Metabolic Disease

A metabolic (meh-tuh-BALL-ik) disease is a condition that interferes with the body's 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 carbohydrate) in the body. This imbalance often interferes with the normal function of various body tissues and organs.

Archibald Garrod and Inborn Errors of Metabolism

The inheritance of the mutant gene from both parents creates problems when the child's body needs to metabolize (meh-TAB-o-lize), or process, certain nutrients and other substances properly. Garrod's hypothesis was revolutionary at the time, because no one had yet suggested that the body's chemical processes might somehow be related to heredity. Moreover, the scientific and medical communities generally believed that only foreign agents from outside the body, such as germs and bacteria, could cause disease.

In lectures delivered in 1908, Garrod described several hereditary diseases caused by too little or a complete lack of certain enzymes * . An enzyme is a protein that speeds up or controls certain chemical reactions in the body. Garrod described three diseases—alkaptonuria (al-cap-to-NYOOR-ee-a), cystinuria (sis-ti-NYOOR-ee-a), and pentosuria (pentos-YOOR-ee-a)—in which the patients experienced abnormally high levels of certain forms of acids and sugar in the urine. This sign showed that the body had not processed these substances correctly, because if it had, the body would have used those substances rather than discarding them in the urine, a waste product. The finding also suggested that the enzymes needed for processing these substances were either absent or not functioning properly. Garrod called these diseases “inborn errors of metabolism,” a name that persists to this day. He published Inborn Errors of Metabolism in 1909, a second edition of which appeared in 1923.

In the decades after Garrod made his discovery, scientists identified hundreds of genetic mutations that cause different metabolic disorders. Some of these disorders are fatal mere hours after birth, but others are treatable, particularly when diagnosed early, and patients may go on to have long and productive lives.

How Does Metabolism Normally Work?

People eat and drink every day, but few think about what happens to that food once the stomach and intestines begin digesting it. Once digestion breaks down food and drink into substances that the body can use, the process called metabolism begins. Metabolism is a series of chemical processes used by the body to put to work the nutrients in food. This process allows the body to carry out a variety of functions, such as growing, maintaining healthy tissues, disposing of wastes, and producing the energy needed for all activities. As a whole, metabolism 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. One way of thinking of metabolism is to consider it a kind of domino effect, with each chemical reaction, or domino, falling into place in sequence to create the end result. Metabolism involves two main phases: building up and breaking down.

Anabolism (building up)

Anabolism (a-NA-bo-liz-um) is the building-up phase. It includes all the processes that occur when the body makes use of nutrients for the purpose of growing and building new tissues, which involves converting simple substances into more complex substances. For example, during digestion, the food releases important compounds called amino (a-MEE-no) acids, which are the building blocks of proteins. Through anabolism, the body converts amino acids 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 hormones * , antibodies * , and enzymes, which are proteins that the body's cells produce to speed up or regulate chemical reactions. Hormones, antibodies, and enzymes are essential to the body's normal function.

Catabolism (breaking down)

Catabolism (ca-TA-bo-liz-um) is the breaking-down phase. It involves processes that move in the opposite direction from anabolism: that is, they break down more complex substances into simpler forms, releasing energy that the body uses 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. Metabolism continues when the glucose breaks down in the body's cells to release energy for fueling body functions.


None of the processes involved in metabolism would be possible without enzymes. Because enzymes are proteins, they are made up of a string of amino acids. Each type of enzyme has its own string with certain amino acids lining up in a specific order. A person's genes are responsible for making sure the string of amino acids is correct. People who are born with metabolic diseases inherit a genetic * mutation * in a specific gene, and that mutation affects the amino acid string so that the body either fails to produce an enzyme at all or produces an enzyme that is inactive. As a result, that enzyme's activity in the body decreases or is completely absent.

One way to think of enzymes and amino acids is to consider enzymes as words and amino acids as letters of the alphabet. When a word is misspelled, its letters are ordered incorrectly and some may even be missing. This may cause its meaning to become confusing or unclear. When an enzyme is “misspelled,” the amino acids are out of order, and some may be missing altogether. Consequently, it cannot function properly, and this defect affects the particular step or steps in metabolism that the enzyme would have otherwise controlled.

What Are Metabolic Diseases?

Metabolic diseases come in a wide assortment. Some of the more common ones include:


Labels on diet soda and other food products containing the artificial sweetener aspartame (ASS-per-tame) feature a special warning: “Phenylketonurics: Contains Phenylalanine.” This is a warning for people with the metabolic disorder phenylketonuria (fen-ul-ke-ton-U-ree-a) that aspartame contains the amino acid called phenylalanine (fen-il-AL-a-neen). People who have phenylketonuria (PKU) lack the enzyme (called phenylalanine hydroxylase) that is needed to convert this amino acid into another substance called tyrosine (TIE-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, which is a problem for people with PKU, it poisons the brain tissue and eventually causes intellectual disability. 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 medical professionals habitually perform on all newborns born in the United States. It involves taking a small blood sample—usually from the heel—from a two- or three-day-old newborn. Because PKU prevents processing of phenylalanine, the amino acid would appear at a high level in the child's blood. Some doctors repeat this test when the child is a week to 10 days old. If the test indicates that the child may have PKU, the doctor will typically take another blood sample from a vein and run the test again to make sure. Only 1 out of every 13,500 to 19,000 babies born in the United States tests positive for PKU, which makes it a rare condition, but this adds up to about 250 or more babies each year.


