CHAPTER 6
GENETIC DISEASES

Even at birth the whole individual is destined to die, and perhaps his organic disposition may already contain the indication of what he is to die from.

—Sigmund Freud, 1924

Genetics, the study of biologic inheritance, explains how and why certain traits, such as hair color and blood types, run in families. Each individual develops from a single fertilized egg, which contains all the information necessary for the development of innate mental and physical characteristics. This information is carried in twenty-three pairs of rod-shaped chromosomes (containing thousands of genes) that are responsible for determining and transmitting hereditary characteristics. Each pair of chromosomes includes one inherited from the mother and one from the father.

Genes determine specific physical features, such as height and the color of skin, hair, and eyes. Genes also direct the production of cell proteins needed for health and development. There are two types of genes—dominant and recessive. If one gene in a pair is dominant, the trait it carries is strong enough to cancel out the trait carried by the recessive gene from the other parent. For a recessive gene to appear in offspring, the gene that carries it must be inherited from both parents.

GENETIC TESTING

The most common form of genetic testing is screening of newborn infants for genetic abnormalities. In the United States, according to a 2003 report by the General Accounting Office (GAO), about four million newborns per year are screened by testing blood obtained from a prick of the newborn's heel within the first few days of life. Specific genetic disorders such as phenylketonuria (PKU) and other medical conditions that are not genetically linked, such as congenital hypothyroidism (underactive thyroid gland), can be found with heel-prick testing.

PKU is an inherited error of metabolism resulting from a deficiency of an enzyme called phenylalanine hydroxylase. The lack of this enzyme can produce mental retardation, organ damage, and postural problems. Children born with PKU must pay close attention to their diets so that they may lead healthy, normal lives.

Genetic screening is intended to identify disorders that require early detection and treatment to prevent serious illness or death. Each state determines which disorders to include in its screening program; the number chosen ranges from four to thirty-six, with eight or less being the most common. Table 6.1 shows the disorders most commonly included in screening programs and how many states require each. To help them decide, states generally consider criteria such as how often the disorder occurs in the population, whether an effective screening test exists, and whether the disorder is treatable. Table 6.2 shows the national incidence of, potential outcomes for, and treatment of each disease. States also may consider the cost of screening, which

may include costs associated with doing more tests, acquiring and implementing new technology, and following up on abnormal test results. According to a GAO report on state newborn screening measures, more than $120 million total was spent on newborn screening in state fiscal year 2001.

There are thousands of genetic diseases, such as sickle cell anemia, CF, and Tay-Sachs disease (TSD), that may be passed from one generation to the next. Genetic testing to determine whether an individual has a gene that if passed onto offspring may produce disease is called carrier identification.

Prenatal genetic testing enables physicians to diagnose diseases in the fetus. Using samples of genetic material obtained from amniocentesis or chorionic villus sampling, physicians can detect disease in an unborn child. Down syndrome is the genetic disease most often identified prenatally.

Genetic testing also can be performed postnatally (after birth) to determine which children and adults are at increased risk of developing specific diseases. Scientists can perform predictive genetic testing to identify which individuals are at risk for CF, TSD, Huntington's disease, amyotrophic lateral sclerosis (ALS; a degenerative neurologic condition commonly known as Lou Gehrig's disease), and several types of cancers (including some cases of breast, colon, and ovarian cancer).

More than 1,000 genetic tests are currently available, but public health professionals do not consider it practical to screen for conditions that are very rare, those that have only minor health consequences, or those for which there is still no effective treatment. Table 6.3 lists selected diseases for which gene tests are currently available.

A positive test result (the presence of a defective or altered gene) from predictive genetic testing does not guarantee that the individual will develop the disease; it simply identifies the individual as genetically susceptible and at increased risk for developing the disease. For example, a woman who tests positive for the BRCA1 gene has about an 80 percent chance of developing breast cancer before age sixty-five. It is also important to note that like other types of diagnostic medical testing, genetic tests are not 100 percent predictive—the results rely on the quality of laboratory procedures and accuracy of interpretations. Further, because tests vary in their sensitivity and specificity, there is always the possibility of false-positive and false-negative test results.

Researchers hope that positive test results will encourage people at higher-than-average risk of developing a disease to be especially vigilant about disease prevention and screening to detect the disease early, when it can be treated most successfully.

Ethical Considerations

As scientists learn more about the genes responsible for a variety of illnesses, they can design tests to predict whether an individual is at risk of developing the disease. The ethical issues involved in genetic testing have turned out to be far more complicated than originally anticipated.

Initially, physicians believed that a test to determine in advance who would develop or escape a disease would be welcomed by at-risk families. They would be able to plan more realistically about having children, choosing jobs, obtaining insurance, and living their lives. Nevertheless, many people with family histories of a genetic disease have decided that not knowing is better than anticipating a grim future and an agonizing, slow death. They prefer to live with the hope that they will not develop the disease rather than the certain knowledge that they will.

There are also concerns about privacy and the confidentiality of medical records and the results of genetic testing. Some people are reluctant to be tested because they fear they may lose their health, life, and disability insurance, or even their jobs, if they are found to be at risk for a disease. Genetic tests are sometimes costly, and some insurers agree to reimburse for testing only if they are informed of the results. Insurance companies believe they cannot risk selling policies to people they know will become disabled or die prematurely.

The discovery of genetic links and the development of tests to predict the likelihood or certainty of developing a disease raise ethical questions for people who carry a defective gene. Should women who are carriers of Huntington's disease or CF have children? Should a fetus with the defective gene be carried to term or aborted? One health insurance company agreed to pay for prenatal CF testing for a mother who already had one affected child, but the company insisted if the baby was affected, the mother would have to terminate the pregnancy or it would not cover the child's future medical bills.

MUSCULAR DYSTROPHY

Muscular dystrophy (MD) is a term that applies to a group of hereditary muscle-destroying disorders. According to the Muscular Dystrophy Association in 2004, some type of MD affects approximately one million Americans. Each variant of the disease is caused by defects in the genes that play important roles in the growth and development of muscles. In MD, the proteins produced by the defective genes are abnormal, causing the muscles to waste away. Unable to function properly, the muscle cells die and are replaced by fat and connective tissue. The symptoms of MD may not be noticed until as much as 50 percent of the muscle tissue has been affected.

