CHAPTER 5
GENETIC DISORDERS

We could wish that … life-histories were found in every family, showing the health and diseases of its different members. We might thus in time find evidences of pathological connections and morbid liabilities not now suspected.

—William Gull, 1896

It has long been known that heredity affects health. Genetics, the study of single genes and their effects on the body and mind, explains how and why certain traits such as hair color and blood types run in families. Genomics, a discipline that is only about two decades old, is the study of more than single genes; it considers the functions and interactions of all the genes in the genome. In terms of health and disease, genomics has a broader and more promising range than genetics. The science of genomics relies on knowledge of and access to the entire genome and applies to common conditions, such as breast and colorectal cancer, Parkinson's disease, and Alzheimer's disease. It also has a role in infectious diseases once believed to be entirely environmentally caused such as human immunodeficiency virus (HIV, which is the virus that causes acquired immune deficiency syndrome [AIDS]) infection and tuberculosis. Like most diseases, these frequently occurring disorders are due to the interactions of multiple genes and environmental factors. Genetic variations in these disorders may have a protective or a causative role in the expression of diseases.

It is commonly accepted that diseases fall into one of three broad categories: those few that are primarily genetic in origin; those that are largely attributable to environmental causes; and those—the majority of conditions—in which genetics and environmental factors make comparable, though not necessarily equal, contributions. As understanding in genomics advances and scientists identify genes involved in more diseases, the distinctions between these three classes of disorders is diminishing. This chapter considers some of the disorders believed to be predominantly genetic in origin and some that are the result of genes acted on by environmental factors.

There are two types of genes: dominant and recessive. When a dominant gene is passed on to offspring, the feature or trait it determines will appear regardless of the characteristics of the corresponding gene on the chromosome inherited from the other parent. If the gene is recessive, the feature it determines will not show up in the offspring unless both the parents' chromosomes contain the recessive gene for that characteristic. Similarly, among diseases and conditions primarily attributable to a gene or genes, there are autosomal dominant disorders and autosomal recessive disorders.

Another way to characterize genetic disorders is by their pattern of inheritance, as single gene, multifactorial, chromosomal, or mitochondrial. Single-gene disorders (also called Mendelian or monogenic) are caused by mutations in the deoxyribonucleic acid (DNA) sequence of one gene. Since genes code for proteins, when a gene is mutated so that its protein product can no longer carry out its normal function, it may produce a disorder. There are more than 6,000 known single-gene disorders, which occur in about one in every 200 births. Examples are cystic fibrosis, sickle-cell anemia, Huntington's disease, and hereditary hemochromatosis (a disorder in which the body absorbs too much iron from food; rather than the excess iron being excreted, it is stored throughout the body, and iron deposits damage the pancreas, liver, skin, and other tissues). Figure 5.1 shows the cystic fibrosis gene and its location on chromosome 7; Figure 5.2 shows the sickle-cell anemia gene found on chromosome 11; and Figure 5.3 shows the hereditary hemochromatosis gene located on chromosome 6. Single-gene disorders are the result of either autosomal dominant, autosomal recessive, or X-linked inheritance.

Multifactorial or polygenic disorders result from a complex combination of environmental factors and mutations in multiple genes. For example, different genes that influence breast cancer susceptibility have been found on seven different chromosomes, rendering it more difficult to analyze than single-gene or chromosomal disorders. Some of the most common chronic diseases are multifactorial in origin. Examples include heart disease, Alzheimer's disease, arthritis, diabetes, and cancer.

Chromosomal disorders are produced by abnormalities in chromosome structure, missing or extra copies of chromosomes, or errors such as translocations (movement of a chromosome section from one chromosome to another). Down's syndrome or trisomy 21 is a chromosomal disorder that results when an individual has an extra copy, or a total of three copies, of chromosome 21. Mitochondrial disorders result from mutations in the nonchromosomal DNA of mitochondria, which are organelles involved in cellular respiration. Compared with the three other patterns of inheritance, mitochondrial disorders occur infrequently.

There are significant differences between the nineteenth-century germ theory of disease and the twenty-first-century genomic theory of disease. By the middle of the twentieth century it became possible to improve the quality of life and to save the lives of people with some genetic diseases. Effective treatment included changes in diet to prevent or manage conditions such as phenylketonuria (PKU) and glucose galactose malabsorption (GGM). PKU is an inherited error of metabolism caused by a deficiency in the enzyme phenylalanine hydroxylase. (See Figure 5.4.) It may result in mental retardation, organ damage, and unusual posture. Dietary changes are also used to treat GGM, a rare metabolic disorder caused by lack of the enzyme that converts galactose into glucose. For people with severe cases of GGM, it is vital to avoid lactose (milk sugar), sucrose (table sugar), glucose, and galactose. Other therapeutic measures may involve surgery to correct deformities and avoidance of environmental triggers, as in some types of asthma.

At the dawn of the twenty-first century, the possibility of preventing and changing genetic legacies appears within reach of modern medical science. Genomic medicine predicts the risk of disease in the individual, whether highly probable, as in the case of some of the well-established single-gene disorders, or in terms of an increased susceptibility likely to be influenced by environmental factors. The promise of genomic medicine is to make preventive medicine more powerful and treatment more specific to the individual, enabling investigation and treatment that are custom-tailored to an individual's genetic susceptibilities, or to the characteristics of the specific disease or disorder.

COMMON GENETICALLY INHERITED
DISEASES

Although many diseases, disorders, and conditions are termed "genetic," classifying a disease as genetic simply means that there is an identified genetic component to either its origin or its expression. Many medical geneticists contend that the majority of diseases cannot be classified as strictly genetic or environmental. The phenotype of genetic diseases can sometimes be modified, even to the point of nonexpression, by controlling environmental factors. Similarly, environmental (infectious) diseases may not be expressed because of some genetic predisposition to immunity. Each disease, in each individual, exists along a continuum between a genetic disease and an environmental disease.

