Introduction to Genetic-Metabolic Disease

Jess G. Thoene, M.D.

We are a set of chemical reactions. The physical basis for life is a series of closely controlled chemical reactions. These reactions govern what we look like, what we are able to eat, and what we are capable of doing. When one of these reactions fails to function, serious consequences to the individual may occur, including failure to develop properly as a fetus, failure to adequately to grow or develop full mental capacity, and failure to live a normal life span.

Each of the chemical reactions in the body is governed by an enzyme that controls the rate of the reaction. The energy of life is provided by controlled oxidation, which is analogous to fire. Obviously, our bodies cannot tolerate open flame. But, through mediation by enzyme-controlled reactions, we are able to "burn" food, and this burning supplies energy and thus allows life to continue.

Each enzyme is itself under the control of a gene that specifies it. Genes are coded within DNA as long strings of the four letters, A T G and C, which represent the chemicals that makeup the DNA molecule. Three of these letters taken together specify one of the twenty amino acids that make up all proteins. The proteins are the molecules that can possess enzymatic activity, as well as provide the structure for the body. Current thinking suggests that humans possess about 25,000 genes. There are more than 25,000 proteins known, so alterations in proteins after they are made from gene information must occur.

Enzymes are encoded by DNA. Within the nucleus of each cell, stretches of DNA called coding regions are transcribed into messenger RNA and then translated into the appropriate protein. An alteration in the sequence of DNA can lead to abnormal construction of a protein, a shortened protein, or an absent protein. Depending on the severity of the error, this process may lead to a defective protein, a protein that is recognized as abnormal by the body and therefore removed, or no protein production at all. Depending on the particular protein involved, the consequences for a person can range from unnoticeable to catastrophic, even leading to spontaneous miscarriage.

Inborn errors of metabolism is the field of genetics devoted to the study of biochemical errors, which involve the many enzyme reactions that control how we metabolize. Basically, all foods are composed of proteins, carbohydrates, or fats. Various inborn errors of metabolism in each of the three groups have been described with potentially severe consequences.

How we inherit errors of metabolism. It is important to remember that one of the basic rules of genetics is that we receive half of our genes from our mother and half of our genes from our father. If we receive a gene that has an abnormality in it from one parent, but the gene from the other parent is intact, then usually this does not lead to an illness. This mode of inheritance is called autosomal recessive, meaning (1) that the defect does not depend upon the sex of the person inheriting it and (2) that persons having only one copy of that defective gene are clinically normal. When both parents are carriers of the same condition, meaning that each parent has one broken copy of a gene and one intact copy, then the chance in each pregnancy for a child to that couple to have the disorder is 25 percent. There is a 50 percent chance that the child will be a carrier like the parents and a 25 percent chance that the child will be normal, with no defective gene for that condition.

Another mode of inheritance is autosomal dominant, which is also sex-independent, but in this case inheriting one copy of the defective gene does result in noticeable illness or deformity. One half of the children of either sex born to a person with this type of disorder will have the gene for that condition.

X-linked disorders are caused by defective genes that normally reside on the X-chromosome. Women have two X chromosomes, whereas men have an X chromosome and a Y chromosome. Carrier females who have a defective gene on one X chromosome but a normal copy on the other X chromosome pass on either one or the other to each child they produce. Since girls receive an X from mother and an X from father, if the father is not a carrier for the condition, then 50% of the female offspring to a carrier mother will be carriers of the condition and 50% of her daughters will be normal. However, when the father donates the Y chromosome, resulting in a male child, 50% of that mother's sons will be affected, because male receives only one X chromosome. Therefore, if she donates her X-chromosome that has the defective gene in it, then the son, having no other X chromosome because he is a male, will display that condition. Half of her sons will be affected and half of her sons will be normal.

It is extremely important to note that when we use words like "normal" and "defective" we remember that all of us are carriers for approximately six genes that, if we have both copies of that gene broken in us, would result in a serious disease. The only difference between normal persons and persons with genetic disorders (or persons who are parents of children with a genetic disorder) is that affected persons know the name of one of the six genes that is broken in their genome. The quality of all our DNA is exactly the same. It is strictly random chance that determines whether we happen to have offspring with a person who is also a carrier for one of the same genes for which we are a carrier.

Inborn errors are rare. Most genetic diseases are quite rare. The inborn errors of metabolism occur with a frequency of about 1/10,000 to 1/300,000 live births. Some of the biochemical disorders with which we deal include conditions known as PKU, galactosemia, or biotinidase deficiency. Most people have never heard of these disorders, and this is understandable because they are so rare. However, all states in the United States screen newborns for certain of these disorders for two reasons: (1) because of the serious consequences if they are not diagnosed early in infancy and (2) because of the potential for near complete correction if appropriate treatment is started in a timely fashion.

Screening for and treatment of inborn errors. Louisiana screens for all three of these inborn errors, and plans are being developed to begin screening all newborns for up to 22 inborn errors of metabolism (using new technology called tandem mass-spectroscopy). Screening begins with a drop of blood collected from the newborn's heel onto filter paper in the nursery, and this blood sample is sent to the State Public Health Laboratory for analysis. Untreated, most of these diseases result in mental retardation or death in the newborn period. With early diagnosis and treatment, good outcomes are possible.

The treatment of inborn errors of metabolism is usually dietary. As noted above, these conditions result from a defect in a gene that affects a chemical reaction. When some chemical reactions in metabolism are inadequate, accumulation of toxic metabolites occurs, causing brain damage or leading to inadequate production of material critical for brain development. For instance, in PKU, the normal amino acid phenylalanine is not converted to tyrosine; this leads to an accumulation of phenylalanine in the blood, producing severe mental retardation. In mothers with PKU, there can be physical defects in her offspring.

PKU was the first disorder of metabolism for which newborn screening was widely applied. When the children are diagnosed in infancy and a low phenylalanine diet is adopted early in the infant's life (ideally in the first two weeks), the child's IQ is normal. Untreated, the children rarely have an IQ greater than 20. Thus it is imperative to detect all such children and to treat them early. The Tulane Hayward Genetics Center is the designated center in Louisiana for treatment of these children. Families of those children confirmed as positive are immediately contacted by a team of specialists, including a geneticist, genetic counselor, and nutritionist, who immediately prescribe a low phenylalanine diet and monitor the infant's progress.

PKU is important to us because it is prevalent in Acadiana. Children from the region are treated with a low phenylalanine diet, and the outcome is uniformly good when the diet is closely followed. Other examples of different diseases with good outcomes may include galactosemia, a disorder of sugar metabolism, and biotinidase deficiency, a disorder of protein metabolism. It is extremely important that every infant born in Louisiana have the simple heel-stick blood test performed. It literally can mean the difference between life and death.

Jess G. Thoene, M.D., is Director of the Hayward Genetics Center and Karen Gore Professor of Pediatrics at the Tulane University Health Sciences Center. His major research interest is clinical and biochemical investigation of cystinosis, a lethal disease of lysosomal cystine storage. He has been active in the orphan disease movement, serving as Chairman of the Board of the National Organization for Rare Disorders and Chair of the National Commission on Orphan Diseases.

Thoene, J. (Ed.) Physician's Guide to Rare Disease (2nd ed.) Montvale, New Jersey: Dowden Press, 1995.

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