All of the various disorders labeled MD cause progressive weakening and wasting of muscle tissues. They vary, however, in the usual age at the onset of symptoms, rate of progression, and initial group of muscles affected. The most common type, Duchenne MD, affects young boys, who show symptoms in early childhood and usually die from respiratory weakness or damage to the heart before adulthood. The gene is passed from the mother to her children. Females who inherit the defective gene generally do not manifest symptoms—they become carriers of the defective genes, and their children have a 50 percent chance of inheriting the disease. Other forms of MD manifest later in life and are usually not fatal.

In 1992 scientists discovered the defect in the gene that causes myotonic dystrophy, the most common form of MD. In people with this disorder, a segment of the gene is enlarged and unstable. This finding helps physicians more accurately diagnose myotonic dystrophy. Researchers since have identified genes linked to other types of MD, including Duchenne MD, Becker MD, limbgirdle MD, and Emery-Dreifuss MD.

In addition to its commitment to MD research, the Muscular Dystrophy Association supports research into the causes and treatment of other groups of related neuro-muscular illnesses, such as ALS, Charcot-Marie-Tooth disease, and myasthenia gravis. All of these are progressive, wasting, and weakening conditions that rob individuals of their ability to live, work, and function normally. Genes linked to these diseases were identified during the 1990s.

Treatment and Hope

There is no cure for MD, but patients can be made more comfortable and functional by a combination of physical therapy, exercise programs, and orthopedic devices (special shoes, braces, or powered wheelchairs) that help them to maintain mobility and independence as long as possible.

Genetic research offers hope of finding effective treatments, and even cures, for these diseases. Gene therapy experiments specifically aimed toward a cure or a treatment for one or more of these types of MD are under way. Research teams have identified the crucial proteins produced by these genes, such as dystrophin, beta sarcoglyan, gamma sarcoglyan, and adhalin.

When defective or absent, these proteins cause MD. Researchers hope that experimental treatments to transplant normal muscle cells into wasting muscles will replace the diseased cells. Muscle cells, unlike other cells in the body, fuse together to become giant cells. Scientists hope that if cells with healthy genes can be introduced into the muscles and accepted by the body's immune system, the muscle cells then will begin to produce the missing proteins.

New delivery methods called vectors also are being tested, such as implanting a healthy gene into a virus that has been stripped of all of its harmful properties, and then injecting the modified virus into a patient. Researchers hope this will reduce the amount of rejection by the patient's immune system, allowing the healthy gene to restore the missing muscle protein.

HUNTINGTON'S DISEASE

Huntington's disease (HD), or Huntington's chorea, is an inherited, progressive brain disorder. It causes the degeneration of cells in the basal ganglia, a pair of nerve clusters deep in the brain that affect both the body and the mind. HD is caused by a single dominant gene that affects both men and women of all races and ethnic groups. It does not usually strike until mid-adulthood, although there is a juvenile form that can affect children and adolescents. Early symptoms, such as forgetfulness, a lack of muscle coordination, or a loss of balance, often are ignored. The disease gradually takes its toll over a ten-to twenty-five-year period.

Within a few years, characteristic involuntary jerking (chorea) of the body, limbs, and facial muscles appears. As HD progresses, speech becomes slurred and swallowing becomes difficult. The patients' cognitive abilities decline, and there are distinct personality changes—depression and withdrawal, sometimes countered with euphoria. Eventually, nearly all patients must be institutionalized, and they usually die as a result of choking or infections.

There is no cure for HD. A number of medications may be prescribed to help control emotional and movement problems associated with HD, but the course of the disease cannot be stopped.

Prevalence of Huntington's Disease

HD, once considered rare, now is recognized as one of the more common hereditary diseases. According to the National Institute of Neurological Disorders and Stroke, HD is known to affect about 30,000 Americans; another 150,000 are at a 50 percent risk of inheriting it from an affected parent. Estimates of its prevalence are about one in every 10,000 people.

Prediction Test

In 1983 researchers identified a DNA marker that made it possible to offer a test to determine, before symptoms appear, whether an individual has inherited the HD gene. In some cases, it is even possible to make a prenatal diagnosis on an unborn child. Many people, however, prefer not to know whether they carry the defective gene.

Some individuals choose to be tested because they feel the results will enable them to make more informed decisions about the future—including education, marriage, and childbearing. Those who choose not to take the test may prefer to forego whatever emotional consequences—along with possible losses of jobs or insurance—may incur from the test results. Each choice is highly individual.

A testing center at Johns Hopkins Hospital in Maryland reported that a high proportion of the people who come in for testing find out that they are not carrying the gene. Of the people who do not choose to be tested, the center's physicians believe that many may already have very mild symptoms and suspect that they have the disease.

Gene Responsible for Huntington's Disease Found

In 1993 an international team of scientists from the United States and the United Kingdom announced that after ten years of research, it had discovered the gene responsible for HD. In the HD gene, the mutation involves a triplet of genetic subunits, or bases, known by the chemical initials CAG. In people who do not have HD, the gene has thirty or fewer of these triplets, but patients with HD have forty or more. These increased multiples either destroy the gene's ability to make the necessary protein or cause it to produce a misshapen and malfunctioning protein. Either way, the defect results in the death of brain cells.

The researchers examined seventy-five families with a history of HD and found the abnormal expansion in each case of an afflicted patient. Currently, they are trying to determine if the exact number of excess triplets bears any relation to when in life a person will be affected by the disease. Some scientists fear that the ability to tell people that they are going to develop an incurable disease and pinpoint when they will develop it will make genetic testing, already a difficult decision, even more complicated.

Promising Research Findings

In December 2001 researchers at the University of South Florida reported that fetal tissue—neurons obtained from fetuses—transplanted into the damaged areas of the brains of patients with HD remained disease-free. Earlier in the same year French researchers had reported similar results, confirming that HD did not appear to enter or affect the implanted fetal tissue.

