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Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 1 - A-L - I

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Asthma

antibody composed of a large Y-shaped protein molecule. The immune system produces this antibody in response to the presence of foreign substances—aller- gens—such as dust mites or pet hair. IgE is made by the plasma cells of the immune system. It is the key culprit in the process that creates the symptoms of asthma. IgE plays a critical role in initiating the inflammation of the respiratory tract, which is a primary cause of asthma attacks. A research study suggests that asthmatic patients produce higher levels of IgE antibodies in response to allergens such as house dust mites than do people without asthma.

A possible explanation for this overproduction of IgE antibodies could be related to a lack of exposure to common childhood illnesses. For example, cold viruses and other respiratory illnesses stimulate the human immune system to produce a certain type of helper T cell that specifically targets these disease agents. However, in the absence of such stimuli, the immune system instead produces another type of helper T cell that initiates the production of the IgE antibody.

IgE antibodies coat the surfaces of mast cells and white blood cells, called basophils, which are part of the immune system. The base of the Y of the IgE molecules attach to basophils in the blood and to mast cells, which are found in the connective tissue of the lungs, skin, tongue, and lining of the nose. Mast cells are sentries that rapidly react to the presence of antigens that trigger acute asthmatic incidents.

Some of the foreign antigens entering the respiratory airways will become attached to the extended arms of IgE molecules on the surface of the mast cells. This combination of antigen and antibody triggers these cells to release histamines and other substances into nearby tissues. Histamines are a type of chemical signal that initiates the inflammatory response, one of the primary symptoms of asthma. Inflammation involves increased blood flow to affected tissues. Histamines stimulate the dilation—widening—of the walls of blood vessels and make them more porous so that more blood fluid and proteins leak out of the blood vessels and into surrounding tissue, causing the swelling and reddening typical of inflammation. This inflammation, along with the constriction of the muscles in walls of the bronchial airways, narrows the air passages and makes breathing more difficult. These changes are what is referred to as an asthma attack.

Other studies have also suggested that the genes that are responsible for making the bronchial passageways “over reactive” (increasing the tendency of constricting or narrowing) in asthmatic patients are quite distinct from the genes that regulate the action of the immune system.

Recent genetic research may result in some major changes in our understanding of the role of specific genes in asthma. British scientists have tentatively identified a single gene that could be responsible for as many as 40–50% of all asthma cases. The U.K. scientists also suggest that four other genes may also play a significant role in the development of asthma. It is generally believed that some genes may simply enhance—magnify or rein- force—the action of other genes that are primarily responsible for triggering asthma. This task of unraveling the genetics of asthma is made more complicated by the variety of ways in which these genes can interact in different people.

Demographics

United States statistics

Asthma is the most prevalent childhood chronic disease. According to the Centers for Disease Control, approximately 17 million Americans exhibit symptoms of asthma—about five million of those are under the age of 18. More than 50% of asthma cases occur in children between two and 17 years of age. At a younger age, studies indicate that boys are twice as likely to develop asthma than girls. But this imbalance disappears in older age groups.

Asthma is the primary cause of school absenteeism. Asthma is also one of the most prevalent diseases in the workplace. Asthma accounts for approximately three million lost work days for adults and 10.1 million lost school days for children each year in the United States.

According to a recent American Lung Association report, double the number of adult female patients require emergency medical care for their asthma than do adult male patients. It is thought that the differences in male and female hormones may cause this disparity.

In the United States, the mortality rate—number of deaths—attributed to asthma increased 56% from 1979 to 1998. Asthma kills more than 5,000 Americans each year. Doctors believe that most of these fatalities could have been prevented with proper care and treatment.

In general, it is difficult to pinpoint the precise causes of the dramatic increase in asthma cases in the United States. One important factor may be partly due to poor diagnosis and management of individual cases of asthma, especially in less privileged or minority populations. However, after many years of rapid increases in asthma cases, some of the most recent evidence suggests that the number of asthma cases may actually be declining slightly. Further studies will be needed to confirm this trend.

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International statistics

Asthma has been described as the fastest growing chronic disease and a world-wide epidemic. Approximately 25,000 children die of asthma each year throughout the world. According to Global Initiative for Asthma (GINA), a world-wide asthma research and education program, there are over 150 million asthmatic individuals worldwide. In most countries, asthmatic cases are increasing 20–50% every decade. Every ten years, asthma claims over one million lives. Some studies have revealed a 75% increase in asthma cases between 1980 and 1994 globally. Children accounted for the greatest increase in numbers.

