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Genetic Disorders

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Genetic Disorders

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 thosemost conditionsin 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,, 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.


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 diseasecoronary atherosclerosis, hypertension (high blood pressure), and hyperlipidemia (elevated blood levels of cholesterol and other lipids)
  • Diabetes
  • Cancerretinoblastomas, colon, stomach, ovarian, uterine, lung, bladder, breast, skin (melanoma), pancreatic, and prostate
  • Neurological disordersAlzheimer'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 conditionsalcoholism, anxiety disorders, attention deficit hyperactivity disorder, eating disorders, Lesch-Nyhan syndrome, and schizophrenia
  • Other genetic disorderscleft 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 conditionsincluding alpha-1-antitrypsin, arthritis, asthma, baldness, congenital adrenal hyperplasia, migraine headaches, obesity, periodontal disease, porphyria, and some speech disorders
The fifteen leading causes of death, 200304
[Rates of death per 100,000 people; columns may not add up to totals because of rounding]
Rank Cause of death Number Death rate Age-adjusted death rate
2004 2003 Percent change
Category not applicable.
Source: Adapted from "Table B. Deaths and Death Rates for 2004 and Age-Adjusted Death Rates and Percentage Changes in Age-Adjusted Rates from 2003 to 2004 for the 15 Leading Causes of Death in 2004: United States, Final 2003 and Preliminary 2004," in "Deaths: Preliminary Data for 2004," National Vital Statistics Reports, vol. 54, no. 19, June 28, 2006, (accessed October 19, 2006)
All causes 2,398,365 816.7 801.1 832.7 3.8
1 Diseases of heart 654,092 222.7 217.5 232.3 6.4
2 Malignant neoplasms 550,270 187.4 184.6 190.1 2.9
3 Cerebrovascular diseases 150,147 51.1 50.0 53.5 6.5
4 Chronic lower respiratory diseases 123,884 42.2 41.8 43.3 3.5
5 Accidents (unintentional injuries) 108,694 37.0 36.6 37.3 1.9
6 Diabetes mellitus 72,815 24.8 24.4 25.3 3.6
7 Alzheimer's disease 65,829 22.4 21.7 21.4 1.4
8 Influenza and pneumonia 61,472 20.9 20.4 22.0 7.3
9 Nephritis, nephrotic syndrome and nephrosis 42,762 14.6 14.3 14.4 0.7
10 Septicemia 33,464 11.4 11.2 11.6 3.4
11 Intentional self-harm (suicide) 31,647 10.8 10.7 10.8 0.9
12 Chronic liver disease and cirrhosis 26,549 9.0 8.8 9.3 5.4
13 Essential (primary) hypertension and hypertensive renal disease 22,953 7.8 7.6 7.4 2.7
14 Parkinson's disease 18,018 6.1 6.1 6.2 1.6
15 Pneumonitis due to solids and liquids 16,959 5.8 5.6 5.9 5.1
All other causes 418,810 142.6


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, 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,, 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, 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, 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, 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.)

Genes for Alzheimer's disease
Age at onset Inheritance Chromosome Gene Protein %AD
Age of onset: early onset: <60 years, late onset: >60 years; inheritance: AD: autosomal dominant, familial: disease in at least one first-degree relative, sporadic: disease in no other family member; chromosome: number, arm, and region; gene: designation of identified gene; protein: name of protein coded for by the gene; % AD: percent of AD caused by or *number of families identified with AD for each gene.
Source: Richard Robinson, ed., "Genes for Alzheimer's Disease," in Genetics, Vol. 1, A-D, Macmillan Reference USA, 2002
Early onset AD 14 PS1 Presenilin 1 <2
Early onset AD 21 APP Amyloid Precursor protein <20 families*
Early onset AD 1 PS2 Presenilin 2 3 families*
Early onset AD ? ? ? ?
Late onset Familial/sporadic 19 APOE Apolipoprotein E 50
Late onset Familial 12p11-q13 ? ? ?
Late onset Familial 9p22.1 ? ? ?
Late onset Familial 10q24 ? ? ?
Late onset ? ? ? ? ?

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,, 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 thesegalantamine, rivastigmine, donepezil, and tacrineare 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 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,, 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 (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,, 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, 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 disorderto 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 gene250,000 nucleotideshave 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 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,, 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, 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.

