Metabolic Disease

Metabolic Disease 2419
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A metabolic (met-a-BOLL-ik) disease is a condition that interferes with the bodys chemical processes involved in growth, maintenance of healthy tissues, disposal of waste products, and production of energy to fuel body functions. As a result, a person may have too much or too little of certain substances (such as protein, fat, or carbobydrate) in the body. This imbalance often interferes with the normal function of various body tissues and organs.


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Endocrine system

Energy metabolism

"Inborn Errors of Metabolism": A Scientist's Discovery

Nearly 100 years ago, a British scientist named Archibald Garrod suggested that people actually could inherit genetic (je-NE-tik) information that causes problems with the body's metabolism. A gene is the unit of heredity that carries physical characteristics from parent to child. The parents usually do not have the particular metabolic problem themselves; however, they both carry a "hidden" mutant (changed or abnormal) gene for the disorder that is passed on to the child.

Inheriting the mutant gene from both parents creates problems for the child when the child's body needs to metabolize (me-TAB-o-lize), or process, certain nutrients and other substances properly. Garrod's theory was revolutionary at the time, since no one had yet suggested that the body's chemical processes might somehow be related to heredity. More-over, it generally was believed that diseases were caused only by things from outside the body, such as germs and bacteria.

In lectures delivered in 1908, Garrod described several hereditary diseases that are caused by too little or complete lack of certain enzymes (EN-zimes). An enzyme is a protein that speeds up or controls certain chemical reactions in the body. In three of the diseases Garrod described—alkaptonuria (al-cap-to-NYOOR-ee-a), cystinuria (sis-ti-NYOOR-ee-a), and pentosuria (pen-tos-YOOR-ee-a)—certain forms of acids and sugar were found at abnormally high levels in the urine, showing that the body had not processed them correctly. This suggested that the enzymes needed for processing were absent or not functioning properly. Dr. Garrod called these diseases "inborn errors of metabolism," a name that persists to this day.

It has been nearly a century since Dr. Garrod made his discovery, and in that time scientists have identified more than 200 genetic mutations that cause different metabolic disorders.

How Does Metabolism Normally Work?

Most people eat and drink every day without giving much thought to what happens inside the body afterwards, beyond the fact that the stomach and intestines help digest what they consume. But in reality, digestion is only the beginning. Once food and drink are broken down into substances that the body can use, the process called metabolism begins. Metabolism actually is a series of chemical processes through which the body makes use of the nutrients in food to carry out its functions: growing, maintaining healthy tissues, disposing of wastes, producing the energy needed for moving, running, jumping, playing … and the list goes on. The process as a whole is quite complex, with hundreds of different reactions happening one after the other to convert nutrients into materials that the body needs for the functions of life. It might help to think of metabolism as a kind of "domino effect," with each "domino," or chemical reaction, falling into place to create the end result. Metabolism involves two main phases: "building up" (anabolism) and "breaking down" (catabolism).


The "building up" phase, also called anabolism (a-NA-bo-liz-um), includes all the processes that occur when the body makes use of nutrients to grow and build new tissues. This involves converting simple substances into more complex substances. For example, during digestion, important compounds called amino (a-MEE-no) acids are released from food. Through anabolism, the body converts these into proteins that are essential to the body's growth, development, and health. Protein is the main building material for all living tissue, including muscles, skin, and internal organs. It also is necessary to form enzymes, hormones * , and antibodies * , all of which are essential to the body's normal function.


The "breaking down" phase, or catabolism (ca-TA-bo-liz-um), involves processes that move in the opposite direction: that is, they break down more complex substances into simpler forms, releasing energy that is used for work, movement, or heat production. For instance, the body's tissues store a carbohydrate called glycogen (GLY-ko-jen) in the liver * and the muscles. When the body needs energy, it breaks down the glycogen into glucose, a form of sugar. Glucose is then metabolized, or broken down, in the body's cells to release energy for fueling body functions.

Enzymes "missing in action"

None of the processes involved in metabolism would be possible without substances called enzymes. These are proteins that the body's cells produce to speed up or regulate chemical reactions. Each enzyme is made up of smaller amino acids, which are the building blocks of all proteins. The sequence of amino acids in an enzyme is determined by a person's genes. People who are born with metabolic diseases inherit a genetic mutation (a change) in a specific gene. That mutation causes the body to fail to produce an enzyme, or to produce an enzyme that is inactive. As a result, the enzyme's activity in the body decreases or is completely absent.

