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Disorders of Carbohydrate Metabolism

by Lee M. Sanders, MD, MPH

Carbohydrates are sugars. Some sugars are simple, and others are more complex. Sucrose (table sugar) is made of two simpler sugars called glucose and fructose. Lactose (milk sugar) is made of glucose and galactose. Both sucrose and lactose must be broken down into their component sugars by enzymes before the body can absorb and use them. The carbohydrates in bread, pasta, rice, and other carbohydrate-containing foods are long chains of simple sugar molecules. These longer molecules must also be broken down by the body. If an enzyme needed to process a certain sugar is missing, the sugar can accumulate in the body, causing problems.

Glycogen Storage Diseases

Glycogen storage diseases occur when there is a defect in the enzymes that are involved in the metabolism of glycogen, resulting in growth abnormalities, weakness, and confusion.

  • Glycogen storage diseases are caused by lack of an enzyme needed to change glucose into glycogen and break down glycogen into glucose.

  • Typical symptoms include weakness, sweating, confusion, kidney stones, and stunted growth.

  • The diagnosis is made by examining a piece of tissue under a microscope (biopsy).

  • Treatment depends on the type of glycogen storage disease and usually involves regulating the intake of carbohydrates.

Glycogen is made of many glucose molecules linked together. The sugar glucose is the body’s main source of energy for the muscles (including the heart) and brain. Any glucose that is not used immediately for energy is held in reserve in the liver, muscles, and kidneys in the form of glycogen and is released when needed by the body.

There are many different glycogen storage diseases (also called glycogenoses), each identified by a roman numeral. These diseases are caused by a hereditary lack of one of the enzymes that is essential to the process of forming glucose into glycogen and breaking down glycogen into glucose. About 1 in 20,000 infants has some form of glycogen storage disease.

Symptoms

Some of these diseases cause few symptoms. Others are fatal. The specific symptoms, age at which symptoms start, and their severity vary considerably among these diseases. For types II, V, and VII, the main symptom is usually weakness. For types I, III, and VI, symptoms are low levels of sugar in the blood and protrusion of the abdomen (because excess or abnormal glycogen may enlarge the liver). Low levels of sugar in the blood cause weakness, sweating, confusion, and sometimes seizures and coma. Other consequences for children may include stunted growth, frequent infections, and sores in the mouth and intestines.

Glycogen storage diseases tend to cause uric acid (a waste product) to accumulate in the joints, which can cause gout (see see Gout), and in the kidneys, which can cause kidney stones (see see Stones in the Urinary Tract). In type I glycogen storage disease, kidney failure is common in the second decade of life or later.


Diagnosis and Treatment

The specific type of glycogen storage disease is diagnosed by examining a piece of muscle or liver tissue under a microscope (biopsy).

Treatment depends on the type of glycogen storage disease. For most types, eating many small carbohydrate-rich meals every day helps prevent blood sugar levels from dropping. For people who have glycogen storage diseases that cause low blood sugar levels, levels are maintained by giving uncooked cornstarch every 4 to 6 hours around the clock. For others, it is sometimes necessary to give carbohydrate solutions through a stomach tube all night to prevent low blood sugar levels from occurring at night.

Types and Characteristics of Glycogen Storage Diseases

Name

Affected Organs, Tissues, or Cells

Symptoms

Type O

Liver or muscle

Episodes of low blood sugar levels (hypoglycemia) during fasting if the liver is affected

von Gierke’s disease (type IA)

Liver and kidney

Enlarged liver and kidney, slowed growth, very low blood sugar levels, and abnormally high levels of acid, fats, and uric acid in blood

Type IB

Liver and white blood cells

Same as in von Gierke’s disease but may be less severe

Low white blood cell count, recurring infections, and inflammatory bowel disease

Pompe’s disease (type II)

All organs

Enlarged liver and heart and muscle weakness

Forbes’ disease (type III)

Liver, muscle, and heart

Enlarged liver or cirrhosis, low blood sugar levels, muscle damage, heart damage, and weak bones in some people

Andersen’s disease (type IV)

