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Metabolic Disease

Metabolic Disease

Metabolism is the sum of the chemical processes and interconversions that take place in the cells and the fluids of the body. This includes the absorption of nutrients and minerals, the breakdown and buildup of large molecules, the interconversion of small molecules, and the production of energy from these chemical reactions. Virtually every chemical step of metabolism is catalyzed by an enzyme . Disorders of these enzymes that result from abnormalities in their genes are known as inborn errors of metabolism.

Inborn errors of metabolism were first recognized by Sir Archibald Garrod, a British physician who noted in 1902 that the principles of Mendelian inheritance applied to certain examples of human metabolic variation. He perceived the genetic basis for a particular metabolic condition that leads to visible effectsalkaptonuria, which results in a black pigment in the urine. Since then, more advanced chemical methods have allowed the discovery of hundreds of enzyme defects that cause metabolic diseases.

Enzymes Control Metabolic Reactions

Enzymes are proteins that control the rate of chemical reactions in the cell. In general, each enzyme controls the rate of only one or a few reactions. Enzymes function by binding to the molecules to be reacted (called substrates or precursors) and altering their chemical bonds, producing products. The binding occurs on the surface of the enzyme, usually in a pocket or groove, called the active site. The enzyme releases the products after reaction. The active site has a specific three-dimensional structure that is required for binding substrates. In addition, it may have other sites that bind regulatory molecules or cofactors. Some cofactors are vitamins, which perform some accessory function critical for enzyme action.

Enzymes are often linked in multistep pathways, such that the product of one reaction becomes the substrate for another. In this way, a simple molecule can be changed step by step into a complex one, or vice versa. In addition, the multiple steps provide additional levels of regulation, and intermediates can be shunted into other pathways to make other products. For instance, some intermediates in the breakdown of sugar can be shunted to make amino acids. When all the enzymes in a pathway are functioning properly, intermediates rarely build up to high concentrations.

Enzyme Defects Cause Metabolic Disorders

The causes of enzyme defects are genetic mutations that affect the structure or regulation of the enzyme protein or create problems with the transport, processing, or binding of cofactors. In general, the consequences of an enzyme deficiency are due to perturbations of cellular chemistry, because of either a reduction in the amount of an essential product, the buildup of a toxic intermediate, or the production of a toxic side-product, as shown in Figure 1.

Except as noted below, most metabolic disorders are inherited as auto-somal recessive conditions. In this inheritance pattern, two defective gene copies are needed (one from each parent) to develop the disease. The parents, each of whom almost always has only one gene copy, will not have the disease but are carriers . The chance that two carrier parents will have a child who inherits two defective gene copies is 25 percent for each birth.

Metabolic disorders tend to be recessive, because they are due to inactivating, or "loss-of-function," mutations. One working copy of the gene is usually enough to maintain sufficient levels of the enzyme, and so with one copy present, no disease develops.

Approaches to Treatment

Treatment approaches for metabolic disorders include (a) modifying the diet to limit the amount of a precursor that is not metabolized properly; (b) using cofactors or vitamins to enhance the residual activity of a defective enzyme system; (c) using detoxifying agents to provide alternative pathways for the removal of toxic intermediates; (d) enzyme replacement, to provide functional enzymes exogenously (from the outside); (e) organ transplantation, which in principle allows for endogenous (internal) production of functional enzymes; and (f) gene therapy, or replacement of the defective gene.

Gene therapy is expected to become the most important approach. It offers the potential for definitive treatment, and it is being actively investigated as a treatment for virtually every one of the metabolic disorders. Most of the genes for the enzymes involved in metabolic diseases have been identified and cloned, and in many cases the genes can be replaced in experimental systems. Genetic approaches have been used to produce mass quantities of enzymes to use for enzyme replacement, but as of 2002, gene therapy has not yet been used successfully to provide the stable expression of active enzymes in the human body.

This chapter will summarize classes of inborn errors of metabolism based upon the type of chemical process involved, and individual disorders will be discussed that illustrate the various disease mechanisms and treatment approaches.

Major Classes of Metabolic Disorders

Cells are constructed from four major types of molecules: carbohydrates, proteins, fats, and nucleic acids. The metabolic pathways involving each are

