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Metabolic Disease

Enzymes Control Metabolic Reactions, Enzyme Defects Cause Metabolic Disorders, Approaches To Treatment, Major Classes Of Metabolic DisordersDisorders of Amino Acid Metabolism, Disorders of Organic Acid Metabolism, Disorders of Fatty

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 effects—alkaptonuria, 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.


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 urine—the effect that allowed Garrod to recognize the genetic inheritance of this inborn error of 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.

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.

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.

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.

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Medicine EncyclopediaGenetics in Medicine - Part 3