Myriad diseases are believed to have strong genetic contributions, including:

• Heart disease—coronary atherosclerosis, hypertension (high blood pressure), and hyperlipidemia (elevated blood levels of cholesterol and other lipids)
• Diabetes
• Cancer—retinoblastomas, colon, stomach, ovarian, uterine, lung, bladder, breast, skin (melanoma), pancreatic, and prostate
• Neurological disorders—Alzheimer's disease, amyotrophic lateral sclerosis (also known as Lou Gehrig's disease), Gaucher's disease, Huntington's disease, multiple sclerosis, narcolepsy, neurofibromatosis, Parkinson's disease, Tay-Sachs disease, and Tourette's syndrome
• Mental illnesses, mental retardation, and behavioral conditions—alcoholism, anxiety disorders, attention deficit hyperactivity disorder, eating disorders, Lesch-Nyhan syndrome, manic depression, and schizophrenia
• Other genetic disorders—cleft lip and cleft palate, clubfoot, cystic fibrosis, Duchenne muscular dystrophy, glucose galactose malabsorption, hemophilia, Hurler's syndrome, Marfan's syndrome, phenylketonuria, sickle-cell disease, and thalassemia
• Other medical conditions—including alpha-1-antitrypsin, arthritis, asthma, baldness, congenital adrenal hyperplasia, migraine headaches, obesity, periodontal disease, porphyria, and some speech disorders

ALZHEIMER'S DISEASE

Alzheimer's disease (AD) is a progressive, degenerative disease that affects the brain and results in severely impaired memory, thinking, and behavior. It is the fourth leading cause of death in adults, and the incidence of the disease rises with age. AD affects an estimated four million American adults and is the most common form of dementia, or loss of intellectual function. The U.S. Department of Health and Human Services (DHHS) estimates that 4.5 million Americans suffered from AD in 2004, and in 2002 it was the eighth-leading cause of death in the United States. AD also contributes to many more deaths that are attributed to other causes, such as heart and respiratory failure. (See Table 5.1.)

The disease was first described by the German physician Alois Alzheimer (1864–1915) in 1907 after he had cared for a patient with an unusual mental illness. Alzheimer observed anatomical changes in his patient's brain and described them as abnormal clumps and tangled bundles of fibers. Nearly a century later, these abnormal findings, now described as amyloid plaques and neurofibrillary tangles, along with abnormal clusters of proteins in the brain, are the characteristic markers of AD.

The disease knows no social or economic boundaries and affects men and women almost equally. While 90% of AD victims are over age sixty-five, AD can strike as early as the thirties, forties, and fifties. Most patients are cared for at home as long as possible, a situation that can be emotionally and physically devastating for the affected individuals and their families.

AD has become a disease of particular concern in the United States because the nation's older adult population is growing rapidly. Approximately 10% of the population over age sixty-five is afflicted with AD. This percentage rises to more than 47% in those over age eighty-five, the fastest-growing segment of our society. By 2050 the United States will have approximately 86.7 million people over age sixty-five, according to projections released by the U.S. Census Bureau in March 2004 (http://www.census.gov/ipc/www/usinterimproj/). According to the Census Bureau, the numbers of cases of AD are expected to increase by more than 12% every five years through 2015. Prevalence (the number of people with a disease at a given time) is partially determined by the length of time people with AD survive. While average survival is eight years after diagnosis, some AD patients have lived longer than twenty years with the disease. Therefore, improvements in AD care, as well as increased length of life of the older adult population in general, will increase the numbers of AD patients.

In November 1994 former president Ronald Reagan, at age eighty-three, announced that he had been diagnosed with AD and wanted to make Americans more aware of the disease. Some observers believe that it is theoretically possible that AD had affected Reagan before he left the White House in January 1989. In 2004 former president Reagan died as a result of the disease. In August 2002 another American legend, actor and activist Charlton Heston, announced that he, too, had been diagnosed with AD.

Genetic Causes of AD

AD is not a normal consequence of growing older, and scientists are continuing to seek its cause. Researchers have found some promising genetic clues to the disease. Table 5.2 shows the different patterns of inheritance, ages of onset (when symptoms begin), genes, chromosomes, and proteins linked to the development of AD. Mutations in four genes, situated on chromosomes 1, 14, 19, and 21, are thought to be involved in the disease, and the best described are PS1 (or AD3) on chromosome 14 and PS2 (or AD4) on chromosome 1. (See Figure 5.5 and Figure 5.6.)

The formation of lesions made of fragmented brain cells surrounded by amyloid-family proteins is characteristic of the disease. Interestingly, these lesions and their associated proteins are closely related to similar structures found in Down's syndrome. Tangles of filaments largely made up of a protein associated with the cytoskeleton have also been observed in samples taken from AD brain tissue.

The first genetic breakthrough was reported in the February 1991 issue of the British journal Nature. Investigators reported that they had discovered that a mutation in a single gene could cause this progressive neurological illness. Scientists found the defect in the gene that directs cells to produce a substance called amyloid protein. Researchers at the Massachusetts Institute of Technology found that low levels of the brain chemical acetylcholine contribute to the formation of hard deposits of amyloid protein that accumulate in the brain tissue of AD patients. In normal people the protein fragments are broken down and excreted by the body. Amyloid protein is found in cells throughout the body. Researchers do not know how it becomes a deadly substance in the brain cells of some people and not others.

In 1995 three more genes linked to AD were identified. One gene appears to be related to the most devastating form of AD, which can strike people in their thirties. When defective, the gene may prevent brain cells from correctly processing a substance called beta amyloid precursor protein. The second gene is linked to another early-onset form of AD that strikes before age sixty-five. This gene also appears to be involved in producing beta amyloid. Researchers believe that the discovery of these two genes will allow them to narrow their search for the proteins responsible for early-onset AD and give them clues to the causes of AD in older people. (See Table 5.2.)