Comparison of type 1 and type 2 diabetes
Type 1 diabetes Type 2 diabetes
*Type 2 diabetes is increasingly diagnosed in younger patients.
Note: HLA is human leukocyte antigen.
Source: Adapted from Laura Dean and Johanna McEntyre, "Table 1. Comparison of Type 1 and Type 2 Diabetes," in The Genetic Landscape of Diabetes, U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2004, (accessed October 19, 2006)
Phenotype (observable characteristics) Onset primarily in childhood and adolescence Onset predominantly after 40 years of age*
Often thin or normal weight Often obese
Prone to ketoacidosis No ketoacidosis
Insulin administration required for survival Insulin administration not required for survival
Pancreas is damaged by an autoimmune attack Pancreas is not damaged by an autoimmune attack
Absolute insulin deficiency Relative insulin deficiency and/or insulin resistance
Treatment: insulin injections Treatment: (1) healthy diet and increased exercise; (2) hypoglycemic tablets; (3) insulin injections
Genotype (genetic makeup) Increased prevalence in relatives Increased prevalence in relatives
Identical twin studies: <50% concordance Identical twin studies: usually above 70% concordance
HLA association: yes HLA association: no

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 (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 symptomsthe 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 changesdepression 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,, 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, 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 (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,, 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 (2006,, 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 nucleotidescytosine (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 symptomsthey 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 (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 triggerdietary phenylalaninewas 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 ( &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 (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 crisesattacks 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,, 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.


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 (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,, 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.

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Genetic Disorders


The traditional method used to study an inherited disease is to observe the pattern of its distribution in families through examination of a pedigree, the construction of which begins with the individual first known to have the disease. The pedigree pattern allows one to judge whether or not the distribution conforms to Mendelian principles of segregation and assortment, and thus represents single-factor inheritance. Patterns that do not conform to Mendelian principles may represent polygenic traits, which represent the cumulative effects of a number of different genes. These complex patterns underlie the vast majority of human diseases.

Disorders caused by single mutant genes show one of four simple (Mendelian) patterns of inheritance: (1) autosomal dominant, (2) autosomal recessive, (3) X-linked dominant, or (4) X-linked recessive. A dominant trait is one that is expressed in the heterozygote (as well as in the homozygote or hemizygote). A recessive trait is one that is expressed in a homozygote (or a hemizygote), but silent in the heterozygote. The terms "dominant" and "recessive" refer to the phenotypic expression of a trait, not to the expression of the gene. Thus it is incorrect to speak of a dominant or recessive gene. A gene is either expressed or not expressed. Whether the trait is considered dominant or recessive often depends upon the level of observation. Sickle cell anemia is a recessive traitit requires a double dose of the abnormal gene for expression at the clinical level. Nevertheless, the sickle gene can be expressed in single dose as well, giving rise to carriers with SA hemoglobin. In a state of reduced oxygen tension, red cells in SA carriers may sickle. Recessive traits may thus be codominant when viewed biochemically at the level of the gene product, or dominant in an altered environment.


By definition, genes that are situated on chromosomes other than the X or Y sex chromosomes are autosomal. Dominant traits are fully evident when only one abnormal gene (mutant allele) is present and the corresponding partner allele on the homologous chromosome is normal (a heterozygous state). The representative initial for the dominant gene is typically capitalized, and the recessive gene is placed in lower case. Thus, if there are two alleles of a given gene that are referred to as "A" and "a," three possible genotypes exist: AA, Aa, and aa. Genotypes AA and aa are homozygotes; Aa is a heterozygote.

Autosomal dominant traits bear the following characteristic features: (1) an affected individual usually bears an equal number of affected and unaffected offspring; (2) unless the condition arose by a new mutation in a germ cell that formed the individual, each affected individual has an affected parent; (3) males and females are affected in equal numbers; (4) each gender can transmit the trait to male and female; (5) normal children of an affected individual have only normal offspring; and (6) when the trait does not impair viability or reproductive capacity, vertical transmission of the trait occurs through successive generations. The best evidence of a dominant trait is three or more generations of male-to-male transmission.

Autosomal dominant disorders often show two additional characteristics that are rarely seen in recessive disorders: (1) marked variability in the severity, or expressivity, of the disorder and (2) delayed age of onset. In heterozygotes the expression of the abnormal gene can be so weak that a generation appears to be skipped because the carrier of the abnormal gene is clinically normal. In such fortunate individuals, the trait is said to be "nonpenetrant." In some diseases, such as Huntington's disease and adult polycystic kidney disease, the disorder may not become manifest clinically until adult life, even though the mutant gene has been present since conception.