* hormones are chemical sub-stances produced in one part of the body that regulate the activities of certain organs or groups of cells in other parts of the body.

* antibodies are proteins produced by the body's infection-fighting immune system to defend against bacteria, viruses, and other foreign organisms or substances.

* liver is the large organ, located in the upper abdomen, that helps cleanse the blood of waste products and toxic substances. It aids in digestion by secreting bile, and serves as a major site of sugar storage in the body.

It might help to think of enzymes as words and amino acids as letters of the alphabet. When a word is misspelled, its letters are ordered incorrectly, and its meaning may be confusing or unclear. When an enzyme is "misspelled," the amino acids are out of order and it cannot function properly. The particular step in metabolism that the enzyme controls does not happen as it should.

There are hundreds of such "misspellings" that can cause many different kinds of metabolic disorders. Some are more serious than others. Many can be treated, but some cannot. If the disease is not treated, particular substances that are not being processed properly—whether car-bohydrate, sugar, fat, or protein—build up excessively in the body, or too little of a needed substance is produced. In either case, the result is an imbalance that causes problems with the function and growth of many body tissues and organs, including the brain.

Metabolic Diseases

Specific examples of metabolic diseases are helpful in understanding metabolic diseases in general. Describing all of them would fill this entire book. Here are some of the more common ones.

When early detection and special diet are key: Phenylketonuria (PKU)

Labels on diet soda and other food products containing the artificial sweetener aspartame feature a special warning: "Phenylketonurics: Contains Phenylalanine." This alerts people with the metabolic disorder phenylketonuria (FEN-il-ke-to-NYOOR-ee-a) that aspartame contains the amino acid called phenylalanine (fen-il-AL-a-neen). People who have PKU lack the enzyme that is needed to convert this amino acid into another substance called tyrosine (TY-ro-seen). In other words, the body cannot process phenylalanine correctly. This amino acid is necessary for normal growth in infants and children and for normal protein production throughout life. However, if too much of it builds up, it poisons the brain tissue and eventually causes mental retardation. It also can cause the skin and urine to give off an unusual musty odor and lead to skin rashes.

Fortunately, doctors can determine whether an infant has PKU almost immediately after birth. In the 1960s, scientists developed a PKU test that is now performed on all newborns in the United States. It involves taking a small blood sample and placing it with a strain of bacterium that cannot grow without phenylalanine. The PKU test is positive if the bacteria reproduce. Only one out of roughly every 10,000 babies born in the U.S. tests positive for PKU, which makes it a rare condition, but this adds up to several hundred babies each year.

When these babies are put on a special diet right away, they can avoid the mental retardation that was the certain result of PKU in the past. This diet cuts out all high-protein foods, which are also high in phenylalanine, such as meat, fish, poultry, milk, eggs, cheese, ice cream, nuts, and many products containing regular flour. However, the particular restrictions will vary from person to person, depending on the severity of the condition. The diet can be difficult to follow, but it is crucial to staying healthy and avoiding retardation. Children with PKU often need to take a special artificial formula that is used as a nutritional sub-stitute for the foods they cannot eat.

Because of early diagnosis and careful dietary restrictions, children with PKU are now growing up normally. They are achieving in school, attending college, and entering a wide range of challenging professions as adults. With the exception of the special diet they must follow, children with PKU can do anything that children without PKU can do.

75 Years Ago: a Discovery
That Changed Children's Lives

Norway, 1934: A mother with two severely mentally retarded children goes to see Dr. Asbjørn Følling. She is desperate for answers about her children's condition, which no doctor has yet explained to her satisfaction. She also wonders about an unusual smell that her children always seem to have. After testing urine samples, Dr. Følling finds that they excrete a substance not found in normal urine. Although he does not have access to the advanced chemical tests that would become available later in the century, eventually he is able to identify the substance as phenylpyruvic acid, a type of amino acid. He immediately wonders whether the buildup of acid has something to do with the children's retardation.

Dr. Følling collects urine samples from hundreds of other mentally retarded patients and finds that eight of them excrete the same acid. He then publishes a paper that draws a connection between the acid levels and retardation in these ten people. He also makes the hypothesis (hi-PO-the-sis) that the acid is present because these patients are unable to metabolize phenylalanine. Eventually, he confirms that hypothesis when he and his colleague figure out a way to use bacteria to test for high levels of phenylalanine in the blood.