The third gene, known as apolipoprotein E (apoE), was actually reported as associated with AD in 1993, but its role in the body was not known at that time. Researchers have since found that the gene plays several roles. Within the body, it regulates lipid metabolism within the organs and helps to redistribute cholesterol. In the brain apoE participates in repairing nerve tissue that has been injured. There are three forms (alleles) of the gene: apoE-2, apoE-3, and apoE-4. Until recently, people with two copies of apoE-4, one from each parent, were thought to have a greatly increased risk of developing AD before age seventy. Between one-half and one-third of all AD patients have at least one apoE-4 gene, while only 15% of the general population have an apoE-4 gene. In 1998, however, researchers discovered that the apoE-4 gene seems to affect when a person may develop AD, not whether the person will develop the disease.

Another newly discovered gene, A2M-2, appears to affect whether a person will develop AD. Nearly one-third (30%) of Americans may carry A2M-2, a genetic variant that more than triples their risk of developing late-onset AD compared to siblings with the normal version of the A2M gene. The discovery of A2M-2 opens up the possibility of developing a drug that mimics the A2M gene's normal function. This has the potential to

protect susceptible persons against brain damage or perhaps even reverse it.

Symptoms of AD

AD begins slowly. The symptoms include difficulty with memory and a loss of cognitive function (intellectual abilities). The AD patient may also experience confusion; language problems, such as trouble finding words; impaired judgment; disorientation in place and time; and changes in mood, behavior, and personality. How quickly these changes occur varies from person to person, but eventually the disease leaves its victims unable to care for themselves. In their terminal stages AD victims require care twenty-four hours a day. They no longer recognize family members or themselves, and they need help with such daily activities as eating, dressing, bathing, and using the toilet. Eventually, they may become incontinent, blind, and unable to communicate. Finally, their bodies may "forget" how to breathe or make the heart beat. Many patients die from pneumonia.

Testing for AD

A complete physical, psychiatric, and neurological evaluation can usually produce a diagnosis of AD that is about 90% accurate. For many years, the only sure way to diagnose the disease was to examine brain tissue under a microscope, which was not possible while the AD victim was still alive. An autopsy of someone who has died of AD reveals a characteristic pattern that is the hallmark of the disease—tangles of fibers (neurofibrillary tangles) and clusters of degenerated nerve endings (neuritic plaques) in areas of the brain that are crucial for memory and intellect. Also, the cortex of the brain is shrunken.

In 1996 a San Francisco biotechnology firm developed a diagnostic test for AD. The test, which involves analysis of blood and spinal fluid, produced conclusive results in 60% of older patients with dementia attributed to AD.

In 2000 researchers at Brigham and Women's Hospital in Boston found that by using magnetic resonance imaging (MRI) they could measure the volume of brain tissue in areas of the brain used for memory, organizational ability, and planning, and using these measurements could accurately identify people with AD and predict who would develop AD in the future. The same year other scientists at New York University Medical Center, the Mayo Clinic, and the National Hospital for Neurology and Neurosurgery in London reported using MRI to identify parts of the brain affected by AD before symptoms appear and to measure brain atrophy to monitor the progression of AD.

In early 2005 researchers Chad Mirkin and William Klein at Northwestern University announced development of yet another diagnostic test that detects small amounts of protein in spinal fluid. The test is called a bio-barcode assay and is as much as a million times more sensitive than other tests. First used to identify a marker for prostate cancer, the test is used to detect a protein in the brain called amyloid-beta-derived diffusible ligand (ADDL). ADDLs are small soluble proteins that may be indicative of Alzheimer's disease. To detect them the researchers used nanoscale particles that had antibodies specific to ADDL. The researchers' findings were reported in the February 9, 2005, issue of the Proceedings of the National Academy of Science.

Investigators continue to look at other biological markers, such as blood tests, for AD and at neuropsychological tests, which measure memory, orientation, judgment, and problem solving, to see if they can accurately predict whether healthy, unaffected older adults will develop AD or whether those with mild cognitive impairment will go on to develop AD.

Physicians and neuroscientists have long been eager for a simple and accurate test that can distinguish people with AD from those with cognitive problems or dementias arising from other causes. An accurate test would allow the detection of AD early enough for the use of experimental medications to slow the progression of the disease, as well as identify those at risk of developing AD. But the availability of tests raises ethical and practical questions: Do patients really want to know their risks of developing AD? Will health insurers use genetic or other diagnostic test results to deny insurance coverage?

Treatments for AD

There is still no cure or prevention for AD, and treatment focuses on managing symptoms. Medication can lessen some of the symptoms, such as agitation, anxiety, unpredictable behavior, and depression. Physical exercise and good nutrition are important, as is a calm and highly structured environment. The object is to help the AD patient maintain as much comfort, normalcy, and dignity for as long as possible.

Until 1997 tacrine (marketed as Cognex®) was the nation's only Alzheimer's medication. But in early 1997 the Food and Drug Administration approved a new drug, donepezil, to be marketed under the trade name Aricept. Both drugs are cholinesterase inhibitors, which produce some delay in the deterioration of memory and other cognitive skills. They offer only mild benefits at best, but currently they are the only alternatives available to AD patients.

By 2002 the National Institute on Aging (NIA) reported that National Institutes of Health (NIH) affiliates and pharmaceutical companies were involved in clinical trials of fifty to sixty new drugs to treat AD. All of the drugs being tested are intended to improve the symptoms of AD and slow its progression, but none is expected to "cure" AD. The investigational drugs aim to address three aspects of AD: to improve cognitive function in persons with early AD, slow or postpone the progression of the disease, and control behavioral problems such as wandering, aggression, and agitation of patients with AD.