It is interesting to note that the incidence of asthma varies greatly throughout the world. While about 2% of children in China display symptoms of asthma, approximately 30% of young people in Britain have indications of this disease. In Australia, the incidence of asthma is very high in Caucasian children, but much lower in Aboriginal children.

Why such variations exist in the prevalence of asthma in different populations remains an unsolved mystery. Some scientists speculate that lifestyle factors, such as a lack of physical activity, increased obesity, and more time spent indoors may contribute to higher rates of asthma in more highly developed countries. It is also possible that environmental irritants such as poor indoor and outdoor air quality, along with the presence of potent irritants such as cockroach allergens, may contribute to higher rates of childhood asthma in poorer communities. Other factors that may prompt the onset of asthma are viral respiratory infections, low birth weight, and smaller than average air passageways in asthmatic patients.

Another area of research concerns the connection between common childhood infections and asthma. Many studies have shown that children who are exposed to viruses that cause the common cold and other respiratory infections at a very young age are less likely to develop asthma than their peers living in a more “hygienic” environment. So children living at home with older siblings and those who spend part of their week in daycare centers may be less likely to develop asthma than children who do not interact with others of their own age group.

A related factor could be the overuse of antibiotics. The frequent use of antibiotic medications to treat relatively minor infections may produce changes in a patient’s immune system that may increase his or her chance of developing asthma at some point later in life.

A young girl is using an inhaler to facilitate breathing.

(Custom Medical Stock Photo, Inc.)

Other studies have documented higher rates of childhood asthma in some less advantaged, minority inner city populations in the United States than in wealthier suburban communities. In these populations, exposure to cockroach allergens may be the major culprit.

Personalities with asthma

The symptoms of asthma have been observed and recorded in the medical literature since the time of Hippocrates, a famous doctor living in ancient Grecian times. The National Library of Medicine-Breath of Life Exhibit identifies many well known personalities who had a medical history of asthma. Despite their illness, they pursued their chosen professions with great vigor and energy. The prolific American musician, Leonard Bernstein, who composed West Side Story as well as many other celebrated scores, struggled with asthma throughout his life. Another classical composer from a much earlier era, Ludwig von Beethoven, wrote some of history’s most memorable music while coping with chronic asthma and without the benefit of modern medical treatment. Robert Joffrey, founder of the avant-garde Joffrey Ballet, pursued an active dancing career in spite of his asthma. Contemporary individuals with asthma include the folk singer Judy Collins, track and field champion Jackie Joyner-Kersee, and professional basketball star Dennis Rodman.

John Kennedy, 35th president of the United States, developed asthma from allergies to dogs, horses, and other animals. Some of his predecessors, including Theodore Roosevelt, Woodrow Wilson, and Calvin Coolidge, also had asthma.

Signs and symptoms

The symptoms experienced by patients with asthma are caused by “hyper responsiveness”—an overly sensi-

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tive response—of the body’s immune system to environmental or behavioral factors, such as allergies and exercise. Asthma patients are encouraged to learn to recognize their own special pattern of early warning signs that signal the start of an asthma episode. Asthma symptoms can be quite variable and are usually reversible. It is possible to classify individual cases of asthma as mild, moderate, or severe. Classification is based on the severity and frequency at which symptoms are experienced. The typical characteristics of each category are:

Mild persistent asthma

Children who experience symptoms of wheezing, coughing, or breathing difficulty less than once a day but more than twice a week.

Moderate asthma

Patients who experience asthma symptoms each day and require daily medication. Symptoms may persist for many days and may interfere with normal physical activity.

Severe asthma

Patients with severe asthma have ongoing, persistent symptoms of this disease. Severe attacks are rare, but much more serious, and can be life threatening.

Asthma episodes can vary from mild to severe attacks. The first signs of a mild or moderate attack could be a slight tightening of the chest, coughing, and spitting up of mucus. The patient may start wheezing as a result of trying to inhale and exhale through constricted air passageways.

Severe attacks can bring on a feeling of extreme tightening of the neck and chest, making breathing increasingly difficult. Patients may struggle to speak or breathe. In advanced stages of severe attacks, lips and fingernails may take on a grayish or bluish tinge indicating declining oxygen levels in the blood. Such attacks can be fatal in the absence of prompt medical attention.