The patients with HD who received the transplants showed measurable improvement in motor and cognitive functions and did not appear to reject the transplanted tissue, leading investigators to speculate that fetal tissue grafts might become the first effective treatment for HD.

CYSTIC FIBROSIS

CF is the most common inherited fatal disease among children and young adults in the United States. It occurs most commonly in white people (in one of every 3,200 births of white children and in one in 3,900 of all Americans), and there are approximately 30,000 young people who have the disease; their median (half above and half below) life span is 33.4 years. However, as more medical advances are made in treating CF, the number of adults with CF is growing; in fact, in 2003 almost 40 percent of those with CF are age eighteen and older. Unfortunately, additional health problems—such as CF-related diabetes and osteoporosis and reproductive problems (95 percent of men with CF are infertile)—occur in adults with CF.

More than ten million Americans, almost all of whom are white, are symptomless carriers of the CF gene. To inherit this disease, a child must receive the CF gene from both parents.

At first, a child with CF does not appear to have a serious illness, but the diagnosis usually is made by the age of three years. Often, the only signs are a persistent cough; a large appetite but poor weight gain; an extremely salty taste to the skin; and large, foul-smelling bowel movements. A simple "sweat test" is currently the standard diagnostic test for CF. The test measures the amount of salt in the sweat; abnormally high levels are the hallmark of CF.

Children with CF have great difficulty breathing. The CF gene causes the body to produce thick, sticky mucus in the lungs and pancreas, causing difficulty in breathing and interference with digestion. This thick drainage must be removed constantly.

Cystic Fibrosis Gene-Screening Falters

In August 1989 researchers isolated the specific gene that causes CF. The mutation of this gene accounts for about 70 percent of the cases of the disease. In 1990 scientists successfully corrected the biochemical defect by inserting a healthy gene into diseased cells grown in the laboratory, a major step toward developing new therapies for the disease. In 1992 they injected healthy genes into laboratory rats by using a deactivated common cold virus as the delivery agent. The rats began to manufacture the missing protein, which regulates the chloride and sodium in the tissues, preventing the deadly buildup of mucus. Scientists were hopeful that within only a few years CF would be eliminated as a fatal disease, giving many children the chance for healthy, normal lives.

In 1993, however, optimism faded when the medical community discovered that the CF gene was more complicated than expected four years earlier. Biologists found that the gene can be mutated at hundreds of points, and more points are being discovered at an alarming rate. At the same time, they discovered that many people who have inherited mutated genes from both parents do not have CF. With so many possible mutations, the potential combinations in a person who inherits one gene from each parent are immeasurable.

The combinations of different mutations create different effects. Some may result in crippling and fatal CF, whereas others may cause less serious disorders, such as infertility, asthma, or chronic bronchitis. To further complicate the picture, other genes can alter the way different mutations of the CF gene affect the body.

Researchers also are finding that CF mutations may be much more common than previously thought. Five thousand healthy women receiving prenatal care at Kaiser Permanente in northern California were tested for the CF gene, thought to be present in less than 1 percent of the population. Of those screened, 11 percent had the mutation. This may show that many more common diseases, such as asthma, may be caused by mutations of the CF gene.

In 2002, results from the Phase III clinical trial of the antibiotic azithromycin supported by the Cystic Fibrosis Foundation were very encouraging. Results showed that patients with CF who took the antibiotic experienced an almost 50 percent reduction in hospitalizations, had a significant improvement in lung function, and gained weight.

Currently, more than two dozen potential CF therapies are in the drug development pipeline. Any one of these—or a combination—could have a profound affect on the lives and future of people with CF, according to the Cystic Fibrosis Foundation.

Cystic Fibrosis Carrier Screening

Since the discovery in 1989 of the gene (called CFTR) that causes CF, more than 900 mutations of the gene have been identified. Screening is available for the most frequent CF mutations.

In 2000 the National Institutes of Health (NIH), American College of Medical Genetics, and American College of Obstetricians and Gynecologists (ACOG) issued a recommendation that CF screening be recommended to every white woman who is pregnant or considering having a baby. The same year the results of a research study conducted at Northwestern University Medical School in Chicago found that many people who carry the CF gene fail to inform family members about their risk.

However, further research ushered another change by ACOG in 2001. As a result of discoveries made by the human genome project, the organization issued the recommendation that obstetrician–gynecologists make DNA screening for cystic fibrosis available to all couples seeking preconception or prenatal care—not just to those with a personal or family history of carrying the CF gene, as recommended in 2000.

SICKLE CELL DISEASE

Sickle cell disease (SCD) is a group of hereditary diseases, including sickle cell anemia and sickle Bthalassemia, in which the red blood cells contain an abnormal hemoglobin, termed hemoglobin S. Hemoglobin S is responsible for the premature destruction of red blood cells, or hemolysis. In addition, it causes the red cells to become deformed, actually taking on a sickle shape, particularly in parts of the body where the amount of oxygen is relatively low. These abnormally shaped cells cannot travel smoothly through the smaller blood vessels and capillaries. They tend to clog the vessels and prevent blood from reaching vital tissues. This blockage produces anoxia (lack of oxygen), which in turn causes more sickling and more damage.

Symptoms of Sickle Cell Anemia

People with sickle cell anemia have the symptoms of anemia, including fatigue, weakness, fainting, and palpitations or an increased awareness of their heartbeat. These palpitations result from the heart's attempts to compensate for the anemia by pumping blood faster than normal.

In addition, patients experience occasional sickle cell crises—attacks of pain in the bones and stomach. Blood clots also may develop in the lungs, kidneys, brain, and other organs. A severe crisis or several acute crises can damage the organs of the body by impeding the flow of blood. This damage can lead to death from heart failure, kidney failure, or stroke. The frequency of these crises varies from patient to patient. A sickle cell crisis, however, occurs more often during infections and after an accident or an injury.

