What are inborn errors of metabolism?

Early Observations

In 1902, Sir Archibald Garrod, a British physician, presented a classic paper in which he summarized his observations and analyses of a condition known as alkaptonuria. The condition is easily diagnosed because the initial major symptom is dark urine caused by the excretion of homogentisic acid. Other symptoms that occur later in life include pigmentation of the connective tissue, spine and joint deterioration, coronary artery calcifications, and cardiac valve deterioration.

Garrod reasoned that individuals with alkaptonuria had a defect in the utilization of amino acids, because homogentisic acid is not normally found in urine and is a by-product of certain amino acids with particular ring structures. Today it is known that alkaptonuria is linked to mutations of the HGD gene, which was mapped to chromosome 3q21-q23. These mutations cause an absence of the enzyme homogentisic acid oxidase. Without the presence of this enzyme, homogentisic acid accumulates and causes the aforementioned symptoms.

Scientists were only beginning to discover the genetic causes of disease at this time. Garrod noted that the condition is often found in two or more siblings and postulated that the occurrence of this condition may be explained by the mechanism of inheritance. In 1908, in “Inborn Errors of Metabolism,” Garrod extended his observations on alkaptonuria to other diseases such as albinism and cystinuria. In each case, he argued that the abnormal or disease condition was caused by a defect in metabolism that resulted in a block of an important metabolic pathway. He speculated that when such a pathway is blocked, there would be an accumulation of products that are not seen in normal individuals, or important substances would be missing or abnormal. He traced the inheritance of these conditions and discovered that they could be passed on from one generation to the next. He was the first to use the term “inborn errors of metabolism” to describe these conditions.

Other investigators have studied more than three thousand additional diseases that can be included in this category. A few of these conditions occur at relatively high frequency in humans. In the U.S. Caucasian population, cystic fibrosis occurs in about 1 in 2,000 births. Some conditions, such as phenylketonuria (PKU), are seen at moderate frequency, about 1 in 10,000. Many of the inborn errors are rare, with frequencies less than 1 in 100,000. A generally accepted definition of an inborn error of metabolism is any condition with actual or potential health consequences that can be inherited in the fashion described by Gregor Mendel in the nineteenth century.

Malfunctioning Proteins and Enzymes

The biochemical causes of the inborn errors of metabolism were discovered many years after Garrod presented his ideas. In 1952, Von Gierke disease was found to be caused by the defective enzyme glucose-6 phosphatase. After this discovery, many inborn errors of metabolism were traced to defects in other enzymes. Enzymes are proteins that catalyze biochemical reactions. They are responsible for increasing the rates of reactions that occur in all cells. These reactions are important steps in metabolic pathways that are responsible for processes such as utilization of nutrients, generation of energy, cell division, and biosynthesis of substances that are needed by organisms. There are many metabolic pathways that can be affected if one of the enzymes in the pathway is missing or malfunctions. In addition to enzymes, defective proteins with other functions may also be considered as candidates for inborn errors of metabolism. For example, there are many types of defective hemoglobin, the protein responsible for oxygen transport. These defective hemoglobins
are the causes of diseases such as sickle-cell disease and thalassemia.

Genetic Basis of Inborn Errors

The cause of these defects in enzymes and proteins has been traced to mutations in the genes that code for them. Alterations in the structure or nucleotide composition of DNA can have various consequences for the structure of the protein coded for by the DNA. Some of the genetic alterations affecting metabolism simply represent normal variation within the population and are asymptomatic. An example of such a genetic alteration is the ability of some individuals to experience a bitter taste after exposure to chemical derivatives of thiourea.

Some asymptomatic variations in genetic coding may lead to complications only after environmental conditions are changed. There are a few “inborn errors” that can be induced by certain drugs. Another class of alterations may be minor, with the resulting protein having some degree of function. Individuals with such alterations may live long lives but will occasionally experience a range of problems associated with their conditions. Depending on the exact nature of the mutation, some of the alterations in the resulting protein structure can lead to a completely nonfunctional protein or enzyme. Consequences of this type of mutation can be quite severe and may result in death.

Many of the inborn errors of metabolism are inherited as autosomal recessive traits. Individuals are born with two copies of the gene. If one copy is defective and the second copy is normal, enough functioning protein or enzyme can be made to prevent the individual from exhibiting any symptoms of the disease. Such individuals will be classified as carriers for the defect since they can pass on the defective gene to their offspring. About one in twenty Caucasians in the United States is a carrier for the cystic fibrosis gene, and about one in thirty individuals of Eastern Jewish descent carries the gene for the lethal Tay-Sachs disease. When an individual inherits two defective copies of the gene, the manifestations of the disease can be much more severe.

Some inborn errors of metabolism, such as Huntington’s disease, are manifested as dominant genetic traits. This means that only one copy of the defective gene is necessary for manifestations of the abnormal condition. Huntington’s disease is linked to mutations in the IT15 gene, and it causes severe neurodegenerative symptoms. Researchers are currently looking into treatments for Huntington’s disease that would actually turn off certain genes instead of adding new ones.