Diagnosis

Medical diagnosis for asthma involves a complete physical checkup. One of the most important tests is the measurement of pulmonary (lung) function—the volume of air a patient can inhale (breathe in) and exhale (breathe out). Peak flow meters and spirometers are devices that are used to measure breathing efficiency and lung capacity.

The patient’s history can also provide critical clues that can confirm a diagnosis of asthma and can help to

identify the factors that contributed to the development of the disease. Doctors need to know about any patterns in the occurrence of symptoms (such as seasonal variations), when asthma symptoms first appeared, any connection between symptoms and exposure to possible allergens, any disturbances in sleep patterns, and the nature of previous illnesses. Other diagnostic tests may include x rays to eliminate other possible causes of airway obstruction (blockage) and allergy tests. Various blood tests may also be performed.

Early clues that indicate a patient may have asthma include difficulty in breathing, restlessness or persistent coughing while sleeping, general feeling of tiredness and lack of energy, a persistent stuffy nose, and frequent sneezing. Other signs are coughing or wheezing during or after physical activity and frequent colds that often involve chest congestion. Asthmatic patients are also more likely to develop other respiratory diseases such as pneumonia.

Asthma triggers

Asthmatic patients are surrounded by an environmental minefield. Many indoor and outdoor factors can trigger or initiate typical symptoms of asthma, including allergies, viral respiratory infections, weather changes, and exercise. Medications containing aspirin also act as an asthma trigger in about 10–20% of adult asthmatic patients. Allergens, such as inhaled dust particles and plant pollen, are substances that can stimulate an allergic response.

Asthma and allergies

Many studies have confirmed that allergies cause the greatest majority of childhood asthma cases. Doctors refer to cases of asthma that are caused by allergies as atopic asthma. Atopic asthma is the most common form of asthma and tends to run in families. It is an inherited over reaction—hypersensitivity—to allergens in the environment and the related overproduction of IgE antibodies by the human immune system. Antibodies produced by the immune system combine with allergens. This action stimulates an asthma attack, in which the immune system releases substances that bring on the constriction and inflammation of the airways of the lungs.

More than 80% of asthmatic patients also suffer from allergies such as hay fever. The medical term for hay fever is allergic rhinitis. Allergic rhinitis is the most common cause of atopic asthma. Many types of allergens can trigger the immune system to produce the typical hay fever symptoms that mainly affect the nasal region, such as stuffiness and a runny nose. The term “hay fever” does not accurately describe this problem, because it is rarely

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caused by hay and does not produce a fever in affected patients. Allergies even aggravate asthma in patients whose asthma was not originally caused by allergic factors. Small amounts of inhaled or swallowed allergens do not directly harm the tissues of the airways and lungs. However, they unfortunately act as triggers that set off the chain of events in the immune system that produce the symptoms typical of asthma.

People with asthma have increased sensitivity to allergens in the air they breathe in. Allergies are the human immune system’s reaction to biological triggers— including indoor allergens such as dust mites, animal dander (pet hair or feathers), saliva, flakes of skin, secretions from pets and insects, mold, and substances found in food. Even “hairless” dogs can be a problem for asthmatic patients. Some foods, such as peanut, dairy products, and seafood, can cause attacks in some asthmatic children. Food additives, such as sulfites, and even natural foods like eggs, shellfish, and raw vegetables can act as triggers for asthma. Endotoxins, which are chemicals produced by molds growing on farm products, may contribute to asthma in agricultural areas. Synthetic (manmade) products like the latex material used in surgical gloves can also trigger asthma episodes.

In some of the more “developed” countries, an important contributing factor in the growing number of atopic asthma cases may be the reduced exposure to common childhood respiratory infections such as the flu and colds. Recent studies have shown that children who live in very clean, hygienic conditions and are relatively isolated from other young people are more likely to develop asthma later in life. This is commonly referred to as the “hygiene theory.” It seems that children with older siblings and who attend day care programs where they may contract such illnesses have a lower risk for developing asthma. A possible explanation for this seemingly strange connection is that a child’s immune system is fine tuned, or conditioned, by contact with these infectious organisms and other foreign agents at a very young age.

Non-allergic factors

Non-allergic factors that can stimulate or aggravate asthma symptoms include tobacco smoke, chalk dust and talcum powder, cooking fumes, and fumes from chemicals such as household cleaners. Certain behaviors such as stress and emotional anxiety can also trigger asthmatic attacks. Young children can develop asthma or cause asthmatic episodes as a result of viral infections such as colds, flu, and pneumonia.