In February 2004 the New England Journal of Medicine (vol. 350, no. 9, February 26, 2004) reported that researchers from the National Institutes of Health and the Howard University Center for Sickle Cell Disease found that one-third of patients with SCD who had been screened with a noninvasive ultrasound method were found to have previously undetected moderate to severe pulmonary hypertension. This confirms earlier suggestions that pulmonary hypertension occurs in about 20–40 percent of patients with SCD, which poses major health risks, including death. The researchers suggested that these findings were "so striking" that all patients with sickle cell should be regularly screened for hypertension and subsequently treated.

Who Contracts Sickle Cell Disease?

Both the sickle cell trait and the disease exist almost exclusively in people of African, American Indian, and Hispanic descent and in people from parts of Italy, Greece, the Middle East, and India. A sickle cell gene is inherited from one parent. Only if both the mother and the father have the trait can they produce a child with sickle cell anemia. According to the National Heart, Lung, and Blood Institute of the National Institutes of Health, SCD occurs in about 72,000 Americans, most of whom are of African descent. The disease occurs in approximately one in 500 African-American births and one in every 1,000–1,400 Hispanic-American births. Approximately two million Americans—including one in every twelve African-Americans—carry the sickle cell trait. Americans of African descent are advised to seek genetic counseling and testing for the trait before starting a family. Testing is done by taking a sample of the amniotic fluid or tissue taken from the placenta as early as the first trimester of pregnancy. A genetic counselor will discuss the results and will be able to tell the parents what the chances are that their child will have sickle cell trait or sickle cell anemia. Table 6.4 shows the average prevalence of SCD per 100,000 live births in the United States among different racial and ethnic groups.

A CALL FOR UNIVERSAL SCREENING.

In 1993 a federal panel of researchers, clinicians, and policy makers called for SCD screening of all newborns because early diagnosis and treatment significantly improves future health. Because of intermarriage, it is becoming more difficult to be certain of a person's racial or ethnic background based on physical appearance, surname, or self-reporting. Many SCD sufferers could possibly be missed by exclusively screening a target population such as African-Americans.

By 1993, thirty-four states and jurisdictions had already instituted the universal screening of infants recommended by an earlier study group of the NIH in 1988. Another ten states had targeted screening aimed at groups traditionally considered at higher risk, and eight states and jurisdictions had no sickle cell screening program. The cost of universal screening has not been studied, but many researchers and policymakers feel that the investment would pay great dividends. A machine to run sickle cell tests could cost between $5,000 and $30,000; material to conduct a single test costs $1 to $3. The American Academy of Pediatrics, the American Nurses Association, the National Medical Association (an organization of African-American physicians), and the Sickle Cell Disease Association of America endorsed the new guidelines for universal screening.

Early diagnosis (soon after birth) could save the lives of children born with SCD. Studies have found wide differences in the mortality rates of children with SCD. To improve survival rates for children with SCD living in high mortality areas, public health advocates recommend further study of the accessibility and quality of available screening and medical care and the duplication of successful treatment programs. In addition, they emphasize the importance of educating parents about the disease and its treatments ("Mortality among Children with Sickle Cell Disease Identified by Newborn Screening during 1990–1994—California, Illinois, and New York," Mortality and Morbidity Weekly Report, vol. 46, no. 9, March 13, 1998; "Geographic

Differences in Mortality of Young Children with Sickle Cell Disease in the United States," Public Health Reports, vol. 112, no. 1, January/February 1997).

Treatment of Sickle Cell Disease

There is no cure for SCD, but the symptoms can be treated. Crises accompanied by extreme pain are the most common problems and usually can be treated with pain relievers. Maintaining healthy eating and behavior habits and prompt treatment for any type of infection or injury are important. Special precautions are often necessary before any type of surgery; for major surgery some patients receive transfusions to boost their levels of hemoglobin (the oxygen-bearing, iron-containing protein in red blood cells). In early 1995 a medication that prevented the cells from clogging vessels and cutting off oxygen was approved. Blood transfusions also may be used to treat or prevent associated problems, such as anemia, spleen enlargement, and recurring stroke.

A federal panel of experts on SCD recommended in 1993 that all infants diagnosed with the disease receive daily doses of penicillin to prevent infections. The cost of preventive penicillin now being administered is estimated to be about $12 monthly for the liquid form and $10 for tablets. Parents are urged to make sure that these children receive the scheduled childhood immunizations and are vaccinated against influenza, pneumonia, and hepatitis B by age two years. In the mid-1980s, 20 percent of children with SCD died before their first birthday; by 1993, primarily because of preventive antibiotics, that proportion had dropped to less than 3 percent. Although there are neither uniform SCD reporting nor national reports of incidence or prevalence, public health professionals believe that antibiotic prophylaxis (preventive treatment) has further reduced SCD mortality.

BIOMEDICAL ADVANCES.

Many adults with SCD now take hydroxyurea, an anticancer drug that causes the body to produce red blood cells that resist sickling. In 1995 a multicenter study showed that among adults with three or more painful crises per year, hydroxyurea lowered the median number of crises requiring hospitalization by 58 percent. A 1996 international study found that bone marrow transplants were successful in curing SCD in sixteen of twenty-two patients—72.7 percent of the patients in the five-year study. All of the participants in the study were under age fourteen years, had advanced symptoms, and had siblings who were compatible bone marrow donors. Four of the patients (18 percent) rejected the donor marrow, and their SCD symptoms returned. Two of the patients (9 percent) died.

Because of the high risks of bone marrow transplants and the difficulties of matching donors, transplants are not appropriate for every patient. Further studies are needed to test the procedure with older patients and to reduce the proportion of tissue rejects. Blood harvested from umbilical cords and placentas has been found to be less likely to trigger rejection or graft-versus-host disease, in which the transplanted cells attack the cells of the bone marrow recipient, causing organ damage.

Researchers have started to succeed in developing drugs that will prevent the symptoms of sickle cell anemia and procedures that may provide a cure.

TAY-SACHS DISEASE

TSD is a fatal genetic disorder in children that causes the progressive destruction of the central nervous system. It is caused by the absence of an important enzyme called hexosaminidase A (hex-A). Without hex-A, a fatty substance builds up abnormally in the cells, particularly the brain's nerve cells. Eventually, these cells degenerate and die. This destructive process begins early in the development of a fetus, but the disease usually is not diagnosed until the baby is several months old. By the time a child with TSD is four or five years old, the nervous system is so badly damaged that the child dies.