Disease Defective Enzyme or System Symptoms Treatment
Disorders of Amino Acid Metabolism
Phenylketonuria (PKU) phenylalanine hydroxylase severe mental retardation screening; dietary modification
Malignant PKU biopterin cofactor neurological disorder
Type 1 tyrosinemia fumarylacetoacetate hydrolase nerve damage, pain, liver failure liver transplantation; preceding enzyme inhibitor plus dietary modification
Type 2 tyrosinemia tyrosine aminotransferase irritation to the corneas of the eyes diet with reduced phenylalanine and tyrosine content
Alkaptonuria disorder of tyrosine breakdown progressive arthritis and bone disease; dark urine
Homocystinuria and Hyperhomocysteinemia cystathionine-β-synthase or methylenetetrahydrofolate reductase or various deficiencies in formation of the methylcobalamin form of vitamin B12 hypercoagulability of the blood; vascular eposides; dislocation of the lens of the eye, elongation and thinning of the bones, and often mental retardation or psychiatric abnormalities vitamin B12, folic acid, betaine, a diet limited in cysteine and methionine
Maple Syrup Urine disease branched-chain ketoacid dehydrogenase complex elevations of branched-chain amino acids, characteristic odor of the urine, episodes of ketoacidosis, death thiamine; careful regulation of dietary intake of the essential branched-chain amino acids
Disorders of Organic Acid Metabolism
Propionic Acidemia propionyl-CoA carboxylase generalized metabolic dysfunction; ketoacidosis; death diet with limited amounts of the amino acids which are precursors to propionyl-CoA
Multiple Carboxylase deficiency pyruvate carboxylase and 3-methylcrotonyl-CoA carboxylase biotin
Methylmalonic Acidemia methylmalonyl-CoA mutase; defects in the enzyme systems involved in vitamin B12 metabolism supplementation with large doses of vitamin B12; diet
Disorders of Fatty Acid Metabolism
Hyperlipidemia and hypercholesterolemia regulation or utilization of lipoproteins cardiovascular disease dietary modifications and use of drugs that inhibit fatty acid synthesis.
Fatty Acid Oxidation disorders very long chain acyl-CoA dehydrogenase; long chain hydroxyacyl-CoA dehydrogenase; dehydrogenase; medium chain acyl-CoA dehydrogenase; short chain acyl CoA dehydrogenase; short chain hydroxyacyl-CoA dehydrogenase low blood sugar (hypoglycemia); muscle weakness; cardiomyopathy avoidance of fasting, intravenous glucose solutions; carnitine; medium chain triglycerides
Glycogen Storage diseases defects in glycogenolysis liver enlargement or damage; muscle weakening or breakdown; disturbed renal tubular function; risk of brain damage
Galactosemia galactose-1-phosphate uridyl transferase liver failure in infancy newborn screening; milk avoidance
Congenital Disorders of Glycosylation defects in the enzymes that build the carbohydrate side-chains on proteins quite variable; multisystem
Disorders of Purine and Pyrimidine Metabolism
Purine Overproduction imbalance between purine synthesis and disposal gout
Lesch-Nyhan syndrome hypoxanthine phosphoribosyl-transferase defective salvage of purines; increase in the excretion ofuricacid; brain neurotransmitter dysfunction; severe spastic movement disorder; self-injurious behavior allopurinol (does not treat neurological symptoms)
Lysosomal Storage Disorders
Gaucher disease Types I and II cerebrosidase enlargement of the spleen and liver; painful and crippling effects on the bones; severe brain disease and death (Type II) enzyme replacement (Type I)
Tay-Sachs disease beta-hexosaminidase A neurological disorders; enlarged head; death in early childhood
Table 1 (continued on next page).
Disease Defective Enzyme or System Symptoms Treatment
Lysosomal Storage Disorders [CONTINUED]
Fabry disease α-galactosidase severe pain; renal failure; heart failure enzyme replacement
Hurler syndrome, Hunter syndrome α-iduronidase (Hurler syndrome);iduronate sultatase (Hunter syndrome) iduronate sultatase (hunter syndrome) enlargement of the liver and spleen; skeletal deformities; coarse facial features; stiff joints; mental retardation; death within 5-15 years enzyme replacement
Sanfilippo syndrome enzymes for heparan sulfate degradation enlargement of the liver and spleen enzyme replacement
Maroteaux-Lamy syndrome arylsulfatase B progressive, crippling and life-threatening physical changes similar to Hurler syndrome, but generally with normal intellect
Morquio syndrome galactose 6-sulfatase; β-galactosidase truncal dwarfism; severe skeletal deformities; potentially life-threatening susceptibility to cervical spine dislocation; valvular heart disease
Disorders of Urea Formation
carbamyl phosphate synthetase deficiency; ornithine transcarbamylase deficiency, citrullinemia, argininosuccinic aciduria hyperammonemia; mental retardation; seizures; coma; death limitation of dietary protein; phenylacetate; liver transplantation
Disorders of Peroxisomal Metabolism
Refsum disease branched-chain fatty acid buildup neurologic symptoms
Alanine-glyoxylate transaminase defect alanine-glyoxylate transaminase oxalic acid increase; organ dysfunction; renal failure liver transplantation
Table 1, continued.

the basis for classification of many of the metabolic disorders. The mitochondria in cells are organelles that play a major role in most metabolic pathways, and mitochondrial disorders are one of the most significant and common types of metabolic disorders. Defects in the storage and disposal of molecules also give rise to metabolic disorders.

Carbohydrates are used primarily as fuel and can be built and broken down rapidly. The major storage form is glycogen. They are also added to proteins to make glycoproteins. Fatty acids are long-chain molecules that are used to construct membranes. Fatty acids are derived from dietary fats. Excess fat is used as fuel by mitochondria. Proteins are made of amino acids.

Humans must eat eight kinds of amino acids and then convert these into twelve other types to make the twenty amino acids found in our proteins. Excess amino acids in the diet are used for fuel by mitochondria. Along the way, they generate organic acids. Nucleic acidsDNA and RNAare the molecules that store and process genetic information. They must be built from smaller units, called nucleotides. The storage and interconversion of different types of nucleotides assures a steady supply.

Below, representative disorders of each system are discussed. Other disorders are listed in Table 1. Many of the disease names end in "emia." This suffix indicates a blood disorder, and the names are derived from the fact that most metabolic disorders are diagnosed by detecting abnormal levels of intermediates or other substances in the blood.