By 2005 five prescription drugs were available to treat people who suffer from AD. Four of these—Reminyl® (galantamine), Exelon® (rivastigmine), Aricept® (donepezil), and Cognex® (tacrine)—are cholinesterase inhibitors and are prescribed for the treatment of mild to moderate AD. These drugs produce some delay in the deterioration of memory and other cognitive skills in some patients. They offer mild benefits at best, and may lose their effectiveness over time, but currently they are the only alternatives available to treat mild to moderate AD.

The fifth approved medication, Namenda® (memantine), is prescribed for the treatment of moderate to severe AD. It acts to delay progression of some symptoms of moderate to severe AD and may allow patients to maintain certain daily functions a little longer. It is thought to act by regulating glutamate, a chemical in the brain that, in excessive amounts, may lead to brain cell death.

Other researchers are examining the roles of the hormones estrogen and progesterone on memory and cognitive function. Since AD involves inflammatory processes in the brain, scientists are also studying the use of anti-inflammatory agents such as ibuprofen or prednisone to reduce the risk of developing AD. Researchers are also investigating the relationship between the various gene sites, particularly the mutation on chromosome 21, and environmental influences that may increase susceptibility to AD. Another NIA-funded study is trying to find out whether antioxidants, such as vitamin E, can prevent people with mild memory impairment from progressing to AD.

In 2005 the NIA and Alzheimer's Association launched the AD Genetics Study, recruiting subjects from families in which two siblings developed AD after age sixty. They hope to compare the genes of the afflicted siblings with those from another family member who does not have AD in an effort to find the genes that contribute to AD.

CANCER

Cancer is a large group of diseases characterized by uncontrolled cell division and the growth and spread of abnormal cells. These cells may grow into masses of tissue called tumors. Tumors composed of cells that are not cancerous are called benign tumors. Tumors consisting of cancer cells are called malignant tumors. The dangerous aspect of cancer is that cancer cells invade and destroy normal tissue.

The mechanisms of action that disrupt the cell cycle are: impairment of a DNA repair pathway, transformation of a normal gene into an oncogene (a hyperactive gene that stimulates cell growth), and the malfunction of a tumor suppressor gene (a gene that inhibits cell division). Figure 5.7 shows the multiple systems that interact to control the cell cycle.

The spread of cancer cells occurs either by local growth of the tumor or by some of the cells becoming detached and traveling through the blood and lymphatic system to develop additional tumors in other parts of the body. Metastasis (the spread of cancer cells) may be confined to a local region of the body, but if left untreated (and often despite treatment), the cancer cells can spread throughout the entire body, causing death. It is perhaps the rapid, invasive, and destructive nature of cancer that makes it, arguably, the most feared of all diseases, even though it is second to heart disease as the leading cause of death in the United States.

Cancer can be caused by both external environmental influences (chemicals, radiation, and viruses) and internal factors (hormones, immune conditions, and inherited mutations). These factors may act together or in sequence to begin or promote cancer. There is consensus in the scientific community that several cancer-promoting influences accrue and interact before an individual will develop a malignant growth. With only a few exceptions, no single factor or risk alone is sufficient to cause cancer. As with other disorders that arise in response to multiple factors, susceptibility to certain cancers is often attributed to a mutated gene. Figure 5.8 shows how the inheritance of a mutated gene increases susceptibility for retinoblastoma (cancer of the eye that affects approximately 300 children in the United States each year).

Genetic Research

Scientists and physicians have known for some time that predisposition to some forms of breast cancer are inherited and have been searching for the gene or genes responsible so that they can test patients and provide more careful monitoring for those at risk. In 1994 doctors identified the BRCA1 gene, and in late 1995 they also isolated the BRCA2 gene. Since then it has been found that variations of the ATM, BRCA1, BRCA2, CHEK2, and RAD51 genes increase the risk of developing breast cancer, and the AR, DIRAS3, and ERBB2 (also called Her-2/neu) genes are associated with breast cancer.

If a woman with a family history of breast cancer inherits a defective form of either BRCA1 or BRCA2, she has an estimated 80% to 90% chance of developing breast cancer. Researchers also think that the two genes are linked to ovarian, prostate, and colon cancer, and BRCA2 likely plays some role in breast cancer in men. Scientists suspect that the two genes may also participate in some way in the development of breast cancer in women with no family history of the disease. Only about 5% of all cases of breast cancer are attributable to the susceptibility genes BRCA1 and BRCA2. Figure 5.9 shows the locations of the BRCA1 gene on the long arm of chromosome 17 at position 2. Figure 5.10 shows the location of the BRCA2 gene on the long arm of chromosome 13 at position 12.3.

A November 1996 study headed by Stephen C. Rubin, a professor and chief of gynecological oncology (cancers of the female reproductive organs) at the University of Pennsylvania, reported a result that was totally unexpected. The study found that women with defective BRCA1 genes who developed ovarian cancer survived longer than those without the mutated gene who developed ovarian cancer. Women with the defective gene lived an average of seventy-seven months after diagnosis, while those without the mutated gene averaged only a twenty-nine-month survival. Researchers do not know if those with the defective gene had less deadly types of cancers or if their cancers responded better to treatment.

Another form of breast cancer, due to multiple copies of a gene called ERBB2, causes an estimated 25% of the approximately 180,000 new cases of the disease in the United States each year. ERBB2 often triggers an aggressive form of cancer that can cause death more quickly than other breast cancers, often within ten to eighteen months after the cancer spreads. The ERBB2 gene produces a protein on the surface of cells that serves as a receiving point for growth-stimulating hormones. Figure 5.11 shows the location of ERBB2 on the long arm of chromosome 17 between positions 11.2 and 12.