Symptoms of Tay-Sachs Disease

A baby with Tay-Sachs disease (TSD) seems normal at birth and usually develops normally for about the first six months of life, but then development slows. The child begins to regress and loses skills one by one—the ability to crawl, to sit, to reach out, and to turn over. The victim gradually becomes blind, deaf, and unable to swallow. The muscles begin to atrophy, and paralysis sets in. Mental retardation occurs, and the child is unable to relate to the outside world. Death usually occurs between ages three and five years. There is no cure or treatment for this disease.

How Is Tay-Sachs Disease Inherited?

TSD is transmitted from parent to child the same way eye or hair color is inherited. Both the mother and the father must be carriers of the TSD gene to give birth to a child with the disease.

People who carry the gene for TSD are entirely unaffected and usually are unaware that they have the potential to pass this disease to their offspring. When only one parent is a carrier, the couple will not have a child with TSD. When both parents carry the recessive TSD gene, they have a one in four chance in every pregnancy of having a child with the disease. They also have a 50 percent chance of bearing a child who is a carrier. Prenatal diagnosis early in pregnancy can predict if the unborn child has TSD. If the fetus has the disease, the couple may choose to terminate the pregnancy.

Who Is at Risk?

Some genetic diseases, such as TSD, occur most frequently in a specific population. Individuals of Eastern European (Ashkenazi) Jewish descent have the highest risk of being carriers of TSD. According to the National Tay-Sachs and Allied Diseases Association, approximately one in every twenty-seven Jews in the United States is a carrier of the TSD gene, and 85 percent of the children who are victims of this disease are Jewish. Italians also have a higher than average risk of being carriers. In the general population, the carrier rate is one in 250.

Genetic Diseases

A genetic disease is due to a faulty gene or group of genes. While not all gene defects cause disease, many do. New genetic diseases are discovered every month; as of 2001, there are estimated to be approximately 1,100 genetic diseases.

How Gene Defects Cause Disease

A gene is a recipe for making a protein . Proteins control cell functions, and defects in the instructions for making a protein can prevent the cell from functioning properly. Genes are made of deoxyribonucleic acid (DNA), a chemical composed of units called nucleotides , and are carried on chromosomes within the cell nucleus . Most genes are present in pairs (corresponding to the two sets of chromosomes inherited from one's parents). As well as coding for proteins, genes are the hereditary material. Therefore, genetic diseases can be inherited.

Genetic defects cause diseases in a variety of ways. The simplest way is through a "loss-of-function" mutation. In this type of defect, a change in the DNA nucleotides prevents the gene from making protein, or prevents the protein from functioning once it is made. Genetic diseases due to loss-of-function mutations are very common, and include cystic fibrosis (which affects the lungs and pancreas), Duchenne muscular dystrophy, and the hemophilias, a group of blood-clotting disorders.

A second mechanism for causing disease is called a "toxic-gain-of-function" mutation. In this type of defect, the gene takes on a new function that is harmful to the organism—the protein produced may interfere with cell functions, or may no longer be controllable by its normal regulatory partners, for instance. Many degenerative diseases of the brain are due to this type of mutation, including Huntington disease.

More complex mechanisms are possible. Most traits are multifactorial, meaning they are determined by many different genes. In the human population, there are several variants (alleles) of most genes, each form of which is functional and does not cause disease by itself. However, some alleles may predispose a person to a certain disease, especially in combination with other alleles or environmental factors that influence the same trait. Such susceptibility alleles have been found in breast cancer and colon cancer, for instance. Carriers of these alleles have an increased likelihood of developing that disease, a risk that can be increased or decreased by such factors as diet, exposure to environmental toxins, or presence of particular alleles for other genes. As more is learned about the human genome , a large number of susceptibility genes are likely to be discovered for a wide variety of conditions.

Disease can also be caused by chromosome abnormalities rather than gene defects. Down syndrome is due to having three copies of chromosome 21, instead of the normal two copies. It is likely the extra protein from the extra gene copies lead directly to the disease symptoms, but this is not yet clear.

Inheritance Patterns in Genetic Disease

Genetic diseases are heritable, meaning they may be passed from parent to child. A disease gene is called recessive if both copies of the gene must be defective to cause the disease. Loss-of-function mutations are often recessive. If the second copy of the gene is healthy, it may be able to serve adequately even if the first copy suffers a loss-of-function mutation. In this case, the carrier of the disease gene will not have the disease.

All humans are thought to carry a number of such defective genes. Close relatives are likely to carry similar genes and gene defects, and are therefore more likely to bear children with recessive genetic diseases if they mate. Because of this, a prohibition against marriage of close relatives is found in virtually every culture in the world.

A disease gene is called dominant if inheriting one copy of it causes the disease. Toxic gain-of-function mutations often create dominant genes, as in the case of Huntington disease.

If having one defective gene causes a different condition than having two, the gene is called incompletely dominant. In familial hypercholesterolemia, having two disease genes leads to very high blood cholesterol levels and death in childhood or early adulthood. Having one disease gene and one normal gene leads to less-elevated cholesterol and a longer but still reduced life span.

Most genes are carried on autosomes, the twenty-two pairs of chromosomes that do not determine sex. Males and females are equally likely to inherit disease genes on autosomes and develop the related diseases, called autosomal disorders. Unlike autosomes, the pair of chromosomes that determine sex (called X and Y) have almost no genes in common. While the Y carries very few genes, the very large X chromosome contains many genes for proteins unrelated to sex determination. Males have one X and one Y, and are more likely than females to develop diseases due to recessive X-linked genes, since they do not have a backup copy of the normal gene. Such disorders are termed X-linked disorders. Females have two X chromosomes, and so usually do not develop recessive X-linked disorders. Duchenne muscular dystrophy, for instance, is an X-linked condition due to a defective muscle protein. It affects boys almost exclusively. Females are carriers for the condition, meaning they have the gene but seldom develop the disease.