Disorders of Mitochondrial Oxidative Metabolism

Most cellular energy is derived from the mitochondrial electron transport chain, which reduces oxygen to water in a series of steps to drive the formation of the high-energy compound ATP. The Krebs cycle creates high-energy intermediates that it feeds to the electron transport chain, the energy of which ultimately is derived from a two-carbon compound called acetate, which is broken down successively to carbon dioxide. Acetate is derived from several pathways of amino acid, carbohydrate, and fat metabolism.

Thus, many pathways of metabolism feed into the Krebs cycle to drive oxidative metabolism in a web of processes requiring hundreds of enzymes. When there are defects in the Krebs cycle or the electron transport chain, one result may be ketoacidosis, which is due to the accumulation of lactic acid and ketone bodies.

The lack of cellular energy may be manifest in many cellular processes and can affect several tissues and organ systems, particularly those that are most dependent upon oxidative metabolism for energy. The brain and muscles are generally affected first, which can cause developmental delay, neurological crisesincluding episodes of coma, stroke-like events, and seizuresand muscle weakness or cardiomyopathy. Kidney functionmost often the tubular function required for retention of electrolytesmay also be affected. Endocrine (hormone) systems may also be affected, resulting in conditions such as diabetes mellitus (caused by effects on the pancreas or by sensitivity to insulin in muscle and fat cells) or adrenal insufficiency (from effects on the adrenal glands).

Disorders of mitochondrial oxidative metabolism are very variable in terms of age of onset, severity, specific symptoms, and clinical course. Even the inheritance patterns of mitochondrial diseases are heterogeneous. Most are inherited in the usual autosomal recessive manner (although the chromosomal locations of only a few of the relevant genes are known). A few are inherited from defects in the mitochondrial DNA, which is passed on in the maternal line.

The mitochondrion contains a circular chromosome of about 16,500 bases. It codes for thirteen components of the electron-transport chain, as well as transfer RNA molecules and ribosomal RNAs required for their expression. Since there are multiple copies of mitochondrial DNA and there may be mixtures of normal and abnormal mitochondrial DNA (a phenomenon known as heteroplasmy), the precise proportion of mutated mitochondrial DNA may vary in an unpredictable manner from individual to individual within a family, and from tissue to tissue within an individual. There may also be variations within an individual tissue over time, adding to the unpredictability of mitochondrial disease and the difficulty in the diagnosis.

Disorders of Amino Acid Metabolism


Phenylketonuria (PKU) is the most common disorder of amino acid metabolism, and it is a paradigm for effective newborn screening. Phenylalanine is an essential amino acid (meaning that it cannot be synthesized but must be taken in through the diet). The first step to its breakdown is the phenylalanine hydroxylase reaction, which converts phenylalanine to another amino acid, tyrosine. A genetic defect in the phenylalanine hydroxylase enzyme is the basis for classical PKU. Untreated PKU results in severe mental retardation, but PKU can be detected by screening newborn blood spots, and the classical form can be very effectively treated by using medical formulas that are limited in their phenylalanine content.

The hydroxylase enzyme requires a cofactor called biopterin, which is also a cofactor for other enzymes. Defects affecting the production of biopterin result in another form, so-called malignant PKU. In this form, the other biopterin-dependent hydroxylases are also affected, resulting in deficient neurotransmitter synthesis and significant neurological symptoms.


Alkaptonuria is a disorder of tyrosine breakdown. The intermediate that accumulates, called homogentisic acid, can polymerize to form pigment that binds to cartilage and causes progressive arthritis and bone disease and that also is excreted to darken the urinethe effect that allowed Garrod to recognize the genetic inheritance of this inborn error of metabolism.

Disorders of Organic Acid Metabolism

Propionic Acidemia.

Propionyl-CoA is formed mainly from the breakdown of four essential amino acids (isoleucine, valine, threonine, and methionine). Defects of the enzyme propionyl-CoA carboxylase result in propionic acidemia, a life-threatening disease characterized by episodes of generalized metabolic dysfunction and ketoacidosis. The basis of treatment is a carefully applied diet containing limited amounts of the amino acids that are precursors to propionyl-CoA.

Methylmalonic Acidemia.

Methylmalonyl-CoA is the product of propionyl-CoA carboxylase. There are a variety of metabolic defects in the further metabolism of this compound, resulting in methylmalonic acidemia. The best-known of these conditions arises from a defect in methylmalonyl-CoA mutase, the vitamin B12-dependent enzyme that converts methylmalonyl-CoA to succinyl-CoA, which enters the Krebs cycle. There are other conditions resulting in methylmalonic acidemia that are due to defects in the enzyme systems involved in vitamin B12 metabolism. In some cases, supplementation with large doses of vitamin B12 is effective, but in most cases of methylmalonic acidemia, a special diet is required, similar to that used to treat propionic acidemia.

Disorders of Fatty Acid Metabolism

Hyperlipidemia and Hypercholesterolemia.

Dietary fats are distributed through the body attached to proteins, in lipoprotein complexes. There are a number of disorders involving the regulation or utilization of lipoproteins, which result in hyperlipidemia and/or hypercholesterolemia, including the common conditions in adults that are associated with cardiovascular disease. Standard treatment approaches include modifying the diet and administering drugs that inhibit fatty acid synthesis.

Disorders of Carbohydrate Metabolism

The most active pathways in carbohydrate metabolism are glycogenolysis (the breakdown of glycogen, a polymerized form of carbohydrate, which is stored primarily in the liver and muscles), which produces glucose and distributes it through the bloodstream, and glycolysis , which releases energy and produces pyruvate. Pyruvate is a three-carbon molecule that can be converted to acetate and enter the Krebs cycle or form several building-block molecules. The reverse processes are referred to as glycogen synthesis and gluconeogenesis, respectively.