Exercise is a common trigger for asthma in about 80% of asthmatic individuals. In some asthmatic patients, exercise induces typical asthma symptoms such as

coughing, wheezing, and shortness of breath. Symptoms may appear during or after participation in physical activity. Pretreatment medications, such as short-acting bronchiodilators, quickly widen the air passages and thus help prevent the onset of asthma while a patient participates in physical activities. Some doctors advise their asthmatic patients to participate in sports like baseball or football that provide frequent breaks in activity rather than prolonged endurance sports such as swimming and long distance running.

Asthma does not have to be a barrier to participating in athletic activities. For example, 67 of the 596 members of the United States team at the 1984 Olympics tested positive for exercise-induced asthma, and that team won 41 Olympic medals. In addition, another survey revealed that 50% of the athletes participating in the 1996 Olympics displayed some form of asthmatic symptoms.

Changes in the weather, such as temperature and humidity variations can also negatively affect asthma patients. Winter is a tough time for people with asthma. They have difficulty in conditioning—warming up and humidifying—the air they breathe in. Some people with asthma wear a surgical mask that can trap warm, moist air that is exhaled with each breath. During cold weather, these individuals tend to spend more time indoors where they are more likely to catch contagious viral infections. Viral infections of the respiratory system are more likely to trigger severe asthmatic attacks during the winter months. In addition, unclean and poorly maintained forced air heating systems release many pollutants that further aggravate asthmatic symptoms.

Some remedies that could improve the quality of life for patients with asthma may also benefit the entire community in which they live. One study provides more evidence for a link between air pollution and asthma. During the 1996 Olympics, there were 42% fewer emergency hospital visits for treatment of severe asthma attacks in the Atlanta area. It is thought that this decline was linked to a sharp, but temporary, reduction in auto pollution caused by more people taking public transit instead of driving their cars during the two week event. So, cutting down on traffic congestion may help asthma patients breathe easier.

Every asthma patient is unique. Because there are so many environmental conditions that can affect people with the genetic predisposition for asthma, it is often difficult to pinpoint the primary cause of the disease in individual cases.

Treatment and management

Like all chronic diseases, asthma requires specialized medical care and attention. Doctors and other health

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professionals work in partnership with asthma patients to develop comprehensive, individualized management plans that help them cope with their asthma on a day to day basis. An effective management plan can reduce the incidence of serious asthma attacks and the need for emergency medical care. The key features of an asthma management plan include:

learning about early warning signs and symptoms of asthma

regular monitoring and recording of the appearance of asthma-related symptoms

monitoring lung function

learning how to use prescribed medications

avoiding activities, such as prolonged exercise, that can trigger an asthma attack

avoiding contact with possible environmental triggers, such as pets, allergens, tobacco smoke, etc.

maintaining healthy lifestyle by controlling weight gain, salt intake, blood pressure, and blood cholesterol levels

Specific goals of asthma management programs include:

controlling and minimizing chronic symptoms such as coughing and breathlessness early in the morning, at night, and after exercise

achieving healthy pulmonary (lung) function as much as possible

requiring the smallest possible dosage of medicine required to effectively control asthma symptoms, so that side effects from medications can be minimized

With the newer, more effective medications now available, it is possible to provide patients with good short term and long term control of asthmatic symptoms. Asthma patients use both rescue medications and controllers, which provide long-term control of asthma symptoms. Most asthma patients take their asthma medicine with the aid of metered-dose inhalers. These handheld devices deliver precise dosages of medication in the form of a pressurized spray that is inhaled orally by the user. Another device that delivers medication in sprayform are “nebulizers,” which are sometimes used by younger children and hospitalized patients who are unable to properly manipulate inhalers.

Rescue medications include bronchodilators, which provide short term, rapid relief from the symptoms of an asthma attack after it has started. These medications act by relaxing the circular muscles in the bronchial tubes that connect to the lungs. As the muscles relax, the air ways become wider, making breathing easier. Broncho-

dilators alleviate or reduce the feeling of tightness in lungs due to inflammation.

Controllers such as corticosteroids are anti-inflam- matory medications that help prevent asthma attacks from happening. They help to prevent or reduce the onset of typical asthma symptoms that interfere with normal breathing, such as the build-up of mucus and the inflammation of the tissues that line the airways and lungs. Most anti-inflammatory drugs work by suppressing or interfering with the action of histamines after they have been released by cells of the immune system. Corticosteroids are often taken twice daily. They provide prolonged relief and help reduce long-term damage to the lungs.