The cell energy organelles called mitochondria also contain a small number of genes. Mitochondria are inherited only from the mother, and so mitochondrial gene defects show maternal inheritance. Leber's hereditary optic neuropathy is a maternally inherited mitochondrial disorder causing partial blindness.

In some diseases, not every person who inherits the gene will develop the disease. Such genes are said to show incomplete penetrance. For instance, fragile X syndrome does not affect about one-fifth of boys who inherit it. This syndrome is due to a large increase in the number of CCG nucleotides at the tip of the X chromosome and leads to characteristic facial features, mental retardation, and behavioral problems.

Unique Features of Genetic Diseases

If a parent is known to carry a disease gene, it is possible to predict the likelihood that an offspring will contract the disease, based on simple laws of probability. In Duchenne muscular dystrophy, for instance, if the mother carries the defective gene, there is a 50 percent chance that each male child will develop the disease, since she will give the child one of her two X chromosomes. It is also possible with many disorders to test the fetus to determine if the gene was in fact inherited. Such information can be used for purposes of family planning.

Different populations may have different frequencies of disease alleles because of long periods of relative genetic isolation. For instance, Jews of European ancestry are much more likely to carry the gene for Tay-Sachs disease, a fatal autosomal recessive disorder of lipid metabolism . Healthy adults in such populations may choose to be tested to see if they carry one Tay-Sachs allele. A person with one disease allele might use this information to avoid choosing a mate who also has one disease allele.

Treatment of genetic diseases is possible in some but not all cases. Missing proteins can be supplied relatively easily to the blood, as for hemophilia, but not to most other organs. The effects of phenylketonuria, which is due to a defect in an enzyme that breaks down phenylalanine, can be partially avoided by reducing the amount of the amino acid phenylalanine in the diet. (This is the reason some diet soft drinks carry a notice that phenylalanine is used in the artificial sweetener.) Most genetic diseases can't be treated, though, except by supplying the missing gene to the tissues in which it acts. This treatment, called gene therapy, is still experimental, but may become an important type of therapy for genetic diseases in the coming decades.

see also Gene Therapy; Genetic Analysis; Genetic Counselor; Mutation; Patterns of Inheritance; Pedigrees and Modes of Inheritance; Sex Chromosomes

Richard Robinson

Bibliography

Bellenir, Karen. Genetic Disorders Sourcebook. Detroit, MI: Omnigraphics, 1996.

Genes and Disease—Information and Chromosome Maps from National Institutes of Health. <http://www.ncbi.nlm.nih.gov/disease/>.

Lewis, Ricki. Human Genetics: Concepts and Applications, 4th ed. New York: McGraw-Hill, 2001.

Genetic Diseases

What Is Heredity?

What Causes Genetic Diseases?

How Are Diseases Inherited?

What Are the Common Inheritance Patterns of Genetic Diseases?

The Past and Future of Genetic Diseases

Resources

Genetic diseases are disorders that are inherited by a person from his or her parents or are refaed to some type of spontaneous genetic change.

KEYWORDS

for searching the Internet and other reference sources

Birth defects

Gene therapy

Genetic counseling

Genetics

Hereditary diseases

Human genome

Prenatal diagnosis

What Is Heredity?

Every person develops under the influence of a mix of genes inherited from his or her mother and father. These genes, or small parts of chromosomes, determine the architecture and activity of the entire body. They determine visible characteristics, such as eye color, skin color, and height, as well as traits that cannot be seen, such as the likelihood of certain diseases, the chemicals made by the body, and the functioning of body systems.

Normally, each cell in the body contains two copies of each gene: one that originally came from the egg of the mother and one from the sperm of the father. In many instances, these two copies are slightly different from each other. The result is a child who has some characteristics from the mother and some from the father, but who is never identical to either parent.

Because there are two copies, a gene that works normally usually can make up for one that has a defect. For example, a gene with a defect that causes a particular disease may be passed through generations of a family without causing illness. That is because the normal gene in the pair may work well enough to mask the defect. However, if a child inherits two genes with the defect, the child will develop the illness. This explains how a child with the disease can be born to parents without it.

What Causes Genetic Diseases?

Genetic disorders can be inherited, in which case people are born with them, even if they are not noticeable at first. Some disorders, however, are not inherited but develop spontaneously when disease-causing mutations* occur during cell division*. These also are genetic disorders, because they involve changes in the genes.

* mutations

(mu-TAY-shuns) are changes in a chromosome or a gene.

* cell division

is the process by which a cell divides to form two daughter cells, each of which contains the same genetic material as the original cell.

Some inherited genetic disorders, such as cystic fibrosis* and phenylketonuria* (PKU), are caused simply by the inheritance of genes that do not work properly. In other disorders, however, genetic and environmental factors seem to work together to cause changes in otherwise normal genes. For example, some forms of radiation or chemicals can cause cancer in people who are prone to be affected because of their genetic makeup.

* cystic fibrosis

(SIS-tik fi-BRO-sis) is a genetic disorder of the body’s mucus-producing glands. It mainly affects the respiratory and digestive systems of children and young adults.

* phenylketonuria

(fen-ul-ke-ton-U-ree-a), or PKU for short, is a genetic disorder of body chemistry that if left untreated, causes mental retardation.

How Are Diseases Inherited?

Wie beginning of modern genetics Gregor Mendel (1822-1884) is considered the father of modern genetics*. Mendel was an Austrian monk. While growing peas in the monastery garden, Mendel noted that certain traits appeared in offspring in predictable patterns, and he began to understand the basic rules of inheritance. These rules are called Mendelian (men-DEL-ee-an) law.

* genetics

is the branch of science that deals with heredity and the ways in which genes control the development and maintenance of organisms.

Under Mendelian law, a dominant (DOM-i-nant) trait is one that appears even when the second copy of the gene for that trait is different. For example, for the seeds of Mendel’s peas, “smooth” is dominant over “wrinkled.” Thus, if a pea plant contains one gene for smooth and one for wrinkled, the seed will be smooth. Wrinkled is a recessive (re-SES-iv) trait, which is one that only appears when two copies of it are present.