In every autosomal dominant disease, some affected persons owe their disorder to a new mutation rather than to an inherited allele. A reasonable estimate of the frequency of mutation is on the order of 5 × 10-6 mutations per allele per generation. Because a dominant trait requires a mutation in only one of the parental gametes, the expected frequency for a new autosomal dominant disease in any given gene is one in 100,000 newborns.

A classic example of a dominant trait in humans is familial hypercholesterolemia, an autosomal dominant disorder characterized by elevation of serum cholesterol bound to low-density lipoprotein (LDL). Mutations in the LDL receptor (LDLR) gene on chromosome 19 cause the disorder. Heterozygotes develop fatty collections on their tendons, a corneal arc, and, of greatest concern, coronary artery disease, which typically presents in the fourth or fifth decade of life. Homozygotes develop these features at an accelerated rate. In the United States, the frequency of homozygotes is approximately one in a million, and the frequency of heterozygotes is approximately one in five hundred. However, among patients with a history of myocardial infarction (heart attacks), the heterozygote frequency is about one in twenty.


Autosomal recessive conditions are clinically apparent only in the homozygous statewhen both alleles at a particular genetic locus are deleterious. In most autosomal recessive disorders the clinical presentation tends to be more uniform than in dominant diseases, and the onset is often early in life. The following features are characteristic: (1) on average, male and female siblings are affected in equal proportions; (2) the parents are clinically normal; (3) all of the children of the union between an affected individual and a homozygous normal individual are heterozygous carriers, but none will be affected; (4) on average, half of the children are affected when an affected individual mates with a heterozygous carrier (a pseudo-dominant pedigree); (5) all of the children of a union between two individuals homozygous for the same mutant gene will be affected; (6) on average, if both parents are heterozygous at the same genetic locus, one-fourth of their children are homozygous affected, one-fourth are homozygous normal, and half are heterozygous carriers of the same mutant gene; and (7) the less frequent the mutant gene is in the population, the greater the likelihood that the affected individual is the product of consanguineous parents.

Consanguinity increases the likelihood of a child presenting with a recessive disease because the likelihood of inheriting the same rare mutation from a distant common ancestor, or "founder" increases. First cousins share, on the average, one-eighth of their genes. When two first cousins marry, an offspring has, on average, one-sixteenth of the loci homozygous for a gene derived from a common ancestor. In general, offspring of first cousins are slightly more likely to have congenital malformations, as well as mental defects and metabolic diseases, than are children born to unrelated parents.

Increased frequency of consanguinity is not observed if the recessive disease is common. Cystic fibrosis exemplifies an autosomal recessive disorder that is common among individuals of Northern European descent. In the United States, the frequency of individuals heterozygous for a mutation in the cystic fibrosis conductance regulator gene (CFTR) is quoted as one in twenty-five. Inheritance of two malfunctioning genes leads to the disruption of pancreatic exocrine function and chronic bronchitis with emphysema, as well as biliary cirrhosis, meconium ileus, and an enhanced loss of salt through the skin, which is the basis of the "sweat test" used for screening purposes. The frequency of individuals affected with cystic fibrosis is one in 2,500, and typically the parents are unrelated.


Diseases or traits that result from genes located on the X chromosome are termed "X-LINKED." Because the female has two X chromosomes, she may be either heterozygous or homozygous for the mutant gene, and the trait may exhibit recessive or dominant expression. The terms "X-LINKED dominant" and "X-LINKED recessive" refer only to expression of the trait in females. The male has only one X chromosome and therefore is hemizygous for X-linked traits. Males can be expected to express X-linked traits regardless of their recessive or dominant behavior in the female. This accounts for the large numbers of X-linked diseases. Affected males do not transmit an X chromosome to their sons; thus an important feature of X-linked inheritance is the absence of male-to-male transmission. In contrast, since all females inherit their fathers' single X chromosomes, their daughters are all obligate carriers.

