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 the human immunodeficiency virus (HIV) and tuberculosis. Like most diseases, these frequently occurring disorders result from 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—most 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 are 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. Because 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. According to the Human Genome Project Information Web site (December 9, 2003, http://www.ornl.gov/sci/techresources/Human_Genome/medicine/assist.shtml), which is operated by the Department of Energy, there are an estimated 6,000 known single-gene disorders, which occur in about 1 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 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 to 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 suscept-ibility 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 most 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.

A myriad of 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 (a syndrome is a set of symptoms or conditions that taken together suggest the presence of a specific disease or an increased risk of developing the disease)
• Mental illnesses, mental retardation, and behavioral conditions—alcoholism, anxiety disorders, attention deficit hyperactivity disorder, eating disorders, Lesch-Nyhan syndrome, 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. The National Center for Biotechnology Information (NCBI) reports in Genes and Disease (2006, http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.193) that 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 National Institute of Mental Health (one of the National Institutes of Health), in "The Numbers Count" (December 26, 2006, https://www.nimh.nih.gov/publicat/numbers.cfm#Alzheimer), estimates that 4.5 million Americans suffer from AD. In 2004 it was the seventh-leading cause of death in the United States. (See Table 5.1.) AD also contributes to many more deaths that are attributed to other causes, such as heart and respiratory failure.

AD has become a disease of particular concern in the United States because the nation's older adult population is growing rapidly. The University of North Texas Center for Public Service reports in "Alzheimer's Disease: Statistics" (August 13, 2001, http://www.cps.unt.edu/alzheimers/disease_statistics.htm) that approximately 10% of the population over age sixty-five is afflicted with AD. 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 (March 18, 2004, http://www.census.gov/ipc/www/usinterimproj/). The Alzheimer's Association estimates that between 2000 and 2025 the number of cases of Alzheimer's disease in the United States will increase by 44%, with the largest growth in southern and western states that have high populations of retirees (June 7, 2004, http://www.alz.org/documents/national/FSADState_Growth.pdf). Prevalence (the number of people with a disease at a given time) is partially determined by the length of time people with AD survive. Even though the 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.

Genetic Causes of AD

AD is not a normal consequence of growing older, and scientists are continuing to seek its cause. Researchers find 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 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 unaffected 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 why 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.)

According to the National Center for Biotechnology Information (2007, http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107741), 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. 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, whereas only 15.5% 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. The article "Late-Onset Alzheimer's Gene Suggests Interplay" (Neuroscience, August 14, 1998) indicates that 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 can protect susceptible people against brain damage or perhaps even reverse it.

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.

Diagnostic tests for AD have included analysis of blood and spinal fluid as well as the use of magnetic resonance imaging (MRI) to measure the volume of brain tissue in areas of the brain used for memory, organizational ability, and planning to accurately identify people with AD and predict who will develop AD in the future.

In "Nanoparticle-Based Detection in Cerebral Spinal Fluid of a Soluble Pathogenic Biomarker for Alzheimer's Disease" (Proceedings of the National Academy of Science, February 15, 2005), Dimitra G. Georganopoulou et al. report development of 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 AD. To detect them, Georga-nopoulou and her colleagues use nanoscale particles that have antibodies specific to ADDL.

Physicians and neuroscientists have 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. However, 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.

By 2005 five prescription drugs were available to treat people who suffer from AD. Four of these—galantamine, rivastigmine, donepezil, and 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, 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 work 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. Because AD involves inflammatory processes in the brain, scientists are also studying the use of anti-inflammatory agents such as ibuprofen and 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. Furthermore, researchers are trying to determine whether antioxidants, such as vitamin E, can prevent people with mild memory impairment from progressing 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 seed 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, eventually 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. (Table 5.1 uses the term malignant neoplasms to describe cancer.)

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.

Viviana Rivera-Varas, in "Breast Cancer Genes and Inheritance" (1998, http://www.cc.ndsu.nodak.edu/instruct/mcclean/plsc431/students98/rivera.htm), notes that 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 that 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. Sung-Won Kim et al. state in "Prevalence of BRCA2 Mutations in a Hospital Based Series of Unselected Breast Cancer Cases" (Journal of Medical Genetics, 2005) that only about 10% of all cases of breast cancer are attributable to the susceptibility genes BRCA1 and BRCA2. Figure 5.9 shows the location of the BRCA1 gene on the long arm of chromosome 17 at position 21. Figure 5.10 shows the location of the BRCA2 gene on the long arm of chromosome 13 at position 12.3.