A Genetic Glossary

• Cells: The units that comprise living beings. The human body is made of about 60 trillion cells.
• Nucleus: A membrane-bound structure inside cells that contains DNA.
• Chromosomes: DNA is packaged into units called chromosomes. Humans have 23 pairs of chromosomes, for a total of 46.
• DNA (deoxyribonucleic acid): A double-stranded molecule, made of chemical bases called nucleotides, that contains the genetic code necessary to build a living being.
• Genes: Segments of DNA located on the chromosomes. Genes are the units of heredity. They help determine a person’s characteristics, from eye color to how various chemicals work in the body.
• Genome: An animal’s entire collection of genes. The human genome contains 50,000 to 100,000 genes.

Dominant and recessive genes

Normally, each person has two copies of every gene, one from the mother and one from the father. A physical feature or a disorder carried by genes can be either a dominant (G) or a recessive (g) trait. If the affected gene is dominant, a person with one or two copies of the gene will have the disorder. Therefore, a person with the patterns (GG) or (Gg) will be affected, but (gg) will not be affected by the disorder. Two copies of a dominant gene produce a much more serious form of the disorder.

If the affected gene is recessive, only a person with two copies of the gene will have the disorder. Therefore, a person with the pattern (gg) will be affected, but (GG) and (Gg) will not be affected by the disorder.

Autosomal and sex-linked traits

Of the 23 pairs of chromosomes in human cells, 22 are autosomes (AW-to-somes), or non-sex chromosomes. The other pair contains the two sex chromosomes, which determine a person’s gender. Females have two X chromosomes (XX), and males have one X and one Y chromosome (XY). The reproductive cells, or eggs and sperm, each have only one set of 23 chromosomes. While an egg always carries an X chromosome, a sperm cell can carry either an X or a Y, so it is the sperm that determines gender.

Inherited genetic disorders that are carried on the sex chromosomes are referred to as sex-linked. Disorders carried on the other chromosomes are referred to as autosomal (aw-to-SOME-al). In general, autosomal disorders are likely to affect males and females equally, but sex-linked disorders usually affect males more often than females. This gender difference has to do with the fact that males have only one X chromosome. The X chromosome

carries genes for which there is no second copy on the Y. Therefore, a male has only one copy of these genes. If his copy is damaged or defective, he has no normal copy to override or mask the defective one. Depending on the problem with the gene, the result can be an X-linked disorder.

What Are the Common Inheritance Patterns of Genetic Diseases?

Single-gene autosomal diseases

Most genetic disorders are caused by defective genes on the autosomes. If an autosomal genetic disorder is caused by a problem with a single gene, then the following rules of inheritance usually apply. There are exceptions to these rules, but they are useful guidelines for understanding inheritance. In an autosomal dominant disorder:

• It takes only one copy of the gene to cause the disorder. So if a child inherits the disease, at least one of the parents has the disease as well.
• It is possible for the gene to change by itself in the affected person. This change is called a mutation.
• Unaffected children of a parent with the disorder have unaffected children and grandchildren.

In an autosomal recessive disorder:

• If two people without the disorder have a child with the disorder, both parents carry one copy of the abnormal gene.
• If a person with the disorder and a carrier* have a child, there is a
• fifty-fifty chance that the child will have the disorder. Any child
• without the disorder will be a carrier.
• If a person with the disorder and a noncarrier have children, all of
• the children will be carriers but will not have the disorder.
• If two people with the disorder have children, all of the children will
• have the disorder.

* carrier

is a person who has one copy of the defective gene for a recessive disorder. Carriers are not affected by the disorder, but they can pass on the defective gene to their children.

Single-gene sex-linked diseases

More than 150 disease traits are carried on the X chromosome. X-linked dominant disorders are rare. In an X-linked recessive disorder:

• Nearly all people with sex-linked disorders are male. The disorder is transmitted through the female, because a son’s X chromosome always comes from his mother. She is unaffected, however, because she has a second X chromosome which usually contains a normal gene for the trait.
• A male with the disorder never transmits it to his sons, because a father passes his X chromosome only to his daughters.
• A son born to a female carrier has a fifty-fifty chance of having the disorder.
• All daughters of an affected male will be carriers.

Multiple-gene diseases

Many disorders are exceptions to the Men-delian laws of inheritance. Genetic disorders caused by a combination of many genes are called multifactorial (mul-tee-fak-TOR-e-al) disorders. In addition, some disorders show reduced penetrance (PEN-e-trance), which means that a gene is not wholly dominant or recessive. For example, a person who has one recessive gene for a disorder might show milder symptoms of the disorder, but someone with two copies will have the full-blown disorder.

Chromosome disorders

Other genetic disorders are caused by extra or missing chromosomes. In Down syndrome*, a person has three copies of chromosome 21, rather than the usual two copies. In a disease called cri du chat*, a piece of chromosome 5 is missing. In Turner syndrome*, which affects only girls, all or part of an X chromosome is missing. In most cases, chromosome disorders are not inherited. Instead, the problems occur for unknown reasons when the egg and sperm meet to form the embryo.

* Down syndrome

is a genetic disorder that can cause mental retardation, shortness, and distinctive facial characteristics, as well as many other features.

* cri du chat

(kree-doo-SHA), French for “cat’s cry,” is a genetic disorder that can cause mental retardation, a small head, and a cat-like whine.

* Turner syndrome

is a genetic disorder that can cause several physical abnormalities, including shortness, and lack of sexual development.

Spontaneous (new) genetic mutations

Particularly in the case of dominantly-inherited disorders, a child may be born with a condition despite the fact that neither parent has the disorder as would be expected. When this happens, it is usually because a spontaneous (or new) mutation in a gene or genes has occurred. The mutation may occur in a parent s egg or sperm cell, or it may occur after the egg has been fertilized and begins to develop into an embryo. This is frequently the case in achondroplasia (a-kon-dro-PLAY-zha), a form of dwarfism in which 90 percent of children born with the condition have unaffected parents. When this child grows up, the child will pass the gene on to his or her children according to the autosomal dominant inheritance pattern described above.