Although genotypically females have two X chromosomes, functionally they behave as though they only have one X chromosome, like their brothers. This is due to the process of X-inactivation, which was first proposed by Mary Lyon and is termed "lyonization" in her honor. During ontogeny, one of the X chromosomes becomes inactive, condensing to form a "Barr body." Inactivation is random, so each cell has an equal probability that the paternally or maternally derived X chromosome will be inactivated. Once one of the two X chromosomes is inactivated, the same X chromosome remains inactive throughout all subsequent cell divisions. Thus, on average, half of the cells of a female express the X chromosome of her father and half of her mother.

For the vast majority of genes on the X chromosome, the normal female is a mosaic, with her cells expressing one or the other X chromosome, but not necessarily a 5050 mosaic. Inactivation of one of the X chromosomes occurs early in development and is random; hence many females may, by chance, have many more cells that carry an active X chromosome derived from one parent than from the other. Similarly, if one of the X chromosomes carries a mutant gene that confers a metabolic disadvantage upon cells with that mutation, these cells may survive less frequently during development, and the female offspring may have cells that carry predominantly or exclusively the active X chromosome without the mutation.

X-linked dominant traits are uncommon. The characteristic features are as follows: (1) females are affected about twice as often as males; (2) heterozygous females transmit the trait to both genders with a frequency of 50 percent; (3) hemizygous affected males transmit the trait to all of their daughters and none of their sons; and (4) the expression is more variable and generally less severe in heterozygous females than in hemizygous affected males. Some rare X-linked dominant disorders occur only in the heterozygous female, because the condition is lethal in the hemizygous affected male. Additional characteristics of this form of inheritance are as follows: (1) an affected mother transmits the trait to half of her daughters (heterozygotes), and (2) an increased frequency of abortions occurs in affected women, the abortions representing affected male fetuses.

X-linked recessive traits are relatively common. The characteristic features are as follows:(1) the disorder is fully expressed only in the hemizygous affected male; (2) heterozygous females are usually normal, although occasionally they may exhibit mild features of the disorder, and in females who have unfortunately inactivated the wrong X chromosome may be almost as severely affected as the hemizygous affected male; (3) on average, a heterozygous female transmits the trait to half of her sons (hemizygous affected), but the other half are normal; (4) on average, half of the daughters of a heterozygous female are carriers and half are normal; (5) all daughters of an affected male and a normal female are carriers, and no sons of such a union are affected (no father-toson transmission); (6) in the rare event of the union of an affected male and a heterozygous female, half of the daughters are homozygous affected and half are heterozygous carriers; while half of the sons are hemizygous affected (maternal inheritance) and half are normal; (7) if the trait is rare, parents and relatives are normal except for male relatives in the female line (e.g., on average, half of maternal uncles are affected). This "uncle and nephew" pattern gives rise to an oblique pedigree pattern, in contrast to the horizontal pattern of autosomal recessive conditions and the vertical pattern of autosomal dominant conditions.

Duchenne muscular dystrophy (DMD) and the milder Becker muscular dystrophy (BMD) are the product of mutations in the dystrophin gene on the X chromosome. The most distinctive feature of Duchenne muscular dystrophy is a progressive proximal muscular dystrophy with characteristic pseudohypertrophy of the calves. On average, a typical patient with DMD is diagnosed around the age of five, is wheelchair dependent at twelve years of age, and is dead before the age of twenty. One-third of cases represent new mutations.


Most phenotypic traits are determined by many genes collaborating at different loci (polygenic) rather than by single gene effects. Parents and offspring, and usually siblings, have 50 percent of their genes in common. Second-degree relatives share, on average, one-fourth of all genes, and third-degree relatives (cousins) share one-eighth. As the degree of relation becomes more distant, the probability of inheriting the same combination of genes is reduced, and the degree of resemblance is likely to be less.

Many common chronic diseases (e.g., essential hypertension, coronary artery disease, and schizophrenia) and the common birth defects of children (e.g., cleft palate, cleft lip, and neural tube defects) that tend to run in families fit best into the category of multifactorial genetic diseases. Multifactorial genetic diseases have both a polygenic component and an environmental component of causative factors. Susceptibility, or risk, genes are present in low frequency in the population at large. However, if any one individual has a particularly large number of such genes, the disease may manifest. When an individual is unfortunate enough to have inherited just the right (or wrong) combination of risk genes, he or she passes beyond a "risk threshold" at which environmental factors may determine the expression and severity of disease. In order for another family member to develop the same disease, that individual would have to inherit the same, or a very similar, combination of genes. The likelihood of such an occurrence is clearly greater in first-degree than in more distant relatives. The chances of another relative inheriting the right combination of risk genes decreases as the number of genes required to express a given trait increases. For example, the recurrence risk for siblings in neural tube defects is almost 4 percent, or ten times greater than the risk in the population as a whole.


