metabolic disease

Any disorder that causes dysfunction of the metabolic action of the body, resulting in loss of control of homeostasis.

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.

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 sis 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.

Table 1

Table 2

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 acids—DNA and RNA—are 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 crises—including episodes of coma, stroke-like events, and seizures—and muscle weakness or cardiomyopathy. Kidney function—most often the tubular function required for retention of electrolytes—may 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

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

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.

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.

Galactosemia

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.

Mucopolysaccharidosis

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.

Bibliography

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. http://www.ncbi.nlm.nih.gov/Omim.

—Bruce A. Barshop

Metabolism may be defined as those changes in liver cells that provide energy for vital processes. "Metabolic diseases" is a term that includes a vast array of genetic disorders whose effects may be exacerbated or ameliorated by diet. Several groups of these are recognizable and treatable.

One group of metabolic diseases is concerned with errors in the body that fail to preserve equilibrium of the water and salts. Dehydration results from excess water loss compared to intake. Normally, this is compensated for by thirst and the subsequent ingestion of water. Diseases result from loss of the thirst mechanism; excessive water is lost with diseases of the kidney or of the pituitary gland (diabetes insipidus). Diseases of the sweat glands may result in excessive loss of salt. Shock due to low salt in the circulation may occur as a normal blood pressure is not maintained.

Cystic fibrosis of the pancreas is a severe metabolic disease caused by an abnormality of a gene on chromosome 7. Infants may be born with obstruction of the intestine, develop severe diarrhea and/or chronic lung disease, or fail to grow properly. At present, treatment includes special easily absorbable formulas, large doses of vitamins, supplements of enzymes that are made in the pancreas, and frequent administration of specific antibiotics to treat or prevent lung infection.

Salt is lost in patients with the genetic disease cystic fibrosis, an error in one aspect of the function of the pancreas. Loss of function or destruction of pancreatic islet cells, another part of the pancreas, causes type 1 diabetes mellitus, one of the severe common metabolic diseases. The islets of the pancreas are the source of insulin, a hormone responsible for the metabolism of sugar. Without insulin, sugar (glucose) rises in the blood and is excreted in the urine together with excessive water and salt (sodium and chloride). Dehydration results in loss of excess sodium (a base or alkali) and results in the tissues becoming acidotic and the body is in "acidosis." Treatment requires administration of fluids and an excess of sodium compared to chloride (chloride functions as an acid in the body). Because insulin functions in fat metabolism, patients with diabetes may develop atherosclerosis, heart disease, and other complications due to abnormal deposition of fat. The amount of carbohydrate, protein, and fat in the diet must be regulated even in those receiving regular amounts of insulin.

In addition to the pancreas, disturbed function of any of the endocrine glands may result in metabolic disease. For example, the pituitary gland secretes growth hormone. Excessive growth hormone results in gigantism and acromegaly (i.e., overgrowth of parts of the body or the whole body, e.g., progressive enlargement of hands, feet, and face). Deficiency of growth hormone results in dwarfism. The thyroid gland secretes thyroxine, a hormone that controls metabolic rate. Excessive thyroxine results in excessive burning of calories, and affected children fail to thrive (Graves's disease). Insufficiency results in hypothyroidism. In the baby, this may be called cretinism (physical shortness and mental deficiency), and in the older child, myxedema (form of inelastic swelling of the connective tissue). If not treated, these children may be mentally retarded and fail to grow properly. The adrenal glands secrete hormones for maintaining blood pressure. Lack of adrenal function may result in shock. The adrenal glands also are important in sugar metabolism and lack of function may result in low blood sugar (hypoglycemia). Abnormalities of the fetal adrenal glands result in abnormalities of the development of the sexual characteristics and in hypotension or low blood pressure. The parathyroid glands are essential for normal bone function and metabolism. Abnormalities may result in a ricketslike syndrome, or in low blood calcium that may cause seizures. Abnormalities of the ovaries or testes result in abnormalities in sexual development. Abnormalities due to endocrine deficiencies may be corrected by replacement hormones. For those with excessive hormone secretion, surgery or treatment with drugs to inhibit the secretion of the hormone may be effective.