There are some inborn errors of metabolism that are sex-linked. Diseases that involve mutations carried on the X chromosome may be severe in males because they have only one X chromosome but less severe or nonexistent in females because females carry two X chromosomes.

Diagnosis and Treatment

Significant progress has been made in the diagnosis of inborn errors of metabolism. Prior to 1980, clinical examination was the primary tool used to diagnose metabolic defects. Biochemical tests detect various substances that accumulate, or are missing, when an enzymatic defect is present. The commonly used screening for phenylketonuria (PKU) relies on detection of phenylketones in the blood of newborns. PKU is caused by a mutation in the phenylalanine hydroxylase gene, which is responsible for encoding the enzyme L-phenylalanine hydroxylase. Hyperphenylalaninemia, or an elevated blood level of phenylalanine, occurs without the presence of the enzyme L-phenylalanine.

For cases in which the genetic defect is known, DNA can often be used for the purpose of genetic testing. Genetic counselors will help parents determine their chances of having a child with a severe defect when parents are identified as carriers. Small samples of cells can be used as a source of DNA, and such cells may even be obtained from amniotic fluid by amniocentesis. This allows diagnosis to be made prenatally. Some parents choose abortion when their fetus is diagnosed with a lethal or debilitating defect.

Although strides have been made in diagnosis, the problem of treatment still remains. For some inborn errors of metabolism such as PKU, dietary modification will often prevent the serious symptoms of the disease condition. Individuals with PKU must limit their intake of the amino acid phenylalanine during the critical stages of brain development, generally the first eight years of life.

Treatment of other inborn errors may involve avoidance of certain environmental conditions. For example, individuals suffering from albinism, a lack of pigment production, must avoid the sun. For other inborn errors of metabolism, there are no simple cures on the horizon. Since the early 1990’s, some medical pioneers have been involved in clinical trials of gene therapy.

The human genome is basically the set of instructions used to create a human being. Scientists are now able to compare the genome of a healthy individual to that of a person with an inborn disease. It is now possible to locate an inborn error on the human genome. The possibility, and future probability, of gene therapy is based on this new information. Diseased cells may one day be replaced with cells that contain the correct version of genetic instructions. This may allow healthy cells to grow in the place of diseased ones.

Researchers have seen some efficacy in treating mice affected with PKU using gene therapy. In addition, embryonic or genetically modified cells are being studied for the treatment of Huntington’s disease. Gene therapy is expected to one day prolong the lives of those suffering from cystic fibrosis, who are currently expected to live only forty years. In general, gene therapies for inborn errors of metabolism are expected, but not yet in practice. Many ethical issues are raised when gene therapy trials are proposed. Nevertheless, scientists are looking more and more toward genetic cures to genetic problems such as those manifested as inborn errors of metabolism.

Key terms



metabolic pathway

:

enzyme-mediated reactions that are connected in a series




metabolism

:

the collection of biochemical reactions occurring in an organism





Bibliography

Econs, Michael J., ed. The Genetics of Osteoporosis and Metabolic Bone Disease. Totowa, N.J.: Humana Press, 2000. International experts discuss the genetic and molecular dimensions of their own research into various aspects of the clinical features and pathophysiology of metabolic bone disease.

Fernandes, John, et al., eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 4th rev. ed. Heidelberg, Germany: Springer Medizin Verlag, 2006. Inborn errors of metabolism are discussed thoroughly along with their diagnoses and their treatments in a manner that is aimed at informing the medical community.

Lee, Thomas F. The Human Genome Project: Cracking the Genetic Code of Life. New York: Plenum Press, 1991. The diagnosis of inborn errors of metabolism, development of molecular methods for diagnosis of these genetic defects, and prospects for treatment of these conditions by gene therapy are highlighted within the context of the Human Genome Project.

O’Rahilly, S., and D. B. Dunger, eds. Genetic Insights in Pediatric Endocrinology and Metabolism. Bristol, England: BioScientifica, 1999. Examines endocrine and metabolic diseases among infants, children, and adolescents. Illustrated.

Pacifici, O. G. M., Julio Collado-Vides, and Ralf Hofestadt, eds. Gene Regulation and Metabolism: Postgenomic Computational Approaches. Cambridge, Mass.: MIT Press, 2002. Explores current computational approaches to understanding the complex networks of metabolic and gene regulatory capabilities of the cell.

Sarafoglou, Kyriakie, ed. Pediatric Endocrinology and Inborn Errors of Metabolism. New York: McGraw-Hill, 2009. An international project aimed at helping physicians to diagnose inborn errors of metabolism in children. Well illustrated and easy to navigate.

Scriver, Charles, et al., eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. 4 vols. New York: McGraw-Hill, 2001. These authoritative volumes on genetic inheritance, by some of the biggest names in the field, survey all aspects of genetic disease, including metabolic disorders. The eighth edition has been thoroughly updated; more than half of the content is new.