Failure of appropriate segregation (nondisjunction) during meiosis by allelic chromosomes or by sister chromatids can lead to an imbalance in the number of chromosomes present in a gamete. The frequency of chromosomal nondisjunction increases with increasing maternal age, with up to 1 percent of the offspring of mothers aged thirty-five and 10 percent of the offspring of mothers aged forty-five or older exhibiting such abnormalities. A zygote with only one copy (monosomy) of any one autosome is nonviable, and three (trisomy) or more copies of any one type of autosomal chromosome are also typically lethal. Exceptions do occur, the most common of which is trisomy 21, or Down syndrome.

Due to lyonization, nondisjunction of the X chromosome is better tolerated. XO individuals (Turner's syndrome) are phenotypically female, but are typically sterile. The Y chromosome is dominant, hence XXY individuals (Klinefelter's syndrome) are phenotypically male. However, affected men are also commonly sterile. Rare individuals with apparent Klinefelter's syndrome have been fertile, but these individuals are typically mosaics, with a sufficient population of chromosomally normal cells to yield viable gametes.

Harry W. Schroeder, Jr.

(see also: Congenital Anomalies; Genes; Genetics and Health; Human Genome Project; Medical Genetics )


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Genetic Disorders

Genetic disorders

Genetic disorders are conditions that have some origin in an individual's genetic make-up. Many of these disorders are inherited and are governed by the same genetic rules that determine dimples and red hair. However, some genetic disorderssuch as Down syndrome, characterized by heart malformation, poor muscle tone, and a flattened faceresult from a spontaneous mutation (gene change) that takes place during embryonic (earliest life) development.

Genetic disorders can be classified according to the way in which they develop. If the disorder is transmitted by genes inherited from only one parent, it is said to be an autosomal dominant disorder. The term autosome applies to any of the 22 chromosomes that are identical in human males and females. (Chromosomes are structures that organize genetic information in the nucleus of cells.) By contrast, disorders that can be inherited only by the transmission of genes from both parents is called an autosomal recessive disorder.

Other genetic disorders are associated with the X (female) or Y (male) chromosome and are called sex-linked disorders because the X and Y chromosomes are related to sexual characteristics in humans. Finally, the development of some genetic disorders involves environmental factors, factors present outside the organism itself. Such disorders are known as multifactorial genetic disorders.

Principles of genetic inheritance

Genetic information in humans is stored in units known as genes located on large complex molecules called chromosomes. A vast range of human characteristics, from eye and hair color to musical and literary talents, are controlled by genes. To say that a person has red hair color, for example, is simply to say that that person's body contains genes that tell hair cells how to make red hair.

Reproduction in humans occurs when a sperm cell from a male penetrates and fertilizes an egg cell from a female. The fertilized egg cell, called a zygote, contains genes from both parents. For example, the zygote will contain two genes that control hair color, one gene from the mother and one gene from the father.

In some cases, both genes carry the same message. For example, the zygote might contain two genes that act as a kind of code that tells a cell to make red hair, one from each parent. In that case, the child will be born with red hair.

Words to Know

Chromosomes: Structures that organize genetic information in the nucleus of cells.

Dominant trait: A trait that can manifest (be expressed) when inherited from one parent.

Gene: A section of a chromosome that carries instructions for the formation, functioning, and transmission of specific traits from one generation to another.

Multifactorial trait: A trait that results from both genetic and environmental influences.

Proteins: Large molecules that are essential to the structure and functioning of all living cells.

Recessive trait: A trait that is expressed in offspring only when identical genes for the trait are inherited from both parents.

Sex-linked disorder: A disorder that generally affects only one sex (male or female).

In other cases, two genes may carry different messages. The zygote might, for instance, carry a gene for red hair from the mother and for brown hair from the father. In such cases, one gene is dominant and the other recessive. As these terms suggest, one gene will "win out" over the other and determine the offspring's hair color. In this example, the gene for brown hair is dominant over the gene for red hair, and the offspring will have brown hair.