Dr. Følling had just discovered phenylketonuria (PKU), and in so doing, he changed the lives of future generations of children who would be born with this condition. He showed that mental retardation could be avoided if the condition was discovered right away and if phenylalanine levels were controlled through dietary changes.

In 1962, President John F. Kennedy awarded Dr. Følling the Joseph P. Kennedy International Award in Mental Retardation for his achievements. At about the same time, a scientist named Dr. Robert Guthrie was using Dr. Følling's discoveries to develop an effective newborn screening test for PKU. The test became available in the early 1960s, and Dr. Guthrie worked diligently to establish screening programs in the United States and many other countries. All babies in the U.S. now are routinely screened for PKU.

When urine smells sweet, like maple syrup (MSUD)

PKU is just one example of several metabolic disorders that occur when the body lacks an enzyme needed to process amino acids. Another is Maple Syrup Urine Disease (MSUD), in which the enzyme needed to process three other amino acids—valine (VAYL-een), leucine (LOO-seen), and iso-leucine (i-so-LOO-seen)—is lacking. These acids are essential for the body's normal growth and function. When they are not metabolized properly, they can build up in the body, causing the urine to smell like maple syrup or sweet, burnt sugar. If left untreated, MSUD can cause mental retardation, physical disability, and even death.

About 1 in 225,000 infants are born with MSUD, making it even rarer than PKU. Not only does their urine smell like maple syrup, but they usually have little appetite and are extremely irritable. Some states require that all newborns be tested for MSUD, but some do not as yet. It is important that the condition be diagnosed and treated right away; otherwise, it can cause seizures, unconsciousness, brain damage, and even death. Treatment takes the form of a carefully controlled diet that cuts out certain high-protein foods that contain the three amino acids the body cannot process. Like children with PKU, those with MSUD are often given an artificial formula that supplies the necessary nutrients they miss by excluding certain foods.

200 Years Ago:
The "Madness" of King George

George III (1738—1820) is remembered as the king of England against whom the American colonists rebelled and fought for their independence. He also is remembered as a king who experienced violent fits of madness that eventually made him incapable of ruling. King George was subject to agonizing pain, excited overactivity, paralysis, and delirium at different times in his life. His "nervous spells" came and went during the last three or four decades of his life, which ended in 1820 when he was 81.

Some historians now believe that King George's problem was in his body, not his mind. When psychiatrists studied the king's letters and examined the notes made by his doctors, they discovered that King George's symptoms included not only nervous attacks but a dark red color of the urine, suggesting that he had the metabolic disease called porphyria. In 1967, two British psychiatrists published a scientific paper called A Clinical Reassessment of the Insanity of George III and Some of Its Historical Implications that made this very argument. Further historical investigation suggests that other members of the royal family may have had the condition too.

So the history books may be wrong about "mad King George." Medicine at the time was not advanced enough to determine how the body's chemical processes might affect the mind. But we now know that people with porphyria actually have a problem in the blood that, in some cases, interferes with the normal functioning of the brain.

Babies who cannot drink milk: Galactosemia

For most babies and young children, mother's milk (or a formula like breast milk) and then cow's milk supply nutrients essential to the body's function and growth. But babies born with the metabolic disease galactosemia (ga-lak-to-SEE-me-a) do not have enough of the enzyme that breaks down the sugar in milk called galactose. This enzyme is usually produced by the liver, but if the liver does not produce enough, galactose builds up in the blood and can cause serious health problems if the condition is not diagnosed and treated.

Symptoms usually appear in the first few days of life, as soon as the baby starts drinking breast milk or formula. The baby often starts vomiting, the liver swells up, and the skin and eyes take on a yellow color (a condition called jaundice). Other symptoms might include infections, irritability, failure to gain weight, and diarrhea. If it is not diagnosed quickly, galactosemia can cause severe damage to the liver, eyes, kidney, and brain. For this reason, many states require that all newborns have a blood test that can detect it. About 1 in 20,000 babies are born with the condition, and it is treated by removing all milk and milk-containing products from the diet. This reduces the risk of permanent damage, but there may still be problems with growth, speech, and mental function as the child gets older.

Fructose intolerance

Galactosemia is just one example of many metabolic diseases in which the body cannot process sugars properly. Another is fructose intolerance, in which a person cannot metabolize a certain form of sugar found in fruit, fruit juices, powdered and table sugar, honey, corn syrup, and other foods. Like galactosemia, it is treated by excluding certain foods from the diet. Fructose must be limited strictly to avoid possible damage to the liver and kidneys and mental retardation.