Glycogen Storage Diseases.

A number of defects may occur in glycogenolysis, giving rise to the disorders known as glycogen storage diseases. Glycogen storage diseases may affect the liver (enlarging it or damaging it due to increased amounts of glycogen) or muscle (weakening muscle or causing breakdown during times of exercise, due to inadequate glucose production). There may be additional problems, including disturbed kidney tubular function (which causes loss of nutrients and minerals), and there is a risk of brain damage in cases that result in critically low blood sugar.


Another common disorder of carbohydrate metabolism is galactosemia, which is due to the inability to form glucose from galactose, the sugar that is found in milk. The classic form of galactosemia is due to a deficiency of the enzyme galactose-1-phosphate uridyl transferase, and, if untreated, it presents in the infant with fatal liver failure. Galactosemia is important because newborn screening (conducted by most developed countries on blood spots collected in the first days of life) has been very successful, and simple alteration of the diet (replacing milk with formulas that contain glucose or glucose polymers) has permitted a generation of individuals to survive with quite normal lives and, in general, normal intellect.

Disorders of Purine and Pyrimidine Metabolism

Purines and pyrimidines are chemicals that form the nucleic acids (DNA and RNA). An important purine compound is adenosine triphosphate (ATP), which is used to transfer chemical energy for processes such as biosynthesis and transport. There are several rare defects in the synthesis of purines and pyrimidines. The most common symptom of purine overproduction is gout, which arises for several reasons, often not associated with an identifiable enzyme defect but rather due to an imbalance between purine synthesis and disposal. Gout manifests when the ultimate product of purine degradation, uric acid, accumulates and crystallizes in the joints.

A very dramatic disorder of purine metabolism is Lesch-Nyhan syndrome, which is due to a defect in the enzyme hypoxanthine phosphoribosyltransferase (HPRT), resulting in defective salvage of purines and, accordingly, in an increase in the excretion of uric acid. For reasons that are still incompletely understood, a severe defect of HPRT also causes brain-neurotransmitter dysfunction, resulting in a severe spastic form of movement disorder and also a stereotypical compulsion for self-injurious behavior. The concentration of uric acid can be reduced by using the drug allopurinol, but there is no satisfactory treatment for the neurological symptoms associated with Lesch-Nyhan disease.

Lysosomal Storage Disorders

Lysosomes are intracellular compartments in which macromolecules are broken down in an acidic environment. Various classes of lysosomal storage disorders arise when there are defects in specific enzymes, and the manifestations of these disorders depend upon the class of macromolecule whose breakdown is affected.

Gaucher's Disease.

The most common lysosomal storage disorder is Gaucher's disease, caused by a deficiency of the enzyme cerebrosidase, which is needed to break down cerebroside, a component of the cell membrane in blood cells and neurons . Partial defects of cerebrosidase cause Type 1 Gaucher's disease, in which material accumulates in the lysosomes of macrophage cells in the spleen, liver, and bone marrow, where most of the cell-turnover takes place. Significant accumulation usually occurs by childhood or early adulthood, resulting in dramatic enlargement of the spleen and liver. Later there may be painful and crippling effects on the bones. Type 1 Gaucher's disease can be effectively treated with enzyme replacement, but the enzyme must be infused intravenously approximately every two weeks for life. More severe defects of cerebrosidase cause Type 2 Gaucher's disease, which is rare, appears in infancy, and presents with the same problems as in Type 1 disease as well as severe brain disease that progresses to death. Very rarely, defects of intermediate severity can give rise to Type 3 Gaucher disease, which is a chronic neuronopathic form.

Tay-Sachs Disease.

Tay-Sachs disease is due to a defect in the beta-hexosaminidase A enzyme, which removes a sugar from certain lipids called gangliosides, which build up in the lysosome. The disease causes neurological symptoms, an enlarged head, and death in early childhood.


Mucopolysaccharidoses are lysosomal storage disorders affecting the breakdown of mucopolysaccharides, which are carbohydrate-protein macromolecules found on several cell types. Hurler syndrome (α-iduronidase deficiency) and Hunter syndrome (iduronate sultatase deficiency) are two disorders that affect the breakdown of the mucopolysaccharides dermatan sulfate and heparan sulfate, which are components of connective tissues throughout the body. The usual clinical manifestations of these syndromes are enlargement of the liver and spleen, skeletal deformities, coarse facial features, stiff joints, and mental retardation. Most cases are severe and progress to death within five to fifteen years, but there are exceptions. By 2002, there were several experimental approaches with enzyme replacement for mucopolysaccharidoses.

Disorders of Urea Formation

The urea cycle is a series of enzyme reactions that removes waste nitrogen from the body, allowing it to be excreted in the urine as urea. Disorders of the enzymes of the urea cycle disrupt this pathway, increasing blood ammonia (hyperammonemia). Hyperammonemia results in mental retardation, and acute episodes can progress to seizures, coma, and death. These conditions are inherited in an autosomal recessive pattern, except for ornithine transcarbamylase deficiency, which is X-linked, affecting males more severely than females. Treatment for these disorders includes limiting dietary protein (the major source of nitrogen intake) and using agents (such as phenylacetate) that provide an alternate mechanism to remove waste nitrogen (through excretion of phenylacetyl-glutamine in urine). Liver transplantation may also be effective in controlling blood ammonia in these conditions.