Dominant genetic disorders

If one parent has an autosomal dominant disorder, then offspring have a 50 percent chance of inheriting that disease. Approximately 2,000 autosomal dominant disorders (ADDs) have been identified. These disorders have effects that range from inconvenience to death. ADDs include Huntington's disorder, polydactyly (extra toes or fingers), Marfan's syndrome (extra long limbs), achondroplasia (a type of dwarfism), some forms of glaucoma (a vision disorder), and hypercholesterolemia (high blood cholesterol).

ADDs may occur early or late in life. People with ADDs that are diagnosed at older ages are faced with very special problems. They may already have had children of their own and transmitted the genetic trait that caused their disorder to their offspring.

Huntington's disease (also known as Huntington's chorea) is an example of an ADD that is typically diagnosed relatively late in life. The

disorder is characterized by progressive involuntary, rapid, jerky motions and mental deterioration. It usually appears in affected individuals between the ages of 30 and 50, and leads to dementia and eventual death in about 15 years.

Marfan's syndrome, also called arachnodactyly, is an ADD characterized by long, thin arms, legs, and fingers. People with Marfan's syndrome also tend to be stoop-shouldered and have a bluish tint to their eyeballs. In addition, these individuals have a high incidence of eye and heart problems. Abraham Lincoln is believed to have had Marfan's syndrome.

Recessive genetic disorders

Recessive genetic disorders (RGD) are caused when both parents supply a recessive gene to their offspring. The probability of such an event's occurring is 25 percent each time the parents conceive. About 1,000 confirmed RGDs exist. Some of the better known examples of the

condition include cystic fibrosis, sickle-cell anemia, Tay-Sachs disease, galactosemia, phenylketonuria (PKU), adenosine deaminase deficiency, growth hormone deficiency, Werner's syndrome (juvenile muscular dystrophy), albinism (lack of skin pigment), and autism.

Some RGDs tend to affect people of one particular ethnic background at a higher rate than the rest of the population. Three such RGDs are cystic fibrosis, sickle-cell anemia, and Tay-Sachs disease. Cystic fibrosis is one of the most common autosomal recessive diseases in Caucasian children in the United States. About 5 percent of Caucasians carry this recessive gene. Cystic fibrosis is characterized by excessive secretion of an unusually thick mucus that clogs respiratory ducts and collects in lungs and other body areas. Cystic fibrosis patients usually die before the age of 20, although some individuals live to the age of 30.

Sickle-cell anemia occurs with an unusually high incidence among the world's black and Hispanic populations. However, some cases also occur in Italian, Greek, Arabian, Maltese, southern Asian, and Turkish people. About 1 in 12 blacks carry the gene for this disorder. Sickle-cell anemia is caused by mutations in the genes responsible for the production of hemoglobin. (Hemoglobin is the compound that carries oxygen in red blood cells to tissues and organs throughout the body.) Sickle-cell anemia patients have red blood cells that live only a fraction of the normal life span of 120 days. The abnormal blood cells have a sickled appearance, which led to the disease's name. Sickle-cell patients also die early, before the age of 30.

The Tay-Sachs gene is carried by 1 in 30 Ashkenazi Jews. Children born with Tay-Sachs disorder seem normal for the first 5 months of their lives. But afterwards, they begin to express symptoms of the disorder. Eventually, the condition leads to blindness and death before the age of four.

Galactosemia and PKU are examples of metabolic RGDs. A metabolic RGD is one in which a person's body is unable to carry out functions that are normal and essential to the body. For example, people with galactosemia lack an enzyme (chemical) needed to metabolize (break down) galactose, a sugar found in milk. If people with galactosemia do not avoid normal milk, mental retardation will eventually develop. People with PKU have a similar problem. They lack an enzyme needed to convert the amino acid phenylalanine to the amino acid tyrosine. The build-up of phenylalanine in the body leads to severe mental retardation.

Adenosine deaminase deficiency is one of few "curable" genetic diseases. It is caused by a mutation in a single gene essential to normal development of the immune system. Bone marrow transplants have been found to be of some value to patients. In addition, gene therapy has been successful at replacing these patients' defective gene with a copy of a correct gene that enables their immune system to function effectively.

Color Blindness

Is the traffic light red or green? Most humans have the ability to distinguish the color we call red from the color we call green. But some people cannot. Such people are said to be color-blind. Color blindness is a defect in vision that makes it difficult or impossible for a person to distinguish between or among certain colors.