Problems with carbohydrate metabolism

The body takes a simple sugar called glucose from foods, converts it into a carbohydrate called glycogen, and stores it in the liver and muscles. When the body needs energy to fuel its activities, certain enzymes then break the glycogen back down into sugar. Some people have problems with one or more of these enzymes, resulting in a condition known as glycogen storage disease.

There actually are seven different types of glycogen storage disease, each involving different enzymes. One example is glucose-6-phosphatase (G6PD) deficiency. Glucose-6-phosphatase is an enzyme normally found in the liver that is needed to release glucose from the liver into the blood-stream so that it can be processed by the body to produce energy. Deficiency of the enzyme can cause the levels of sugar in the blood to fall dangerously low if glucose is not taken in from the diet every few hours.

In G6PD deficiency and other glycogen storage diseases, glycogen is stored in too large amounts in various parts of the body, causing problems with the liver, muscles, blood cells, heart, brain, and/or other organs. Treatment for these conditions usually involves changes in diet.

When the blood gets out of balance: Porphyria

The body uses a special chemical called porphyrin (POR-fir-in) to make heme, which is the substance in the blood that carries oxygen to the tissues. Eight different enzymes are in charge of the metabolic process that uses porphyrin to make heme. When any of these enzymes are missing or do not function properly, too much porphyrin builds up in the body, and it is eventually released from the body in the urine or stool. As a result, not enough heme is produced to keep the person healthy. This condition is called porphyria (poor-FEER-ee-a).

People who have porphryria can experience symptoms that involve the skin, the nervous system, and/or other internal organs. When porphyria affects the skin, the person may have blisters, itching, swelling, or extreme sensitivity to the sun. When it affects the brain, it can cause hallucinations * , delirium * , seizures, depression, anxiety, and paranoia * . Other physical symptoms may include chest or stomach pain, muscle cramps, weakness, or urine that is dark purple or reddish in color.

Doctors can test someone's blood, urine, or stool to diagnose por-phyria. A drug called hemin, which is like heme, can be given, along with other medications to relieve symptoms. Sometimes, a high-carbo-hydrate diet also can help.

What Does It All Mean?

There are many other metabolic diseases besides those described above. However, these few examples illustrate the chain of events that happen in many inherited metabolic diseases:

  1. A person inherits a genetic mutation, or abnormality.
  2. Because of this, a certain enzyme is not produced or does not work as it should.
  3. Consequently, a certain step in metabolism does not occur normally.
  4. The substance that should have been metabolized (broken down or changed into another form) builds up in the body, and/or other important substances needed by the body are not produced in adequate amounts.

The person's system gets "out of balance," so to speak, and this can cause damage if the problem is not corrected with diet or medication. In some cases, the imbalance cannot be corrected and may cause permanent damage or even death.

* hallucinations are perceptions by the senses that are not based on reality, for example, seeing or hearing things that do not exist,

* delirium is a serious mental disorder that may be marked by confusion, speech disorders, anxiety, excitement and/or hallucinations,

* paranoia is a mental disorder marked by feelings of self-importance or suspicion that other people are "out to get' the paranoid person.


U.S. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Building 31, Room 9A04, Bethesda, MD 20892. NIDDK is the government institute that oversees research on endocrine and metabolic diseases. Its website posts fact sheets and has links to more than 30 organizations serving patients and their families.

American Association of Clinical Endocrinologists, 1000 Riverside Avenue, Suite 205, Jacksonville, FL 32204. An organization of physicians who specialize in treating metabolic diseases.

Endocrine Society, 4350 East West Highway, Suite 500, Bethesda, MD 20814-4410. An organization of scientists and physicians who specialize in research and publications covering metabolic diseases.

National Organization for Rare Disorders, P.O. Box 8923, New Fairfield, CT 06812-8923.
Telephone 800-999-6673

American Porphyria Foundation, P.O. Box 22712, Houston, TX 77227.
Telephone 713-266-9617

National PKU News: News and Information about Phenylketonuria, 6869 Woodlawn Avenue NE, Number 116, Seattle, WA 98115-5469.

Parents of Galactosemic Children, 2148 Bryton Drive, Powell, OH 43605.

The Maple Syrup Urine Disease Family Support Group.

See also
Birth Defects
Genetic Diseases
Growth Disorders
Mental Retardation
Thyroid Disease

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