Herceptin, a genetically engineered antibody, increases the benefits of chemotherapy by shrinking tumors and slowing the progression of ERBB2. Herceptin became available in late 1998.

CYSTIC FIBROSIS

Cystic fibrosis (CF) is the most common inherited fatal disease of children and young adults in the United States. It occurs in about one in every 3,000 Caucasian births, one in 15,000 African-Americans and one in 31,000 Asian-Americans. According to the NIH (http://www.genome.gov/10001213), approximately 30,000 young people had the disease in 2005; their median (half above and half below) life span is thirty years. An estimated twelve million Americans (one in twenty-five), almost all of whom are white, are symptomless carriers of the CF gene. Like sickle-cell disease, it is a recessive genetic disorder—in order to inherit this disease, a child must receive the CF gene from both parents.

In 1989 the CF gene was identified, and in 1991 it was cloned and sequenced. It is located on the long arm of chromosome 7 at position 31.2 (See Figure 5.12.) The gene was called cystic fibrosis transmembrane conductance regulator (CFTR) because it was discovered to encode a membrane protein that controls the transit of chloride ions across the plasma membrane of cells. Nearly 1,000 mutations of the large gene—250,000 nucleotides—have been identified. Though most are extremely rare, several account for more than two-thirds of all mutations. Figure 5.13 shows three types of defects in cystic fibrosis transmembrane conductance regulator that can cause CF. The most frequently occurring mutation causes faulty processing of the protein such that the protein is degraded before it reaches the cell membrane.

The mutated versions of the gene found in people with CF were seen to cause relatively modest impairment of chloride transport in cells. But this seemingly minor defect can result in a multisystem disease that affects organs and tissues throughout the body, provoking abnormal, thick secretions from glands and epithelial cells. Ultimately, these secretions fill the lungs and cause affected children to die of respiratory failure.

The progression from the defective gene and protein it encodes to life-threatening illness follows this complex path:

1. The defect in chloride passage across the cell membrane indirectly produces an accumulation of thick mucus secretions in the lungs.
2. The bacteria Pseudomonas aeruginosa grows in the mucus.
3. In a campaign to combat the bacterial invasion, the body's immune system is activated but is unable to access the bacteria because the thick mucus protects it.
4. The immune reaction persists and becomes chronic, resulting in inflammation that harms the lung.
5. Ultimately, it is the affected individual's own immune response, rather than the defective CF gene, protein, or the bacterial infection, that produces the often fatal damage to the lungs.

At first, a child with CF does not appear to be suffering from a serious illness, but the diagnosis is usually made by the age of three. 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 cystic fibrosis. Over time children with CF develop great difficulty in 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.

CF Gene-Screening Falters

In August 1989 researchers isolated the specific gene that causes CF. The mutation of this gene accounts for about 70% 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 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. Scientists found that the gene can be mutated at more than 950 points, and more points are appearing at an alarming rate. At the same time, they discovered that many people who have inherited mutated genes from both parents do not have cystic fibrosis. 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, while 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.

In 2005 the Cystic Fibrosis Foundation continued to support clinical research studies in human gene therapy. Several studies used the adenovirus rather than the common cold virus as the vehicle for delivering healthy genes to lung or nasal tissue. Another study is using liposomes (fat cells) as a delivery vehicle. Still another form of gene therapy uses a compacted DNA technology. The nonviral gene transfer system compacts single copies of the healthy CFTR gene so that they are small enough to pass through a cell membrane into the nucleus. The goal is for the DNA to produce the CFTR protein that is needed to correct the basic defect in CF cells.

Researchers are also finding that CF mutations may be much more common than previously thought. For example, 5,000 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% of the population. Of those screened, 11% had the mutation. This finding may indicate that many more common diseases, such as asthma, may be caused by mutations of the CF gene. Other scientists have speculated that the frequency of CF carriers among people of European descent may have, at some point in time, conferred immunity to some other disorder, in much the same way that the sickle-cell carriers were protected from malaria.

CF Carriers Do Not Always Inform Family Members

Since there is a relatively high frequency of carriers of the defective gene in the general population, in 2000 the NIH, the American College of Medical Genetics, and the American College of Obstetricians and Gynecologists issued a recommendation that CF screening be offered to every white woman who is pregnant or considering having a baby. However, 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.

The investigators and other health educators believe that if carriers were better informed about their risks they might be more likely to disclose them. Pretest education and counseling were seen as key to increasing carriers' understanding of the significance of findings and their family planning options. For example, when both parents are carriers, the risk of their child having CF is one in four, and the risk of their child being a carrier is one in two. In this case parents may choose to have prenatal diagnosis using chorionic villus sampling (CVS) or amniocentesis to find out whether their unborn child will have the disease. Alternatively, they may choose to use assisted reproductive technology such as in vitro fertilization (in which the egg and sperm are united outside of the body) because it offers the option of preimplantation diagnosis. This is a genetic test that enables parents undergoing in vitro fertilization to screen an embryo for CF genetic mutations before it is implanted in the uterus to grow and develop.

DIABETES

Diabetes is a disease that affects the body's use of food, causing blood glucose (sugar levels in the blood) to become too high. Normally, the body converts sugars, fats, starches, and proteins into a form of sugar called glucose. The blood then carries glucose to all the cells throughout the body. In the cells, with the help of the hormone insulin, which facilitates the entry of glucose into the cells, the glucose is either converted into energy for use immediately or stored for the future. Beta cells of the pancreas, a small organ located behind the stomach, manufacture the insulin. The process of turning food into energy via glucose (blood sugar) is important because the body depends on glucose for its energy source.