Disorders of Peroxisomal Metabolism

Several specialized metabolic functions are performed in the subcellular organelles known as peroxisomes. Severe defects in the biogenesis of peroxisomes result in Zellweger syndrome, which is characterized by structural and developmental abnormalities and which is generally fatal in infancy. Defects in individual peroxisomal enzymes are also encountered, including Refsum disease, which results in the buildup of a branched-chain fatty acid (phytanic acid) and progressive problems in the nervous system. A defect in the enzyme alanine-glyoxylate transaminase causes an increase in the production of oxalic acid, an insoluble chemical that is progressively deposited in the tissues of the body and, over years, causes organ dys-function, including renal failure. Renal transplantation does not prevent recurrence, but liver transplantation is effective in preventing the progression of the disease in the kidneys and other organs.

see also Cell, Eukaryotic; Inheritance Patterns; Mitochondrial Diseases; Population Screening; Proteins; Tay-Sachs Disease.

Bruce A. Barshop


Berg, Jeremy, John Tymoczko, and Lubert Stryer. Biochemistry, 5th ed. New York:W. H. Freeman, 2001.

Internet Resource

Online Mendelian Inheritance in Man. Johns Hopkins University, and National Center for Biotechnology Information.>.

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Diabetes Mellitus

Diabetes Mellitus

Diabetes mellitus is a common metabolic disorder resulting from defects in insulin action, insulin production, or both. Insulin, a hormone secreted by the pancreas, helps the body use and store glucose produced during the digestion of food. Characterized by hyperglycemia , symptoms of diabetes include frequent urination, increased thirst, dehydration , weight loss, blurred vision, fatigue , and, occasionally, coma. Uncontrolled hyperglycemia over time damages the eyes, nerves, blood vessels, kidneys, and heart, causing organ dysfunction and failure. A number of risk factors are attributed to the incidence of diabetes, including family history, age, ethnicity, and social group characteristics, as well as behavioral , lifestyle, psychological , and clinical factors.

The World Health Organization estimates that 150 million people had diabetes worldwide in 2002. This number is projected to double by the year 2025. Much of this increase will occur in developing countries and will be due to population growth, aging, unhealthful diets, obesity , and sedentary lifestyles. In the United States, diabetes is the sixth leading cause of death. While 6.2 percent of the population has diabetes, an estimated 5.9 million people are unaware they have the disease. In addition, about 19 percent of all deaths in the United States for those age twenty-five and older are due to diabetes-related complications.

The prevalence of diabetes varies by age, gender, race, and ethnicity. In the United States, about 0.19 percent of the population less than twenty years of age (151,000 people) have diabetes, versus 8.6 percent of the population twenty years of age and older. In addition, adults sixty-five and older account for 40 percent of those with diabetes, despite composing only 12 percent of the population. Considerable variations also exist in the prevalence of diabetes among various racial and ethnic groups. For example, 7.8 percent of non-Hispanic whites, 13 percent of non-Hispanic blacks, 10.2 percent of Hispanic/Latino Americans, and 15.1 percent of American Indians and Alaskan Natives have diabetes. Among Asian Americans and Pacific Islanders, the rate of diabetes varies substantially and is estimated at 15 to 20 percent. The prevalence of diabetes is comparable for males and females8.3 and 8.9 percent respectively. Nevertheless, the disease is more devastating and more difficult to control among women, especially African-American and non-Hispanic white women. In fact, the risk for death is greater among young people (3.6 times greater for people from 25 to 44 years of age) and women (2.7 times greater for women ages 45 to 64 than men of the same age).

Types of Diabetes

Diabetes mellitus is classified into four categories: type 1, type 2, gestational diabetes, and other. In type 1 diabetes, specialized cells in the pancreas are destroyed, leading to a deficiency in insulin production. Type 1 diabetes frequently develops over the course of a few days or weeks. Over 95 percent of people with type 1 diabetes are diagnosed before the age of twenty-five. Estimates show 5.3 million people worldwide live with type 1 diabetes. Although the diagnosis of type 1 diabetes occurs equally among men and women, an increased prevalence exists in the white population. Type 1 diabetes in Asian children is relatively rare.

Family history, diet , and environmental factors are risk factors for type 1 diabetes. Studies have found an increased risk in children whose parents have type 1 diabetes, and this risk increases with maternal age. Environmental factors such as viral infections, toxins , and exposure to cow's milk are being contested as causing or modifying the development of type 1 diabetes.

Type 2 diabetes is characterized by insulin resistance and/or decreased insulin secretion. It is the most common form of diabetes mellitus, accounting for 90 to 95 percent of all diabetes cases worldwide. Risk factors for type 2 diabetes include family history, increasing age, obesity, physical inactivity, ethnicity, and a history of gestational diabetes. Although type 2 diabetes is frequently diagnosed in adult populations, an increasing number of children and adolescents are currently being diagnosed. Type 2 diabetes is also more common in blacks, Hispanics, Native Americans, and women, especially women with a history of gestational diabetes.