Color-blindness is usually passed on genetically, and is more common in men than in women. About 6 percent of all men and roughly one-tenth of that many women inherit the condition. Individuals also can acquire the condition through various eye diseases. There is no treatment for color blindness.

The most common form of color-blindness involves the inability to distinguish reds from greens. A less common condition involves the inability to distinguish green from yellow.

Color blindness is caused by a lack of pigment in the retina of the eye. Normally, the retina contains molecules capable of detecting every color in the spectrum. However, if some of these molecules are not present, the various colors in the spectrum can not be distinguished from each other, and the person is color-blind.

Color blindness is a sex-linked characteristic. The gene involved in the disorder occurs only on the X chromosome, which is passed to the child by the mother. The Y chromosome, which is passed to the child by the father, does not carry the defective gene. As a result, children inherit color blindness only from their mothers.

Sex-linked genetic disorders

Sex-linked genetic disorders (XLGDs) can be either dominant or recessive. Dominant XLGDs affect females, are usually fatal, and cause severe disorders in males who survive. A high percentage of male embryos with dominant XLGD spontaneously abort early in a pregnancy. Dominant XLGD's include conditions such as Albright's hereditary osteodystrophy (seizures, mental retardation, stunted growth), Goltz's syndrome (mental retardation), cylindromatosis (deafness and upper body tumors), oral-facial-digital syndrome (no teeth, cleft tongue, some mental retardation), and incontinentia pigmenti (abnormal swirled skin pigmentation).

Recessive XLGDs are passed to sons through their mothers. Major XLGDs include severe combined immune deficiency syndrome (SCID), color blindness, hemophilia, Duchenne's muscular dystrophy (DMD), some spinal ataxias, and Lesch-Nyhan syndrome. Roughly one-third of these XLGDs result from a spontaneous mutation. Of these disorders, color blindness is the least harmful.

Hemophilia is an example of a serious XLGD. This disorder is caused by the absence of a protein responsible for the clotting of blood. Lacking this protein, a person with hemophilia may easily bleed to death from simple cuts and injuries that would be of little danger to the average person. Hemophilia A is the most severe form of this disease, and is characterized by extreme bleeding. It affects males primarily, although it has been known to occur in females. The disorder has often been associated with royalty. England's Queen Victoria was a carrier whose descendants became rulers in several European countries.

Other usually fatal XLGDs affect the immune, muscular, and nervous systems. SCID, for example, is a disorder affecting the immune system. It is characterized by a very poor ability to combat infection. One way to treat patients with SCID is to completely enclose them in a large plastic bubble that protects them from germs present in the air. The only known cure for SCID involves a bone marrow transplant from a close relative.

DMD afflicts young boys and is apparent by age three or four. It is characterized by wasting leg and pelvic muscles. Patients with DMD are usually wheelchair-bound by the age of 12, and die before the age of 20, often as the result of heart problems.

Multifactorial genetic disorders

Scientists often find it difficult to determine the relative role of heredity and environment in certain medical disorders. One way to answer this question is with statistical and twin studies. Identical and fraternal twins who have been raised in different and identical homes are evaluated for these MFGDs. If fraternal twins have a higher than normal incidence of a disorder and identical twins show an even higher rate of the disorder, then genetic inheritance is believed to contribute to development of the disorder.

Among the most likely candidates for multifactorial genetic disorders are certain medical conditions associated with diet and metabolism, such as obesity, diabetes, alcoholism, rickets, and high blood pressure; some infectious diseases, such as measles, scarlet fever, and tuberculosis; schizophrenia and some other psychological illnesses; club foot and cleft lip; and various forms of cancer.

The tendency of some people to be more susceptible to a particular MFGD and not another is characteristic of human genetics. All healthy humans have a similar body form with very similar physiological functions. Still, it is easy to see tremendous human diversity that results from a diverse gene pool. This diversity explains why certain groups of people with similar kinds of genes are more prone to some disorders, whereas others have resistance to the same disorders. This diversity protects the human race from being wiped out by a single kind of medical problem.

[See also Birth defects; Cancer; Chromosome; Embryo and embryonic development; Gene; Genetic engineering; Human Genome Project; Mendelian laws of inheritance; Mutation; Nucleic acid ]

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