In Norway in 1934, a mother with two severely intellectually disabled children went to see Asbjørn Følling (1888–1973), seeking an explanation for her children's condition. She also wondered about an unusual smell that her children always seemed to have. After testing urine samples, Følling discovered that the children excreted a substance not found in normal urine. Although he did not have access to the advanced chemical tests that would become available later in the 20th century, eventually Følling was able to identify the substance as a compound called phenylpyruvic (fee-nul-PY-roo-vik) acid. He immediately wondered whether the buildup of acid had something to do with the children's developmental delays.

Følling collected urine samples from hundreds of other intellectually disabled patients and found that eight of these individuals excreted the same acid. He then published a paper that drew a connection between the acid levels and developmental problems in these 10 people. He also made the hypothesis (hy-PAH-the-sis) that these people are unable to break down another compound called phenylalanine, which is an amino acid (a building block of proteins), and this excess phenylalanine converted into an elevated amount of phenylpyruvic acid. Eventually, he confirmed his hypothesis when he and his colleague figured out a way to use bacteria to test for high levels of phenylalanine in the blood.

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

In 1962, President John F. Kennedy awarded Følling the Joseph P. Kennedy International Award in Mental Retardation for his achievements. At about the same time, scientist Robert Guthrie was using Følling's discoveries to develop an effective newborn screening test for PKU. The test became available in the early 1960s, and Guthrie worked diligently to establish screening programs in the United States and many other countries. As of the early 2000s, doctors routinely screen all babies in the United States for PKU.

With early diagnosis and careful dietary restrictions, children with PKU are able to grow up normally. They achieve in school, attend college, and enter 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.

Maple syrup urine disease

George III (1738–1820) was the king of England against whom the American colonists rebelled during the War of Independence. History books note that George III experienced violent fits of madness that eventually made him incapable of ruling. He suffered through bouts of agonizing pain, overactivity, paralysis, and delirium. These so-called nervous spells occurred during the last three or four decades of his life, which ended in 1820 when he was 81.

Some historians believe that the king's problem was physiological. When psychiatrists studied the king's letters and examined the notes made by his doctors, they discovered that King George's symptoms included dark red urine, a tell-tale symptom of the metabolic disease porphyria. In 1967 two British psychiatrists published a scientific paper, “A Clinical Reassessment of the Insanity of George III and Some of Its Historical Implications,” in which they asserted that the king had porphyria. Further historical investigation suggested that other members of the royal family may have had the condition, too.

While George III was alive, medical science could not explain what was wrong with him. The body's chemical processes and their effect on the mind was not understood. As of 2016, however, much was known about this relationship. Porphyria is actually a problem in the blood that, in some cases, interferes with normal brain function and causes numerous mental symptoms.

MSUD is even rarer than PKU. Only about 1 in 185,000 infants worldwide are born with MSUD. In addition to urine that smells like maple syrup, individuals with MSUD usually have little appetite and are extremely irritable. As of 2011, all states require that all newborns be tested for MSUD as part of their newborn screening programs. Unless medical professionals diagnose and begin to treat MSUD right away, the disease can cause seizures * 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. Babies born with the metabolic disease galactosemia (ga-lak-to-SEE-me-a), however, do not have enough of the enzyme that breaks down the sugar (called galactose) in milk. 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 medical professionals fail to diagnose it 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 30,000 to 60,000 babies are born with the condition. Treatment involves removing all milk and milk-containing products from the diet. Doing so reduces the risk of permanent damage, but the child may still have problems with growth, speech, and mental function as he or she gets older.

Fructose intolerance

Besides galactosemia, many other metabolic diseases cause patients to be unable to process sugars properly. One of these is fructose (FROOK-tos) intolerance, in which a person cannot metabolize fructose, which is a certain form of sugar found in fruit, fruit juices, powdered and table sugar, honey, corn syrup, and other foods. Like the treatment for galactosemia, the treatment for fructose intolerance involves excluding certain foods from the diet. The patient must strictly limit fructose to avoid possible damage to the liver and kidneys and possible intellectual disability.

Glycogen storage disease

In a healthy person, 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, specific enzymes then reverse the process and break down the glycogen into sugar. People with certain metabolic diseases have problems with one or more of these enzymes, resulting in a condition known as glycogen storage disease.

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


The body uses a special chemical called porphyrin (POEfir-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 this excess eventually leaves the body in the urine or stool. It also causes the individual's body to produce too little heme to keep the person healthy. This enzyme deficiency is called porphyria (por-FEER-ee-a).

People who have porphyria 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 red.

Doctors can test someone's blood, urine, or stool to diagnose porphyria. They may prescribe various drugs to treat the illness. In some cases, they may also recommend that the patient take glucose or beta-carotene. In one form of porphyria, in which the patient's body has an excess of iron, patients often benefit from systematic draining of the blood, in which medical professionals remove a pint of blood from the patient's body once or twice a week for several weeks, until iron levels drop to normal.

