, as well as supplementation with medium-chain fatty acids, which do not require CPT-I to produce energy.

As noted, glucose and fatty acids are important energy sources for the body. During exercise, the muscles initially use glucose as their primary fuel. After some time, however, glucose is depleted and the muscles switch to using fatty acids by a chemical process called oxidation. CPT-II deficiency results in a decrease in LCFAs that can be used by the mitochondria, and the muscles eventually exhaust their energy supply. This explains why prolonged exercise may cause an attack of muscle fatigue, stiffness, and pain in people with CPT-II deficiency. The ability to exercise for short periods is not affected. Infections, stress, muscle trauma, and exposure to cold also put extra demands on the muscles and can trigger an attack. Fasting, or a diet high in fats and low in carbohydrates (complex sugars), deplete glucose reserves in the muscles and are risk factors as well.

In some cases, CPT deficiency results in the breakdown of muscle tissue, a process called rhabdomyolysis, and it causes some components of muscle cells to "leak" into the bloodstream. Myoglobin, the muscle-cell equivalent of hemoglobin in the blood, is one of these components. Myoglobin is filtered from the blood by the kidneys and deposited in the urine, causing myoglobinuria. Dark-colored urine is the typical sign of myoglobinuria. Severe and/or repeated episodes of rhabdomyolysis and myoglobinuria can cause serious kidney damage.