The Past and Future of Genetic Diseases

Mendel figured out the basic concepts of inheritance in the 1800s, before people knew that genes are the units of inheritance. It was not until 1953 that the structure of DNA was described. From the 1980s to the present, scientists’ understanding of genes and how they work has grown at an incredibly rapid pace. Many disease-causing genes now have been identified, opening the door to research on ways to fix genetic defects. This field of science is referred to as gene therapy.

Gene therapy

Genetic disorders can be treated in a number of ways. In some disorders, special diets are used to prevent the buildup in the body of compounds that are toxic to patients. In other disorders, the treatment involves blocking or rerouting chemical pathways. A third kind of treatment is new and controversial. It involves actually replacing defective genetic material with normal genetic material inside the cells. Researchers currently are looking for ways to do this. A variety of methods are being considered, including the use of microscopic “bullets” coated with genetic material and viruses to deliver normal genes to cells.

Prenatal testing

A fetus* can be tested for many genetic disorders before it is born. Tests for prenatal (before birth) diagnosis are done on samples taken from the tissue or fluid surrounding a fetus. The fetus’s chromosomes then can be studied using a karyotype (KAR-e-o-type), which is a visual display of the chromosomes from cells viewed under a microscope. Newer techniques enable scientists and doctors to look directly at the DNA that makes up the genes contained in the chromosomes. Common prenatal tests include:

* fetus

(FEE-tus) in humans is the developing offspring from nine weeks after conception until birth.

• Amniocentesis (am-nee-o-sen-TEE-sis): In amniocentesis, a needle is passed through the mother’s belly into her uterus* to collect some of the fluid in which the fetus lives. This fluid, called amniotic fluid, contains cells from the fetus.
• Chorionic villus (kor-e-ON-ik VIL-us) sampling (CVS): CVS also involves collecting cells from the fetus with a needle. In this case, the cells are taken from the chorionic villi, which are structures in the uterus that are part of the placenta.
• Percutaneous umbilical (per-ku-TAY-ne-us um-BIL-i-kal) blood sampling (PUBS): In PUBS, fetal blood is taken from the umbilical cord*.

* uterus

(U-ter-us), also called the womb, is the organ in a woman’s body in which a fertilized egg develops into a fetus.

* umbilical cord

(um-BIL-i-kal cord) is the flexible cord that connects a fetus at the navel with the placenta, the organ that allows for the exchange of oxygen, nutrients, and other substances between mother and fetus.

Genetic testing and counseling

Geneticists believe that each person probably carries about 5 to 10 defective recessive genes. Thus,

both potential parents may be worried about having a child with birth defects. If relatives have genetic disorders—or if ethnic or other background factors increase the risk of certain genetic diseases—parents-to-be may worry even more.

Punnett Squares

Punnett squares often are used to visualize the chances of inheriting a particular gene. Using G for a healthy gene and g for an affected recessive gene, the Punnett Square shows which offspring are likely to inherit two healthy genes, which offspring are likely to be carriers of the gene, and which are likely to have the disorder caused by the defective gene.

Many medical centers now offer genetic testing and genetic counseling. Parents and relatives can be tested to determine whether they carry genes for a variety of disorders. Using this information, a genetic counselor can help couples calculate genetic risks realistically, and inform them about the options they may have to increase the likelihood of having a healthy child.

Ethical concerns

Increasingly, people will have the option to be tested to find out if they carry genes for genetic disorders. For example, women now can find out if their unborn children have certain genetic defects or if they themselves have genes that make them more likely to develop breast cancer. Already there is controversy about how this information should be used. Genetic testing can have far-reaching social, financial, and ethical effects. For example, a woman who thinks she will develop breast cancer might opt not to have children, or she might decide to have her breast tissue removed before cancer cells develop, or her insurance company might decide not to insure her because she is a high-risk client. With knowledge comes responsibility, and genetic testing surely will be at the forefront of debates about medical ethics in the twenty-first century.

See also

Albinism

Birth Defects

Breast Cancer

Color Blindness

Colorectal Cancer

Cystic Fibrosis

Down Syndrome

Dwarfism

Growth Disorders

Hemophilia

Huntington’s Disease

Muscular Dystrophy

Neurofibromatosis

Sickle-Cell Anemia

Tay-Sachs Disease

Turner Syndrome

Resources

Books

Baker, Catherine. Your Genes, Your Choices. Washington, DC: American Association for the Advancement of Science, 1997. A clear introduction to the ethical, legal, and social issues raised by genetic research. The full text of this book can be found on the association’s website. http://www.aaas.org

Jackson, John F Genetics and You. Totowa, NJ: Humana Press, 1996. This book explains the basic principles of genetics, genetic counseling, and prenatal testing.

Organizations

Alliance of Genetic Support Groups, 4301 Connecticut Avenue Northwest, Number 404, Washington, DC 20008-2304. This national organization is an alliance of support groups for people who have or who are at risk for genetic disorders. Telephone 800-336-GENE http://www.geneticalliance.org

March of Dimes Birth Defects Foundation, 1275 Mamaroneck Avenue, White Plains, NY 10605. This large, national organization provides information about genetic birth defects. Telephone 888-MODIMES http://www.modimes.org

U.S. National Human Genome Research Institute, 31 Center Drive, Building 31, Room 4B09, MSC 2152, Bethesda, MD 20892. This government institute is home to the Human Genome Project, an international research effort aimed at mapping the human genome. http://www.nhgri.nih.gov

U.S. National Center for Biotechnology Information, National Library of Medicine, Building 38A, Room 8N805, Bethesda, MD 20894. This division of the U.S. National Library of Medicine provides detailed information about genes and genetic diseases. http://www.ncbi.nlm.nih.gov

World Health Organization (WHO), Avenue Appia 20, 1211 Geneva 27, Switzerland. The World Health Organization posts an extensive list of publications from its Human Genetics Programme at its website. http://www.who.int/ncd/hgn/hgn_pub.htm

genetic diseases Also known as inborn errors of metabolism. Diseases due to a single defective gene, with a characteristic pattern of inheritance in families. Many affect the ability to metabolize individual amino acids or carbohydrates and can be treated by dietary restriction. See also amino acid disorders; disaccharide intolerance.