Liver, muscle, and most tissues

Cirrhosis, muscle damage, and delayed growth and development

McArdle disease (type V)

Muscle

Muscle cramps or weakness during physical activity

Hers’ disease (type VI)

Liver

Enlarged liver

Episodes of low blood sugar during fasting

Often no symptoms

Tarui’s disease (type VII)

Skeletal muscle and red blood cells

Muscle cramps during physical activity and red blood cell destruction (hemolysis)


Galactosemia

Galactosemia (a high blood level of galactose) is caused by lack of one of the enzymes necessary for metabolizing galactose, a sugar present in lactose (milk sugar). A metabolite that is toxic to the liver and kidneys builds up. The metabolite also damages the lens of the eye, causing cataracts.

  • Galactosemia is caused by lack of one of the enzymes needed to metabolize the sugar in milk.

  • Symptoms include vomiting, jaundice, diarrhea, and abnormal growth.

  • The diagnosis is based on a blood test.

  • Even with adequate treatment, affected children still develop mental and physical problems.

  • Treatment involves completely eliminating milk and milk products from the diet.

Galactose is a sugar that is present in milk and in some fruits and vegetables. A deficient enzyme or liver dysfunction can alter the metabolism, which can lead to high levels of galactose in the blood (galactosemia). There are different forms of galactosemia, but the most common and the most severe form is referred to as classic galactosemia.

Symptoms

Newborns with galactosemia seem normal at first but, within a few days or weeks, lose their appetite, vomit, become jaundiced, have diarrhea, and stop growing normally. White blood cell function is affected, and serious infections can develop. If treatment is delayed, affected children remain short and become intellectually disabled or may die.


Diagnosis

Galactosemia is detectable with a blood test. This test is done as a routine screening test for newborns in all states in the United States. Before conception, adults with a sibling or child known to have the disorder can be tested to find out whether they carry the gene that causes the disease. If two carriers conceive a child, that child has a 1 in 4 chance of being born with the disease.


Prognosis

If galactosemia is recognized at birth and adequately treated, liver and kidney problems do not develop, and initial mental development is normal. However, even with adequate treatment, children with galactosemia may have a lower intelligence quotient (IQ) than their siblings, and they often have speech problems. Girls often have ovaries that do not function, and only a few are able to conceive naturally. Boys, however, have normal testicular function.


Treatment

Galactosemia is treated by completely eliminating milk and milk products—the source of galactose—from an affected child’s diet. Galactose is also present in some fruits, vegetables, and sea products, such as seaweed. Doctors are not sure whether the small amounts in these foods cause problems in the long term. People who have the disorder must restrict galactose intake throughout life.


Hereditary Fructose Intolerance

Hereditary fructose intolerance is caused by lack of the enzyme needed to metabolize fructose. Very small amounts of fructose cause low blood sugar levels and can lead to kidney and liver damage.

In this disorder, the body is missing an enzyme that allows it to use fructose, a sugar present in table sugar (sucrose) and many fruits. As a result, a by-product of fructose accumulates in the body, blocking the formation of glycogen and its conversion to glucose for use as energy. Ingesting more than tiny amounts of fructose or sucrose causes low blood sugar levels (hypoglycemia), with sweating, confusion, and sometimes seizures and coma. Children who continue to eat foods containing fructose develop kidney and liver damage, resulting in jaundice, vomiting, mental deterioration, seizures, and death. Chronic symptoms include poor eating, failure to thrive, digestive symptoms, liver failure, and kidney damage. For most types of this disorder, early diagnosis and dietary restrictions started early in infancy can help prevent these more serious problems.

The diagnosis is made when a chemical examination of a sample of liver tissue determines that the enzyme is missing. Treatment involves excluding fructose (generally present in sweet fruits), sucrose, and sorbitol (a sugar substitute) from the diet. Severe attacks of hypoglycemia respond to glucose given by vein. Milder attacks are treated with glucose tablets, which should be carried by anyone who has hereditary fructose intolerance.