How Does an Inherited Metabolic Disease Develop?

Many metabolic diseases exist beyond those described here. These few examples, however, 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 inherited genetic mutation, the body either does not produce a certain enzyme or produces an enzyme that does not work as it should.
  3. Consequently, a certain necessary 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 available in adequate amounts.

As a result, the normal processes of a person's system no longer work properly, which can cause damage if the problem is not corrected with diet or medication. In some cases, medical professionals cannot correct the problem, and it may cause permanent damage or even death. Many people with metabolic diseases, however, can go on to live healthy, productive lives if they follow their doctors’ instructions precisely.

See also Birth Defects: Overview • Diabetes • Genetic Diseases: Overview • Growth and Growth Disorders • Hypoglycemia • Intellectual Disability • Obesity • Phenylketonuria (PKU) • Porphyria • Seizures • Tay-Sachs Disease • Thyroid Disease


Books and Articles

Garrod, Archibald E. Inborn Errors of Metabolism: The Croonian Lectures Delivered Before the Royal College of Physicians of London, in June, 1908. London, UK: Forgotten Books, 2015.

Nyhan, William L., Bruce A. Barshop, and Aida I Al-Aqeel. Atlas of Inherited Metabolic Diseases, Third Edition. Boca Raton, FL: CRC Press, 2011.

Poufarzam, Morteza, and Fouzieh Zadhoush. “Newborn Screening for Inherited Metabolic Disorders; News and Views.” Journal of Research in Medical Sciences 18, 9 (2013): 801–08. (accessed November 19, 2015).

Wang, Stanley S. “Metabolic Syndrome.” Medscape, November 3, 2014. (accessed October 27, 2015).


Genetics Home Reference. “Galactosemia.” National Institutes of Health. (accessed November 19, 2015).

MedlinePlus. “Metabolic Disorders.” U.S. National Library of Medicine, National Institutes of Health. (accessed November 19, 2015).

Merck Manual: Consumer Version. “Hereditary Metabolic Disorders.” (accessed November 19, 2015).

National Organization for Rare Disorders. “Maple Syrup Urine Disease.” (accessed November 19, 2015).

National Organization for Rare Disorders. “Phenylketonuria.” (accessed November 19, 2015).


American Association of Clinical Endocrinologists. 245 Riverside Ave., Suite 200, Jacksonville, FL 32202. Telephone: 904-353-7878. Website: (accessed October 27, 2015).

American Porphyria Foundation. 4900 Woodway, Suite 780, Houston, TX 77056. Toll-free: 866-273-3635. Website: (accessed October 27, 2015).

Endocrine Society. 2055 L St. NW, Suite 600, Washington, DC 20036. Toll-free: 888-363-6274. Website: (accessed October 27, 2015).

Galactosemia Foundation. PO Box 2401, Mandeville, LA 70470. Toll-free: 866-900-PGC1. Website: (accessed October 27, 2015).

Maple Syrup Urine Disease Family Support Group. 82 Ravine Rd., Powell, OH 43065. Telephone: 740-548-4475. Website: (accessed October 27, 2015).

March of Dimes. 1275 Mamaroneck Ave., White Plains, NY 10605. Telephone: 914-997-4488. Website: (accessed November 11, 2015).

National Organization for Rare Disorders. 55 Kenosia Ave., PO Box 1968, Danbury, CT 06813. Toll-free: 800-999-6673. Website: (accessed October 27, 2015).

National PKU Alliance. PO Box 501, Tomahawk, WI 54487. Telephone: 715-437-0477. Website: (accessed August 11, 2015).

* enzymes (EN-zimes) are proteins that help speed up a chemical reaction in a cell or organism.

* hormones are chemical substances that are produced by various glands and sent into the bloodstream carrying messages that have certain effects on other parts of the body.

* antibodies (AN-tih-bah-deez) are protein molecules produced by the body's immune system to help fight specific infections caused by microorganisms, such as bacteria and viruses.

* liver is a large organ located beneath the ribs on the right side of the body. The liver performs numerous digestive and chemical functions essential for health.

* genetic (juh-NEH-tik) refers to heredity and the ways in which genes control the development and maintenance of organisms.

* mutation (myoo-TAY-shun) is a change in an organism's gene or genes.

* seizures (SEE-zhurs), also called convulsions, are sudden bursts of disorganized electrical activity that interrupt the normal functioning of the brain, often leading to uncontrolled movements in the body and sometimes a temporary change in consciousness.

* hallucinations (ha-LOO-sin-AYshuns) occur when a person sees or hears things that are not really there. Hallucinations can result from nervous system abnormalities, mental disorders, or the use of certain drugs.

* delirium (dih-LEER-e-um) is a condition in which a person is confused, is unable to think clearly, and has a reduced level of consciousness.

* paranoia (pair-a-NOY-a) refers to either an unreasonable fear of harm by others (delusions of persecution) or an unrealistic sense of self-importance (delusions of grandeur).

Disclaimer:   This information is not a tool for self-diagnosis or a substitute for professional care.

(MLA 8th Edition)