Vitamins

Inappropriate vitamin intake also causes metabolic disease. Vitamin A deficiency results in blindness; night blindness is due to lack of a specific metabolic product, rhodopsin, of vitamin A. Excessive vitamin A may result in increased intracranial pressure due to abnormalities of metabolism of cerebral spinal fluid. Thiamine is necessary for carbohydrate metabolism, and lack of thiamine results in beriberi, a very severe disease involving edema and heart failure. Some people with thiamine deficiency develop central nervous system abnormalities. Niacin is necessary for carbohydrate metabolism. Deficiency results in pellagra, a condition marked by diarrhea, abnormal coloration of the skin, central nervous system abnormalities, and death. Pyridoxine, vitamin B₆, is necessary for nerve and other functions. Deficiency results in seizures, abnormal sensation in the hands and feet, and anemia. Biotin is necessary for protein and fatty acid metabolism. Deficiency of biotin results in abnormalities of the hair and skin. Deficiency may occur in those who eat significant amounts of raw eggs. Deficiency of folic acid results in anemia. Deficiency in a pregnant woman results in a fetus with abnormalities of the spinal cord (e.g., spina bifida, myelomeningocele). Vitamin B₁₂ deficiency results in abnormalities of nucleotides that are essential for gene replication and transcription. Clinically, vitamin B₁₂ deficiency manifests as pernicious anemia, which, in addition to anemia, includes abnormalities of the central nervous system. Vitamin C (ascorbic acid) is necessary for the metabolism of interstitial (collagen) support substance. Deficiency results in bleeding, bone pain, and scurvy. Vitamin D is necessary for calcium metabolism. Deficiency results in abnormal bone formation and rickets. Deficiency also may result in secondary hypoparathyroidism, low serum calcium, and seizures. Excess may result in abnormal deposition of calcium in the kidneys and brain resulting in kidney failure and brain abnormalities. Vitamin E participates as an antioxidant. Vitamin K functions in clotting mechanism and bone metabolism. Treatment of any of the vitamin deficiencies or excesses requires control of intake, unless due to primary metabolic diseases that may inhibit absorption of the vitamin or its proper metabolism.

Minerals

Of the sixteen minerals said to be essential to humans, several are of special importance. Sodium, already discussed, is essential for acid-base homeostasis (maintenance of a steady state). Potassium is essential for nerve transmission and its importance is noted in maintaining heart rate regularity. Chloride is essential for water homeostasis and acid-base balance. Low sodium and chloride may result in hypotension, and elevated sodium chloride, in hypertension. Calcium and phosphorus participate in bone metabolism and in nerve transmission. Low serum calcium may result in seizures. Iron and copper are necessary for hemoglobin formation. Copper is also important in protein formation. Iodine is essential for thyroid metabolism. Zinc participates as a cofactor for many of the liver enzymes. Other trace minerals have been suggested as essential elements. Deficiency or excess of any of the minerals may be prevented by appropriate dietary intake unless, like the vitamins, metabolic errors due to genetic abnormalities may relate significantly to ranges of intake needed to avoid deficiency or excess.

Organs

Any of the organs may participate in metabolic disease. Two are especially prominent, liver and kidney. The liver enzymes participate in protein, carbohydrate, and fat metabolism. Low protein intake may result in edema due to lack of serum albumin. Liver enzymes help maintain glucose homeostasis, and levels of vitamin and fat metabolism. Common metabolic diseases seen with liver failure include albumin deficiency, hematologic disease, hypoglycemia, abnormalities of vitamin D metabolism, abnormalities of fat metabolism, and metabolism of some of the minerals. The liver also is essential for acid-base homeostasis. The liver enzymes are most responsible for detoxification of various chemicals. Liver failure may manifest itself by high serum ammonia levels and ammonia intoxication. Liver scarring (cirrhosis) may be the end result of several insults. Dietary treatment usually includes a low-protein diet that helps avoid ammonia toxicity and may help hepatic healing. Dietary supply of those substances that cannot be produced because of deficient liver metabolism may mitigate deficiencies partially.