In a body with diabetes, food is converted to glucose, but there is a problem with insulin. In one type of diabetes the pancreas does not manufacture enough insulin, and in another type the body has insulin but cannot use the insulin effectively (this latter condition is called insulin resistance). When insulin is either absent or ineffective, glucose cannot get into the cells to be converted into energy. Instead, the unused glucose accumulates in the blood. If a person's blood-glucose level rises high enough, the excess glucose "spills over" into the urine, causing frequent urination. This, in turn, leads to an increased feeling of thirst as the body tries to compensate for the fluid lost through urination.

Types of Diabetes

There are two distinct types of diabetes. Insulin-dependent diabetes (also called Type 1 or juvenile diabetes), the most severe form of the disease, occurs most often in children and young adults. The pancreas stops manufacturing insulin, and the hormone must be injected daily. Non-insulin-dependent diabetes (also known as Type 2) is most often seen in adults. In this type the pancreas produces insulin, but it is not used effectively and the body resists its effects. Table 5.3 compares the phenotype (presentation) and genotype of Type 1 and Type 2 diabetes.

According to the American Diabetes Association (ADA; http://www.diabetes.org/) in early 2005, approximately 18.2 million Americans (6.3% of the population) had diabetes. Of these, approximately one-third had not been diagnosed. The ADA reported that more than thirteen million Americans have Type 2 diabetes. The individuals most at risk for Type 2 diabetes are usually overweight, over forty years old, and have a family history of diabetes. Type 2 patients represent about 90% of diabetes patients. Type 1 accounts for only about 5 to 10% of diabetes cases.

Causes of Diabetes

The causes of both Type 1 and Type 2 diabetes are unknown, but a family history of the disease increases the risk for both types, leading researchers to believe there is a genetic component. Some scientists believe that a flaw in the body's immune system may be a factor in Type 1 diabetes. Poor cardiovascular fitness is another risk factor for developing diabetes.

Mutations in several genes probably contribute to the origin and onset of Type 1 diabetes. For example, an insulin-dependent diabetes mellitus (IDDM1) site on chromosome 6 may harbor at least one susceptibility gene for Type 1 diabetes. The role of this mutation in increasing susceptibility is not yet known; however, since chromosome 6 also contains genes for antigens (the molecules that normally tell the immune system not to attack itself), there may be some interaction between immunity and diabetes. In Type 1 diabetes the body's immune system mounts an immunological assault on its own insulin and the pancreatic cells that manufacture it. Some ten sites in the human genome, including a gene at the locus IDDM2 on chromosome 11 and the gene for glucokinase, an enzyme that is crucial for glucose metabolism, on chromosome 7, appear to increase susceptibility to Type 1 diabetes.

In noninsulin-dependent diabetes, heredity may be a factor, but since the pancreas continues to produce insulin, the disease is considered a problem of insulin resistance, in which the body is not using the hormone efficiently. In people prone to Type 2 diabetes, being overweight can set off the disease because excess fat prevents insulin from working correctly. Maintaining a healthy weight and keeping physically fit can usually prevent noninsulin-dependent diabetes. To date, insulin-dependent diabetes (Type 1) cannot be prevented.

Blacks are somewhat more likely to develop Type 2 diabetes than whites, while Hispanic Americans are much more likely to develop this type of the disease than the general population. Diabetes is also prevalent among many Native Americans. The Pima Indians of southern Arizona, for example, have the highest incidence of Type 2 diabetes in the world (50% of those over age thirty-five).

Complications of Diabetes

Because diabetes deprives body cells of the glucose needed to function properly, several complications can develop to further threaten the lives of victims. The healing process of the body is slowed or impaired and there is increased risk of infection. Complications of diabetes include higher risk and rates of heart disease; circulatory problems, especially in the legs, often severe enough to require surgery or even amputation; diabetic retinopathy, a condition that can cause blindness; kidney disease that may require dialysis; dental problems; and problems of pregnancy.

Failure to follow the proper diet can be particularly dangerous to those who suffer from Type 1 diabetes. People who pay close attention to the roles of diet, exercise, weight management, and pharmacological control (proper use of insulin and other medication) to manage their disease suffer the fewest complications.

HUNTINGTON'S DISEASE

Named for an American physician, George Sumner Huntington (1850–1916), 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 men and women of all races and ethnic groups. Figure 5.14 shows the inheritance pattern of HD.

Gene Responsible for HD Found

The gene mutation that produces HD was mapped to chromosome 4 in 1983 and cloned in 1993. In the HD gene the mutation involves a triplet of nucleotides, cytosine (C), adenine (A), and guanine (G), known as CAG. The mutation is an expansion of a nucleotide triplet repeat in the DNA that codes for the protein huntingtin. In unaffected persons the gene has thirty or fewer of these triplets, but HD patients 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 international team of scientists from the United States and the United Kingdom that discovered the gene responsible for HD examined seventy-five families with a history of HD and found the abnormal expansion in each case of an afflicted patient. The number of repeated triplets is inversely related to the age when the individual first experiences symptoms—the more repeated triplets, the younger the age of onset of the disease. Like myotonic dystrophy, in which the symptoms of the disease often increase in severity from one generation to the next, the unstable triplet repeat sequence can lengthen from one generation to the next, with a resultant decrease in the age when symptoms first appear.

HD does not usually strike until mid-adulthood, between ages thirty and fifty, 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, are often ignored, delaying the diagnosis. The disease gradually takes its toll over a ten- to twenty-five-year period.

Within a few years, characteristic involuntary movement (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.

Prevalence of HD

HD, once considered rare, is now recognized as one of the more common hereditary diseases. It is known to affect about 30,000 Americans, according to the National Institute of Neurological Disorders and Stroke (NINDS) in Huntington's Disease: Hope through Research (NIH Publication No. 98-49). Another 150,000 are at a 50% risk of inheriting it from an affected parent. NINDS estimates its prevalence at about one in 10,000 persons.

Prediction Test

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

A testing center at Johns Hopkins Hospital in Maryland reports 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.

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 does not appear to enter or affect the implanted fetal tissue.