According to Els M. Berns et al. in "Oncogene Amplification and Prognosis in Breast Cancer: Relationship with Systemic Treatment" (Gene, June 14, 1995), another form of breast cancer, due to multiple copies of a gene called ERBB2, causes an estimated 25% of the approximately 213,000 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.

In "The BARD1 Cys557Ser Variant and Breast Cancer Risk in Iceland" (PLOS Medicine, July 2006), Simon N. Stacey et al. report their discovery of another mutation that when present with BRCA1 or BRCA2 significantly increases the risk of developing breast cancer. Stacey and his coauthors studied 1,090 Icelandic women who had breast cancer and compared them to 703 similar women without the disease. They found a specific mutation, BARD1, in 2.8% of women with cancer but only 1.6% of those without cancer. They also found that women with both the BARD1 andBRCA2 mutations were twice as likely to develop breast cancer as women without these mutations.

Another study (Sheila Seal et al., "Truncating Mutations in the Fanconi Anemia J Gene, BRIP1, Are Low Penetrance Breast Cancer Susceptibility Alleles," Nature Genetics, November 2006), identifies a new genetic mutation, BRIP1, that doubles the risk of breast cancer in carriers. Although BRIP1 increases a woman's breast cancer risk twofold, other gene mutations raise it much more. Seal and the other researchers find that mutations in BRCA1, BRCA2, and another gene, TP53, increase the carrier's risk of breast cancer by ten- to twentyfold by age sixty. Mutations in other genes such as CHEK2, ATM, and the newly identified BRIP1 gene are associated with a more moderate risk increase. Like some of the other known breast cancer genes such as BRCA1 and BRCA2, BRIP1 is a DNA-repair gene, so women with a faulty version of this gene cannot repair damaged DNA correctly. Individuals with faulty DNA-repair genes have an increased risk of cancer because their healthy cells are more likely to accumulate genetic damage that can trigger the cell to replicate uncontrollably.

CYSTIC FIBROSIS

Cystic fibrosis (CF) is the most common inherited fatal disease of children and young adults in the United States. According to the National Library of Medicine's Genetics Home Reference (January 5, 2007, http://ghr.nlm.nih.gov/condition%3Dcysticfibrosis), CF occurs in about 1 out of 3,200 whites, 1 out of 15,000 African-Americans, and 1 out of 31,000 Asian-Americans. The National Institutes of Health's National Human Genome Research Institute (NHGRI; March 2006, http://www.genome.gov/10001213) notes that approximately 30,000 young people had the disease in 2006; their median life span was thirty years (meaning half would live longer and half would not live this long). An estimated 10 million Americans, almost all of whom are white, are symptomless carriers of the CF gene. Like sickle-cell disease, it is a recessive genetic disorder—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 CFTR 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. However, 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.

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.

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 with 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 com-plicated than expected. Scientists found that the gene can be mutated at more than 950 points, and more points are being recognized 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, 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.

The Cystic Fibrosis Foundation supports clinical research studies in human gene therapy. One form of gene therapy uses a compacted DNA technology. This 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, Stephanie A. Cohen and Lyn Hammond, in "Abstracts from the Nineteenth Annual Education Conference of the National Society of Genetic Counselors (Savannah, Georgia, November 2000)" (Journal of Genetic Counseling, December 2000), cite a study of 5,000 healthy women receiving prenatal care at Kaiser Permanente in northern California who were tested for the CF gene, which is 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 speculate 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.

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 person 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 is excreted from the body via 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. Type 1 diabetes (also called juvenile diabetes) occurs most often in children and young adults. The pancreas stops manufacturing insulin, so the hormone must be injected daily. Type 2 diabetes 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 Centers for Disease Control and Prevention (CDC; October 26, 2005, http://www.cdc.gov/od/oc/media/pressrel/fs051026.htm), in 2005 approximately 21 million Americans (7% of the population) had diabetes. Of these, approximately one-third had not been diagnosed. In 2004 diabetes was the sixth leading cause of death and in 2005, 1.5 million new cases of diabetes were diagnosed. (See Table 5.1 and Figure 5.14.) The individuals most at risk for Type 2 diabetes are usually overweight, over forty years old, and have a family history of diabetes. The CDC (January 31, 2005, http://www.cdc.gov/diabetes/pubs/general.htm) reports that Type 2 patients represent 90% to 95% of diabetes patients, while Type 1 accounts for 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, because 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 Type 2 diabetes heredity may be a factor, but because 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.