Mucopolysaccharidoses

Mucopolysaccharidoses are a group of hereditary disorders in which complex sugar molecules are not broken down normally and accumulate in harmful amounts in the body tissues. The result is a characteristic facial appearance and abnormalities of the bones, eyes, liver, and spleen, sometimes accompanied by intellectual disability.

  • Mucopolysaccharidoses occur when the body lacks enzymes needed to break down and store complex sugar molecules (mucopolysaccharides).

  • Typically, symptoms include short stature, hairiness, stiff finger joints, and coarseness of the face.

  • The diagnosis is based on symptoms and a physical examination.

  • Although a normal life span is possible, some types cause premature death.

  • A bone marrow transplant may help.

Complex sugar molecules called mucopolysaccharides are essential parts of many body tissues. In mucopolysaccharidoses, the body lacks enzymes needed to break down and store mucopolysaccharides. As a result, excess mucopolysaccharides enter the blood and are deposited in abnormal locations throughout the body.

During infancy and childhood, short stature, hairiness, and abnormal development become noticeable. The face may appear coarse. Some types of mucopolysaccharidoses cause intellectual disability to develop over several years. In some types, vision or hearing may become impaired. The arteries or heart valves can be affected. Finger joints are often stiff.

A doctor usually bases the diagnosis on the symptoms and a physical examination. The presence of a mucopolysaccharidosis in other family members also suggests the diagnosis. Urine tests may help but are sometimes inaccurate. X-rays may show characteristic bone abnormalities. Mucopolysaccharidoses can be diagnosed before birth by using amniocentesis or chorionic villus sampling (see see Procedures : Chorionic Villus Sampling).

Prognosis and Treatment

The prognosis depends on the type of mucopolysaccharidosis. A normal life span is possible. Some types, usually those that affect the heart, cause premature death.

In one type of mucopolysaccharidosis, attempts at replacing the abnormal enzyme have had limited, temporary success. Bone marrow transplantation may help some people. However, death or disability often results, and this treatment remains controversial.


Disorders of Pyruvate Metabolism

Pyruvate metabolism disorders are caused by a lack of the ability to metabolize a substance called pyruvate. These disorders cause a buildup of lactic acid and a variety of neurologic abnormalities.

  • A deficiency in any one of the enzymes involved in pyruvate metabolism leads to one of many disorders.

  • Symptoms include seizures, intellectual disability, muscle weakness, and coordination problems.

  • Some of these disorders are fatal.

  • Some children are helped by diets that are either high in fat and low in carbohydrates or high in carbohydrates and low in protein.

Pyruvate is a substance that is formed in the processing of carbohydrates and proteins and that serves as an energy source for cells. Problems with pyruvate metabolism can limit a cell’s ability to produce energy and allow a buildup of lactic acid, a waste product. Many enzymes are involved in pyruvate metabolism. A hereditary deficiency in any one of these enzymes results in one of a variety of disorders, depending on which enzyme is missing. Symptoms may develop any time between early infancy and late adulthood. Exercise and infections can worsen symptoms, leading to severe lactic acidosis. These disorders are diagnosed by measuring enzyme activity in cells from the liver or skin.

Pyruvate Dehydrogenase Complex Deficiency

This disorder is caused by a lack of a group of enzymes needed to process pyruvate. This deficiency results in a variety of symptoms, ranging from mild to severe. Some newborns with this deficiency have brain malformations. Other children appear normal at birth but develop symptoms, including weak muscles, seizures, poor coordination, and a severe balance problem, later in infancy or childhood. Intellectual disability is common.

This disorder cannot be cured, but some children are helped by a diet that is high in fat and low in carbohydrates.


Absence of Pyruvate Carboxylase

Pyruvate carboxylase is an enzyme. A lack of this enzyme causes a very rare condition that interferes with or blocks the production of glucose from pyruvate in the body. Lactic acid and ketones build up in the blood. Often, this disease is fatal. Children who survive have seizures and severe intellectual disability, although there are recent reports of children with milder symptoms. There is no cure, but some children are helped by eating frequent carbohydrate-rich meals and restricting dietary protein.


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