The HD patients 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.

MUSCULAR DYSTROPHY

Muscular dystrophy (MD) is a term that applies to a group of more than thirty types of hereditary muscle-destroying disorders. Approximately one million Americans are affected by one of the forms of MD. Each variant of the disease is caused by defects in the genes that play important roles in the growth and development of muscles. Duchenne muscular dystrophy (DMD) is one of the most frequently occurring types of MD and is characterized by rapid progression of muscle degeneration that occurs early in life. The disorder was named for the French neurologist Guillaume Benjamin Amand Duchenne (1806–75), who first described it. In all forms of 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% of the muscle tissue has been affected.

DMD is X-linked, affects mostly males, and, according to the National Center for Biotechnology Information, strikes one in 3,500 boys worldwide. The gene for DMD is located on the X chromosome and encodes a large protein called dystrophin. (See Figure 5.15.) Dystrophin provides structural support for muscle cells and without it, the cell membrane becomes penetrable, allowing extracellular components into the cell. (See Figure 5.16.) These additional components increase the intracellular pressure, causing the muscle cell to die.

With myotonic dystrophy the muscles contract but have diminishing ability to relax, and there is muscle weakening and wasting. Typically, the initial complaints are the loss of hand strength or tripping while walking or climbing stairs. Along with decreased muscle strength, myotonic dystrophy may cause mental deficiency, hair loss, and cataracts. It is an autosomal dominant disorder that occurs in one in 20,000 people; it usually begins in young adulthood but can start at any age and varies in terms of severity.

The myotonic dystrophy gene is a protein kinase gene found on the long arm of chromosome 19. (See Figure 5.17.) The defect is a repeated set of three nucleotides—cytosine (C), thymine (T), and guanine (G)—in the gene. The symptoms of myotonic dystrophy frequently become more severe with each generation because mistakes in copying the gene from one generation to the next result in amplification of a genomic AGC/CTG triplet repeat, similar to the process observed in Huntington's disease. Unaffected individuals have CTG repeats with between three and thirty-seven iterations (repetitions) of the triplet. In contrast, people with the mild phenotype of myotonic dystrophy have between forty and 170, and those with more serious forms of the disease have between 100 and 1,000 iterations.

The symptoms of this disorder generally become more severe with each successive generation. This is because mistakes in the reliable copying of the gene from one generation to the next result in the amplification of a genomic "AGC/CTG triplet repeat," similar to that found in Huntington's disease.

All of the various disorders labeled MD cause progressive weakening and wasting of muscle tissues. They vary, however, in terms of the usual age at the onset of symptoms, rate of progression, and initial group of muscles affected. The most common type, DMD, 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% chance of inheriting the disease. Other forms of MD appear later in life and are usually not fatal.

In 1992 scientists discovered the defect in the gene that causes myotonic dystrophy. In people with this disorder, a segment of the gene is enlarged and unstable. This finding helps physicians more accurately diagnose myotonic dystrophy, which affects at least one in 8,000 people. Researchers have since identified genes linked to other types of MD, including DMD, Becker MD, limb-girdle MD, and Emery-Dreifuss MD.

In January 2005 researchers from the Mayo Clinic in Rochester, Minnesota, identified a new form of muscular dystrophy that involves mutations in a protein called ZASP, which binds to cardiac (heart) and skeletal muscles. The researchers detected ZASP mutations in eleven patients; in seven of these, they observed a dominant pattern of inheritance (Duygu Selcen and Andrew G. Engel, "Mutations in ZASP Define a Novel Form of Muscular Dystrophy in Humans," Annals of Neurology, February 2005).

In addition to its commitment to MD research, the Muscular Dystrophy Association supports research into the causes and treatment of related neuromuscular illnesses, such as amyotrophic lateral sclerosis (also known as Lou Gehrig's disease), 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 known 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 designed to find a cure or a treatment for one or more of these types of MD are ongoing. Research teams have identified the crucial proteins produced by these genes, such as dystrophin, beta sarcoglyan, gamma sarcoglyan, and adhalin. One experimental treatment approach involves substituting a protein of comparable size, such as utrophin for dystrophin, to compensate for the loss of dystrophin. (See Figure 5.16.)

Since defective or absent 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 will then begin to produce the missing proteins.

New delivery methods called vectors are also 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.

PHENYLKETONURIA

Phenylketonuria (PKU) is an example of a disorder caused by a gene-environment interaction. As a result of the defect, the affected individual is unable to convert phenylalanine into tyrosine. Phenylalanine in the body accumulates in the blood and can reach toxic levels. (See Figure 5.4.) This toxicity may impair brain and nerve development and result in mental retardation, organ damage, unusual posture, and, when it occurs during pregnancy, may jeopardize the health and viability of the unborn child.

Originally, PKU was considered simply an autosomal recessive inherited error of metabolism that occurred when an individual received two defective copies, caused by mutations in both alleles of the phenylalanine hydroxylase gene found on chromosome 12. (See Figure 5.18.) The environmental trigger—dietary phenylalanine—was not identified at first because phenylalanine is so prevalent in the diet, occurring in common foods such as milk and eggs and in the artificial sweetener aspartame. Recognition of dietary phenylalanine as a critical environmental trigger has enabled children born with PKU to lead normal lives when they are placed on low-phenylalanine diets, and mothers with the disease can bear healthy children.

To identify people at risk of PKU, all newborns in the United States and many other countries are screened at birth for high levels of phenylalanine in the blood. After additional screening of those with elevated blood levels, approximately one in 10,000 infants is diagnosed with PKU and, with proper diet, is likely to lead a healthy, normal life.

SICKLE-CELL DISEASE

Sickle-cell disease (SCD) is a group of hereditary diseases, including sickle-cell anemia (SCA) and sickle B-thalassemia, in which the red blood cells contain an abnormal hemoglobin, termed hemoglobin S (HbS). HbS 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. (See Figure 5.19.)