Genetics and environmental factors are the main contributors to type 2 diabetes. Physical inactivity and adoption of a Western lifestyle (particularly choosing foods with more animal protein , animal fats, and processed carbohydrates ), especially in indigenous people in North American and within ethnic groups and migrants, have contributed to weight gain and obesity. In fact, obesity levels increased by 74 percent between 1991 and 2003. Increased body fat and abdominal obesity are associated with insulin resistance, a precursor to diabetes. Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are two prediabetic conditions associated with insulin resistance. In these conditions, the blood glucose concentration is above the normal range, but below levels required to diagnose diabetes. Subjects with IGT and/or IFG are at substantially higher risk of developing diabetes and cardiovascular disease than those with normal glucose tolerance. The conversion of individuals with IGT to type 2 diabetes varies with ethnicity, anthropometric measures related to obesity, fasting blood glucose (a measurement of blood glucose values after not eating for 12 to 14 hours), and the two-hour post-glucose load level (a measurement of blood glucose taken exactly two hours after eating). In addition to IGT and IFG, higher than normal levels of fasting insulin, called hyperinsulinemia, are associated with an increased risk of developing type 2 diabetes. Insulin levels are higher in African Americans than in whites, particularly African-American women, indicating their greater predisposition for developing type 2 diabetes.

The complexity of inheritance and interaction with the environment makes identification of genes involved with type 2 diabetes difficult. Only a small percentage (25%) of diabetes cases can be explained by single gene defects and are usually atypical cases. However, a "thrifty gene," although not yet identified, is considered predictive of weight gain and the development of type 2 diabetes. Thrifty-gene theory suggests that indigenous people who experienced alternating periods of feast and famine gradually developed a way to store fat more efficiently during periods of plenty to better survive famines. Regardless of the thrifty gene, the contribution of genetic mutations in the development of type 2 diabetes has not been established, due to the number of genes that may be involved.

Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. This definition applies regardless of whether insulin or diet modification is used for treatment, and whether or not the condition persists after pregnancy. GDM affects up to 14 percent of the pregnant populationapproximately 135,000 women per year in United States. GDM complicates about 4 percent of all pregnancies in the U.S. Women at greatest risk for developing GDM are obese , older than twenty-five years of age, have a previous history of abnormal glucose control, have first-degree relatives with diabetes, or are members of ethnic groups with a high prevalence of diabetes. Infants of a woman with GDM are at a higher risk of developing obesity, impaired glucose tolerance, or diabetes at an early age. After a pregnancy with GDM, the mother has an increased risk of developing type 2 diabetes.

Other forms of diabetes are associated with genetic defects in the specialized cells of the pancreas, drug or chemical use, infections, or other diseases. The most notable of the genetically linked diabetes is maturity onset diabetes of the young (MODY). Characterized by the onset of hyperglycemia before the age of twenty-five, insulin secretion is impaired while minimal or no defects exist in insulin action. Drugs , infections, and diseases cause diabetes by damaging the pancreas and/or impairing insulin action or secretion.

Diabetes Complications

People with diabetes are at increased risk for serious long-term complications. Hyperglycemia, as measured by fasting plasma glucose concentration or glycosylated hemoglobin (HbA1c), causes structural and functional changes in the retina, nerves, kidneys, and blood vessels. This damage can lead to blindness, numbness, reduced circulation, amputations, kidney disease, and cardiovascular disease. Type 1 diabetes is more likely to lead to kidney failure. About 40 percent of people with type 1 diabetes develop severe kidney disease and kidney failure by the age of fifty. Nevertheless, between 1993 and 1997, more than 100,000 people in the United States were treated for kidney failure caused by type 2 diabetes.

African Americans experience higher rates of diabetes-related complications such as eye disease, kidney failure, and amputations. They also experience greater disability from these complications. The frequency of diabetic retinopathy (disease of the small blood vessels in the retina causing deterioration of eyesight) is 40 to 50 percent higher in African Americans than in white Americans. In addition, the rate of diabetic retinopathy among Mexican Americans is more than twice that of non-Hispanic white Americans. Furthermore, African Americans with diabetes are much more likely to undergo a lower-extremity amputation than white or Hispanic Americans with diabetes. Little is known about these complications in Asian and Pacific Islander-Americans.

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemia state (HHS) are serious diabetic emergencies and the most frequent cause of mortality. Both DKA and HHS result from an insulin deficiency and an increase in counter-regulatory hormones (a.k.a. hyperglycemia). Hyperglycemia leads to glycosuria (glucose in the urine), increased urine output, and dehydration. Because the glucose is excreted in the urine, the body becomes starved for energy . At this point, the body either continues to excrete glucose in the urine making the hyperglycemia worse (HHS), or the body begins to break down triglycerides causing the release of ketones (by-products of fat breakdown) into the urine and bloodstream (DKA). The mortality rate of patients with DKA is less than 5 percent while the mortality rate of HHS patients is about 15 percent. Infection (urinary tract infections and pneumonia account for 30 to 50 percent of cases), omission of insulin, and increased amounts of counter-regulatory hormones contribute to DKA and HHS. Type 1 and type 2 diabetic patients may experience DKA and HHS. However, DKA is more common in type 1 diabetic patients, while HHS is more common in type 2 diabetic patients. Treatment of DKA and HHS involves correction of dehydration, hyperglycemia, ketoacidosis, and electrolyte deficits and imbalances.

Treatment for Diabetes

Treatment for diabetes involves following a regimen of diet, exercise, self-monitoring of blood glucose, and taking medication or insulin injections. Although type 1 diabetes is primarily managed with daily insulin injections, type 2 diabetes can be controlled with diet and exercise. However, when diet and exercise fail, medication is added to stimulate the production of insulin, reduce insulin resistance, decrease the liver's output of glucose, or slow absorption of carbohydrate from the gastrointestinal tract. When medication fails, insulin is required.