The kidney is important in excreting and conserving water. If the body is alkaline, the kidney secretes base; if the body is acidotic, the kidney secretes acid. The kidney regulates secretion of small proteins, amino acids, and glucose. Kidney disease (nephrosis, where body swelling is related to the loss of serum protein, or nephritis, due to inflammation of the kidney) may result in loss of protein. The kidney is active in the metabolism of vitamin D, and deficiency results in abnormalities of bone and parathyroid metabolism. Kidney disease may result in retention or excess of normal products such as ammonia and urea, or excretion of essential substances such as water. Lack of control of water excretion is renal diabetes insipidus (excessive urine due to kidney abnormality), in contrast to pituitary diabetes insipidus (excessive urine due to pituitary abnormality, resulting in a deficiency of the antidiuretic hormone).

"Inborn errors of metabolism" was a term first used by Sir Archibald Garrod in his Croonian lectures published in 1908. He defined these inborn errors as blocks in metabolic pathways causing genetically determined diseases. He developed the concept that certain diseases of lifelong duration occur because an enzyme governing a single metabolic step is reduced in activity or missing completely, based on his observations of patients with alkaptonuria (urine that turns black upon exposure to light due to the presence of an amino acid breakdown product), albinism (lack of pigment in body tissues, such as hair, due to a lack of enzymes associated with melanin), cystinuria (excessive amounts of the amino acid cystine in urine resembling a form of kidney stone), and pentosuria (abnormal excretion in the urine of pentose, a form of sugar not utilized by humans).

When Garrod diagnosed these patients, most were adults who had been asymptomatic in infancy and childhood. Moreover, he noted that these conditions occurred in families and in many of the families more than one sibling was affected. Parents and other relatives usually were normal. A high incidence of intermarriage was common among affected families.

Following Garrod's work, others began to look for distinguishing characteristics in related families. For example, in 1934, Folling was working in an institution for the mentally delayed. He tested urine with a chemical, ferric chloride, and found a number of severely retarded children and adults whose urine turned purple upon that reagent's addition. The cause of the color change was found to be due to phenyl ketone. He and others determined that the phenyl ketone resulted from an error in the metabolism of phenylalanine, an amino acid found in nearly all proteins ( Jervis). Many patients were identified with phenylketonuria (PKU) over the next twenty years, but little could be done to prevent mental delays that accompanied this condition.

Though chromatography was invented in Russia at the end of the nineteenth century, it was a technique used mainly for identification of complex substances. In the early 1950s, a number of investigators, particularly Armstrong and co-workers (Armstrong et al.), developed a technique to remove phenylalanine from milk proteins and the ability to diagnose this condition in growing infants became available. A formula with low phenylalanine content was developed at about this time. This formula was prescribed for those diagnosed with PKU and is very similar to the formula that is fed infants with phenylketonuria today. Though the infants with phenylketonuria progressed better than previously and indeed some progressed normally, a large number continued to experience delays in mental development. It was not until the Guthrie test was developed in the mid-1960s (Guthrie) that the diagnosis of phenylketonuria could be made almost at birth. This permitted the diet to be started at a much younger age. Many patients treated from birth progress normally.

Phenylketonuria is due to a disorder of the phenylalanine hydroxylating system. The gene for phenylalanine hydroxylase has been localized. Phenylalanine hydroxylase converts phenylalanine to tyrosine. Excess phenylalanine may be toxic or may convert to other toxic substances, or lack of the product tyrosine may be detrimental. Attempts to treat PKU only with added tyrosine did not completely correct the condition.

Newer instrumentation, gene analysis, and dietary control permit screening of the newborn for a large number of amino acid and other abnormalities; thus, many inborn errors of metabolism can be identified in the newborn and for some of these effective or palliative treatment is instituted. The studies of PKU are a model for many of the errors of amino acid metabolism (Barness and Barness). Each of these inborn errors of metabolism may present as a medical emergency, particularly in the newborn. One group of amino acids, termed branch-chain amino acids because of their chemical structure, improperly may form substances that smell like maple syrup. The disease is called maple syrup urine disease. Its treatment requires adjusting the intake of the branched-chain amino acids. Another group of branched-chain amino acids results in severe acidosis and depression of the bone marrow when inadequately metabolized. Two disorders are relatively common, methylmalonic acidemia and propionic acidemia. Some of these individuals respond to diet manipulation and large doses of vitamin B₁₂. Some patients present with an odor of sweaty feet due to a defect in the metabolism of leucine, one branched-chain amino acid. Decreasing dietary protein may ameliorate some of the worst signs of this disease.