Sickle-cell anemia is an autosomal recessive disease caused by a point mutation in the hemoglobin beta gene (HBB) found on chromosome 11p15.4. (See Figure 5.20.) A mutation in HBB results in the production of hemoglobin with an abnormal structure. Figure 5.19 shows how in SCA a point mutationcauses the amino acid glutamine to be replaced by valine to produce abnormal hemoglobin called HbS. It also shows how when red blood cells with HbS are oxygen-deprived they become sickle shaped and may cause blockages that result in tissue death.

Symptoms of SCA

People with SCA 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 abdomen. Blood clots may also develop in the lungs, kidneys, brain, and other organs. A severe crisis or several acute crises can permanently damage various organs of the body. 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.

Who Contracts SCD?

Both the sickle-cell trait and the disease exist almost exclusively in people of African, Native American, and Hispanic descent and in those from parts of Italy, Greece, Middle Eastern countries, and India. When one parent has the sickle-cell gene, a couple's offspring will carry the trait but only if both the mother and the father have the trait can they produce a child with sickle-cell anemia. This trait is relatively common among African-Americans, and about six in 1,000 black couples carry the risk of having a child with the disease. People of African descent are advised to seek genetic counseling and testing for the trait before starting a family. The sickle-cell trait is present in one in twelve African-Americans, or about two million people. According to the National Heart Lung and Blood Institute (NHLBI), in the United States the disease afflicts approximately 72,000 people, most of whose ancestors come from Africa. SCA occurs in approximately one in 500 African-American births and in one in 1,000 to 1,400 Hispanic-American births. Numbers are much lower for other groups.

A CALL FOR UNIVERSAL SCREENING.

In 1993 a federal panel of researchers, clinicians, and policy makers called for sickle-cell screening of all newborns because early diagnosis and treatment significantly improve 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 sickle-cell 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 National Institutes of Health 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. As of 2005, according to the NHLBI, forty-four states, the District of Columbia, Puerto Rico, and the Virgin Islands screened all newborns for sickle-cell disease, and the remaining six states provided screening at the request of parents.

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 SCD

There is no universal cure for SCD, but the symptoms can be treated. Crises accompanied by extreme pain are the most common problems and can usually be treated with painkillers. Maintaining healthy eating and behavior and prompt treatment for any type of infection or injury is important. Special precautions are often necessary before any type of surgery, and 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.

The 1993 federal panel of experts on SCD recommended that all infants diagnosed with the disease receive daily doses of penicillin to prevent infections. Parents are urged to make sure that these children receive the scheduled childhood immunizations and are vaccinated against influenza, meningitis, pneumonia, and hepatitis B. In the mid-1980s, 20% of children with SCD died before their first birthday; by 1993, primarily because of preventive antibiotics, that proportion had dropped to less than 3%. Although there is neither uniform SCD reporting nor national reports of incidence or prevalence, public health professionals believe that the antibiotic prophylaxis (prevention) 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%. In 2003 an extension of that study showed that not only do patients on hydroxyurea have fewer crises but they also have a significant survival advantage when compared to SCD patients who do not take the medication. Subjects treated with it overall showed 40% lower mortality than others. (Martin H. Steinberg et al., "Effect of Hydroxyurea on Mortality and Morbidity in Adult Sickle Cell Anemia: Risks and Benefits Up to 9 Years of Treatment," Journal of the American Medical Association, April 2, 2003).

An international study conducted in 1996 found that bone marrow transplants were successful in curing SCD in sixteen out of twenty-two patients, or 72.7% of the patients in the five-year study. All of the participants in the study were under age fourteen, had advanced symptoms, and had siblings who were compatible bone marrow donors. Of the remaining six patients, four (18%) rejected the donor marrow, and their sickle-cell symptoms returned, while two (9%) died.

Because of the risks associated with bone marrow transplants and the difficulties of finding matching donors, transplants are not appropriate for most patients. Further studies are needed to test the procedure for older patients and to reduce the proportion of transplant 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.

TAY-SACHS DISEASE

Tay-Sachs disease (TSD) is caused by mutations in the HEXA gene, located on the long arm of chromosome 15. (See Figure 5.21.) It 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 called GM2 ganglioside builds up abnormally in the cells, particularly the brain's nerve cells. (Figure 5.22 shows how the absence of, or defect in, the hex-A protein prevents complete processing of GM2 ganglioside.) Eventually, these cells degenerate and die. This destructive process begins early in the development of a fetus, but the disease is not usually 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.

TSD was named for Warren Tay (1843–1927), a British ophthalmologist who first described a patient with a cherry-red spot on the retina of the eye that has become a hallmark of TSD, and Bernard Sachs (1858–1944), a New York neurologist who provided the first description of the cellular changes in TSD. Dr. Sachs also recognized the inheritance pattern of the disorder and observed that most cases of Tay-Sachs disease occurred in families of eastern European Jewish origin.

Symptoms of TSD

A baby with 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. There is no cure or treatment for this disease.

How Is TSD Inherited?

TSD is an autosomal recessive genetic disorder caused by mutations in both alleles of the HEXA gene on chromosome 15. Both the mother and the father must be carriers of the defective TSD gene in order to produce a child with the disease.

People who carry the gene for TSD are entirely unaffected and usually unaware that they have the potential to pass this disease to their offspring. A blood test distinguishes Tay-Sachs carriers from noncarriers. Blood samples may be analyzed by enzyme assay or DNA studies. Enzyme assay measures the level of hex-A in blood. Carriers have less hex-A than noncarriers. 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% chance of bearing a child who is also 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. As Dr. Sachs observed, individuals of east 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 twenty-seven Jews in the United States are carriers of the TSD gene, and 85% 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.