Complications of Diabetes

Because diabetes deprives body cells of the glucose needed to function properly, complications can develop that threaten the lives of diabetics. 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; impaired healing and increased risk of infection; and problems of pregnancy. 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

Huntington's disease (HD) 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 5.15 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. (See Figure 5.16.) 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 people 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 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 the 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. According to the Genetics Home Reference (January 5, 2007, http://ghr.nlm.nih.gov/condition=huntingtondisease), HD affects 3 to 7 per 100,000 people of European ancestry. HD appears to be less common in other populations, including people of Japanese, Chinese, and African descent. The NHGRI (October 2006, http://www.genome.gov/10001215) reports that in the United States about 30,000 people have HD, an additional 35,000 people exhibit some symptoms, and 75,000 people carry the abnormal gene that will cause them to develop the disease.

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, researchers 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.

MUSCULAR DYSTROPHY

Muscular dystrophy (MD) is a term that applies to a group of more than thirty types of hereditary muscle-destroying disorders. More than a 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. 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 NCBI (2007, http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.161), strikes 1 out of 3,500 boys worldwide. The gene for DMD is located on the X chromosome and encodes a large protein called dystrophin. (See Figure 5.17.) Dystrophin provides structural support for muscle cells and without it the cell membrane becomes penetrable, allowing extracellular components into the cell. (See Figure 5.18.) 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. According to HealthAtoZ.com (2006, https://www.healthatoz.com/healthatoz/Atoz/common/standard/transform.jsp?requestURI=/healthatoz/Atoz/ency/myotonic_dystrophy.jsp), it is an autosomal dominant disorder that occurs in 1 out of 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 5.19.) 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 40 and 170, and those with more serious forms of the disease have between 100 and 1,000 iterations.

All 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. Researchers have since identified genes linked to other types of MD, including DMD, Becker MD, limb-girdle MD, and Emery-Dreifuss MD.

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

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 sarcoglycan, gamma sarcoglycan, 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 5.18.)

Because 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, and unusual posture. When it occurs during pregnancy, it 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 hydrox-ylase gene found on chromosome 12. (See Figure 5.20.) 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.

The March of Dimes reports that to identify people at risk of PKU, all newborns in the United States are screened at birth for high levels of phenylalanine in the blood (http://search.marchofdimes.com/cgi-bin/MsmGo.exe?grab_id=0 &page_id=162&query=PKU&hiword=PKU%20). After a second screening is done for those with elevated blood levels, approximately 1 out of 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, called 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 sick-ling and more damage.

SCA is an autosomal recessive disease caused by a point mutation in the hemoglobin beta gene (HBB) found on chromosome 11p15.5. (Figure 5.2.) A mutation in HBB results in the production of hemoglobin with an abnormal structure. Figure 5.21 shows how a point mutation in SCA causes 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 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. If one parent has the sickle-cell gene, then the couple's offspring will carry the trait; if both the mother and the father have the trait, then their children may be born with SCA. This trait is relatively common among African-Americans. People of African descent are advised to seek genetic counseling and testing for the trait before starting a family. According to the World Health Organization (March 10, 2006, http://www.who.int/genomics/public/geneticdiseases/en/index2.html#SCA), the sickle-cell trait is present in one out of twelve African-Americans, or about 2 million people. SCD is the most common inherited blood disorder in the United States, affecting 72,000 Americans, most of whom have African ancestry. SCA occurs in approximately 1 out of 500 African-American births and in 1 out of 1,000 to 1,400 Hispanic births. The occurrence of SCA in other groups is much lower.

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 by the Food and Drug Administration.

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 Martin H. Steinberg et al. reported in "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) that not only do patients on hydroxyurea have fewer crises but also they have a significant survival advantage when compared to SCD patients who do not take the medication. Subjects treated with it showed 40% lower mortality than others.

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 5.22.) 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 5.23 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.

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 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 the American neurologist Bernard 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 (2007, http://www.tay-sachs.org/taysachs.php), approximately one out of twenty-seven Jews in the United States is a carrier of the TSD gene. French-Canadians and Cajuns also have the same carrier rate as Ashkenazi Jews. In the general population the carrier rate is 1 out of 250.