Following the diagnosis of diabetes, a diabetic patient undergoes medical nutrition therapy. In other words, a registered dietician performs a nutritional assessment to evaluate the diabetic patient's food intake, metabolic status, lifestyle, and readiness to make changes, along with providing dietary instruction and goal setting. The assessment is individualized and takes into account cultural, lifestyle, and financial considerations. The goals of medical nutrition therapy are to attain appropriate blood glucose, lipid, cholesterol , and triglyceride levels, which are critical to preventing the chronic complications associated with diabetes. For meal planning, the diabetic exchange system provides a quick method for estimating and maintaining the proper balance of carbohydrates, fats, proteins, and calories . In the exchange system, foods are categorized into groups, with each group having food with similar amounts of carbohydrate, protein, fat, and calories. Based on the individual's diabetes treatment plan and goals, any food on the list can be exchanged with another food within the same group.

Exercise and blood glucose monitoring are also critical components of a diabetic patient's self-management. Exercise improves blood glucose control, increases sensitivity to insulin, reduces cardiovascular risk factors, contributes to weight loss, and improves well-being. Exercise further contributes to a reduction in the risk factors for diabetes-related complications. Daily self-monitoring of blood glucose levels allows diabetic patients to evaluate and make adjustments in diet, exercise, and medications. Self-monitoring also assists in preventing hypoglycemic episodes.

Diabetes, Heart Disease, and Stroke

Many people with diabetes are not aware that they are at particularly high risk for heart disease and stroke, which can result from the poor blood flow that is a symptom of diabetes. In addition, people with type 2 diabetes have higher rates of hypertension and obesity, which are additional risk factors. Diabetics are two to four times more likely to have a heart attack than nondiabetics, and at least 65 percent of people with diabetes die from heart attack or stroke. While deaths from heart disease have been declining overall, deaths from heart disease among women with diabetes have increased, and deaths from heart disease among men with diabetes have not declined nearly as rapidly as they have among the general male population. The National Diabetes Education Program has launched a campaign to bring the problem to public attention. Patients are advised to work with medical personnel to control their glucose level, blood pressure, and cholesterol level and, of course, to avoid smoking.

Diabetes mellitus is a chronic and debilitating disease. Attributed to genetics, physical inactivity, obesity, ethnicity, and a number of environmental factors, diabetes requires lifestyle changes and medication adherence in order to control blood glucose levels. Due to the damage caused by hyperglycemia, diabetic patients also experience a number of complications related to the disease. With good self-management practices, however, individuals with diabetes can live a long and productive life.

see also Carbohydrates; Exchange System; Glycemic Index; Hyperglycemia; Hypoglycemia; Insulin.

Julie Lager


American Diabetes Association (2003) "Gestational Diabetes Mellitus." Diabetes Care 26(1):S103S105.

American Diabetes Association (2003) "Hyperglycemic Crises in Patients with Diabetes Mellitus." Diabetes Care 26(1):S109S117.

American Diabetes Association (2003) "Physical Activity/Exercise and Diabetes Mellitus." Diabetes Care 26(1):S7377.

American Diabetes Association (2003) "Standards of Medical Care for Patients with Diabetes Mellitus." Diabetes Care 26(1):S33S50.

Atkinson, Mark A., and Eisenbarth, George S. (2001). "Type 1 Diabetes: New Perspectives on Disease Pathogenesis and Treatment." Lancet 358:221229.

Black, Sandra A. (2002). "Diabetes, Diversity, and Disparity: What Do We Do with the Evidence?" American Journal of Public Health 92(4):543548.

Chiasson, Jean-Louis; Aris-Jilwan, Nahla; Belanger, Raphael; Bertrand, Sylvie; Beauregard, Hugues; Ekoe, Jean-Marie; Fournier, Helene; and Havrankova, Jana (2003). "Diagnosis and Treatment of Diabetic Ketoacidosis and the Hyperglycemic Hyperosmolar State." Canadian Medical Association Journal 168(7):859866.

Green, Anders (1996). "Prevention of IDDM: The Genetic Epidemiologic Perspective." Diabetes Research and Clinical Practice 34:S101S1006.

Mandrup-Paulson, Thomas (1998). "Recent Advances: Diabetes." British Medical Journal 316(18):12211225.

Mokdad, Ali H.; Ford, Earl S.; Bowman, Barbara A.; Dietz, William, H.; Vinicor, Frank; Bales, Virginia, S.; and Marks, James S. (2003). "Prevalence of Obesity, Diabetes, and Obesity-Related Health Risk Factors, 2001." Journal of the American Medical Association 289(1):7679.

Jovanovic, Lois, and Pettitt, David J. (2001). "Gestational Diabetes Mellitus." Journal of the American Medical Association 283(20):25162518.

Kitabchi, Abbas E.; Umpierrez, Guillermo E.; Murphy, Mary Beth; Barrett, Eugene J.; Kreisberg, Robert A.; Malone, John I.; and Wall, Barry M. (2001). "Management of Hyperglycemic Crises in Patients with Diabetes." Diabetes Care 24(1):131153.