One group of infants with amino acid and metabolic error may present with the odor of ammonia. They may become comatose rapidly. They have errors related to the breakdown into urea of one of the five amino acids. They cannot make urea from ammonia. Urea is a benign substance easily excreted in the urine. Affected infants are treated with a low-protein diet and frequently must also be treated with dialysis and ammonia-binding drugs to prevent catastrophic effects to the nervous system (Brusilow et al.).

Fatty acid metabolic disorders are causes of several muscle weakness diseases. Some patients affected by these conditions present with high blood ammonia, heart abnormalities, and coma. Liver disease may be a complication (DeVivo). These are divided according to the size (length) of the implicated fat. Many of the affected fats normally are excreted conjugated to the amino acid carnitine. Some of the worst effects of these disorders respond to the administration of carnitine and to limited intakes of the implicated fatty acid. Symptoms are aggravated by fasting, and intravenous glucose may be required.

Mason and Turner in 1935 reported a reducing substance identified as galactose in the urine of a number of children who were delayed markedly in development. The substance was found to be galactose and its source was human or cow's milk. Very young infants with the abnormal urinary substance were identified by this test. If allowed to drink milk, these infants frequently had seizures, became jaundiced, and vomited perniciously. They did not grow well. When milk was removed from the diet, they seemed to thrive. They experienced improved growth when they were fed with a soybean-based formula that contained no lactose, the principal sugar found in milks, human and other. Lactose is normally digested to galactose and glucose. The condition is called galactosemia because of the abnormally elevated galactose concentration in the blood.

Since the discovery and treatment of galactosemia, other errors in the metabolism of carbohydrates have been recognized. Some children cannot utilize fructose and develop symptoms similar to those experienced by untreated galactosemics. Children with hereditary fructose intolerance are interesting in that they consume breast milk and infant formulas made with lactose without difficulty. However, when given any food with table sugar, their symptoms become frightening. They quickly learn to avoid sugar or any food containing the fruit sugar, fructose. They grow normally and have wonderfully noncarious teeth. Other diseases of carbohydrate metabolism result in liver, heart, and kidney abnormalities. Some are accompanied by physical abnormalities.

Pauling and colleagues (1949) studied hemoglobin structure and found a specific mutation causing an alteration in the structure of hemoglobin. This led to the discovery of the errors in sickle cell disease. Subsequently, other genetic abnormalities have been identified as responsible for many hereditary anemias.

A common disease in adults is arteriosclerotic heart disease. Genetic abnormalities in cholesterol metabolism are believed to be responsible for atherosclerotic heart disease in some who suffer from this condition. Dietary manipulations and exercise beneficially affect a large percentage of these individuals. Others require drugs. Another group of patients with heart disease demonstrates a defect in metabolism of the amino acid homocystine. Treatment of the elevated homocystine with the same agents used for the treatment of the inborn error homo-cystinuria may reverse the condition.

Over four hundred inborn errors of metabolism have been diagnosed. Future genetic studies may reveal many more. Many carbohydrate, amino acid, and fatty acid abnormalities have yielded to effective treatment that must be maintained lifelong—a form of treatment is available for approximately forty to fifty of these conditions, with a similar number having experimental approaches. Some complex abnormalities, particularly those related to body structures and muscle diseases, await gene modification for effective therapy. Although each of the inborn errors, excluding the more common hematologic ones, may occur in only 1 in 4,000 to 1 in 100,000 live births, cumulatively they account for more than 1 in 1,000 of live births. Early diagnosis may prevent severe disabilities in progeny.

Bibliography

Armstrong, M. D., K. N. F. Shaw, and K. S. Robinson. "Studies on Phenylketonuria." K. Bop. Cje. 213 (1955): 797–799.

Barness, E. G., and L. Barness. Metabolic Diseases. Foundations of Clinical Management, Genetics, and Pathology. Natick, Mass.: Eaton Publishers, 2000.

Brusilow, S. W., M. L. Batshaw, and L. Waber. "Neonatal Hyperammonemic Coma." Advances in Pediatrics 29 (1982): 69–86.

DeVivo, D. C. "Reye Syndrome." Neurologic Clinics 3 (1985): 95–114.

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—Lewis A. Barness