Simpson, R. W.; Shaw, J. E.; and Zimmet, P. Z. (2003). "The Prevention of Type 2 DiabetesLifestyle Change or Pharmacotherapy? A Challenge for the 21st Century." Diabetes Research and Clinical Practice 59:165180.

Yki-Jarvinen, Hannele (1998). "Toxicity of Hyperglycemia in Type 2 Diabetes." Diabetes/Metabolism Reviews 14:S45S50.

Internet Resources

American Diabetes Association. "Basic Diabetes Information." Available from <>

Centers for Disease Control and Prevention. "Diabetes Public Health Resource." Available from <>

National Diabetes Information Clearinghouse (NDIC). "Diabetes." Available from <>

World Health Organization. "Fact Sheets: Diabetes Mellitus." Available from <>

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Metabolic Disorders

Metabolic disorders

How are your enzymes working today? Enzymes are chemical compounds that increase the rate at which reactions take place in a living organism. Without enzymes, most chemical changes in an organism would proceed so slowly that the organism could not survive. As an example, all of the metabolic reactions that take place in the body are made possible by the presence of specific enzymes. As a group these chemical reactions are referred to as metabolism.

So what happens if an enzyme is missing from the body or not functioning as it should? In such cases, a metabolic disorder may develop.

A metabolic disorder is a medical condition that develops when some metabolic reaction essential for normal growth and development does not occur.

The disorder known as phenylketonuria (PKU) is an example. PKU is caused by the lack of an enzyme known as phenylalanine hydroxylase. This enzyme is responsible for converting the amino acid phenylalanine to a second amino acid, tyrosine. Tyrosine is involved in the production of the pigment melanin in the skin. Individuals with PKU are unable to make melanin and are, therefore, usually blond haired and blue eyed.

But PKU has more serious effects than light hair and eye color. When phenylalanine is not converted to tyrosine, it builds up in the body and is converted instead to a compound known as phenylpyruvate. Phenylpyruvate impairs normal brain development, resulting in severe mental retardation in a person with PKU. The worst symptoms of PKU can be prevented if the disorder is diagnosed early in life. In that case, a person can avoid eating foods that contain phenylalanine and developing the disorder that would follow.

Other examples of metabolic disorders include alkaptonuria, thalassemia, porphyria, Tay-Sachs disease, Hurler's syndrome, Gaucher's disease, galactosemia, Cushing's syndrome, diabetes mellitus, hyperthyroidism, and hypothyroidism. At present, no cures for metabolic disorders are available. The best approach is to diagnose such conditions as early as possible and then to arrange a person's diet to deal as effectively as possible with that disorder. Gene therapy appears to have some long-term promise for treating metabolic disorders. In this procedure, scientists attempt to provide those with metabolic disorders with the genes responsible for the enzymes they are missing, thus curing the disorder.

[See also Metabolism ]

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Metabolic Disease

Metabolic Disease

Inborn Errors of Metabolism: A Scientists Discovery

How Does Metabolism Normally Work?

Metabolic Diseases

What Does It All Mean?


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 carbohydrate) in the body. This imbalance often interferes with the normal function of various body tissues and organs.


for searching the Internet and other reference sources


Endocrine system

Energy metabolism

Inborn Errors of Metabolism: A Scientists 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 bodys 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 childs body needs to metabolize (me-TAB-o-lize), or process, certain nutrients and other substances properly. Garrods theory was revolutionary at the time, since no one had yet suggested that the bodys chemical processes might somehow be related to heredity. Moreover, 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 bodys 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 bodys normal function.

are chemical substances produced in one part of the body that regulate the activities of certain organs or groups of cells in other parts of the body.
are proteins produced by the bodys infection-fighting immune system to defend against bacteria, viruses, and other foreign organisms or substances.


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 bodys 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 bodys cells to release energy for fueling body functions.

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.

Enzymes missing in action

None of the processes involved in metabolism would be possible without substances called enzymes. These are proteins that the bodys 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 persons 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 enzymes activity in the body decreases or is completely absent.

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 properlywhether carbohydrate, sugar, fat, or proteinbuild 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 substitute 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,

75 Years Ago: A Discovery That Changed Childrens Lives

Norway, 1934: A mother with two severely mentally retarded children goes to see Dr. Asbjorn Foiling. She is desperate for answers about her childrens 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. Foiling 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 childrens retardation.

Dr. Foiling 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. Foiling 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. Foiling 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. Föllings 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.

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.

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 acidsvaline (VAYL-een), leucine (LOO-seen), and iso-leucine (i-so-LOO-seen)is lacking. These acids are essential for the

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 Georges problem was in his body, not his mind. When psychiatrists studied the kings 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 bodys 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.

bodys 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.

Babies who cannot drink milk: Galactosemia

For most babies and young children, mother s milk (or a formula like breast milk) and then cows milk supply nutrients essential to the bodys 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 bloodstream 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.

are perceptions by the senses that are not based on reality, for example, seeing or hearing things that do not exist.
is a serious mental disorder that may be marked by confusion, speech disorders, anxiety, excitement, and/or hallucinations.
is a mental disorder marked by feelings of self-importance or suspicion that other people are out to get the paranoid person.

Doctors can test someones blood, urine, or stool to diagnose porphyria. A drug called hemin, which is like heme, can be given, along with other medications to relieve symptoms. Sometimes, a high-carbohydrate 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 persons 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.

See also

Birth Defects


Genetic Diseases

Growth Disorders



Mental Retardation




Thyroid Disease


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.

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