Bronchodilators and corticosteroids are the principle medications for the treatment and management of persistent asthma symptoms. Patients can also monitor the function of the their respiratory system with the aid of peak flow meters and spirometers. These devices measure the amount of air exhaled with each breath. They are used to regularly monitor the severity of asthma symptoms and to evaluate and manage treatment procedures for individual patients.

Emergency treatment

Emergency care in a hospital setting includes treating patients with bronchodilators and corticosteroids. Asthma attacks reach the life-threatening stage when the patient’s airway continues to constrict—referred to as airflow obstruction—and breathing becomes weaker and weaker. In critical cases, additional medications and oxygen may be administered in an attempt to restore normal respiratory activity. Delayed access to emergency treatment can lead to complete respiratory failure—the patient simply stops breathing and cannot be revived.

Under diagnosis

Unfortunately, many asthmatic children receive inadequate treatment and access to asthma medications. One survey reported that less than 40% of children had regular access to controller medications. In this group there was a clear over-dependence on rescue medications. This under-treated population required more frequent emergency hospital visits than those patients who were on a well-managed program. Under diagnosis and poor treatment are also major causes of mortality, or death, due to asthma.

Health providers advise coaches and other sporting officials to be more aware of emergency treatments, such as dealing with asthmatic attacks, that may be required for asthmatic students participating in sporting activities.

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Allergy shots

Allergy shots, also known as allergen immunotherapy, are recommended for people who suffer from atopic asthma when their daily routine makes it difficult for them to avoid contact with suspect allergens, such as dust mites, pet dander, and grass pollen. A series of shots with gradually increasing amounts of allergen may be given over a number of months or even years. The shots are actually vaccines containing various allergens, such as pollen or dust mites. This increased exposure to the allergen seems to desensitize the body’s immune system to these allergy triggers. Allergy shots can diminish the severity of asthma symptoms and also lower the dosages of other asthma medications that patients must take to keep their asthma under control.

In more detail, research studies suggest that allergy shots work by modifying the behavior of the important Th1 and Th2 cells of the immune system. Immunotherapy might activate Th1 cells (which produce “normal” immune responses) and depress the activity of Th2 cells, which release substances that stimulate plasma cells to make the IgE antibody.

Medical research and experimental treatments

A new experimental procedure involves injecting “anti-IgE” substances that combine with IgE in the blood. This prevents IgE from stimulating the release of histamine from mast cells. It is hoped that anti-IgE treatments would reduce the amount of corticosteroid use by asthmatic patients. So far, this form of treatment provides only temporary relief and scientists are actively searching for more effective anti-IgE medications.

Future research may lead to the development of genetic screening tests that can identify children who may be at risk for developing asthma. Such at-risk children could then be placed in early intervention programs that would be designed to help them avoid specific situations that could set off their immune systems and produce typical asthma symptoms.

A number of major gene therapy research projects are now focusing on developing new techniques for controlling the activity of genes involved in producing symptoms of asthma. Researchers want to figure out how to shut off or reduce the intensity of typical symptoms of asthma without impairing normal body function.

Currently, no cure exists for asthma. However, medical research is continuing its quest to gain a better understanding of the physiological and genetic basis of asthma. New medications are providing more effective long term and short term control of asthma symptoms.

Resources

BOOKS

Berger, William E. Allergies and Asthma for Dummies. IDG Books Worldwide, 2000.

Brynie, Faith Hickman. 101 Questions About Your Immune System You Felt Defenseless to Answer . . . Until Now.

Twenty-First Century Books, 2000.

DeSalvo, Louise A. Breathless: An Asthma Journal. Beacon

Press, 1997.

Peacock, Judith. Asthma. LifeMatters, 2000.

Simpson, Carolyn. Everything You Need To Know About Asthma. First edition. Rosen Pub. Group, 1998.

Sompayrac, Lauren. How The Immune System Works.

Blackwell Science, 1999.

Welch, Michael J. American Academy of Pediatrics Guide to Your Child’s Allergies and Asthma: Breathing Easy and Bringing Up Healthy Active Children. Villard Books, 2000.

PERIODICALS

“Asthmatic Youngsters May Not Get Optimal Therapy.” Journal of Allergy and Clinical Immunology 106 (2000): 1108–1114.

“Asthma in the Workplace.” Book review. The New England Journal of Medicine 342 (April 13, 2000): 15.

Borish, Larry. “Genetics of allergy and asthma.” Annals of Allergy 82 (May 1999): 413.

“Clearing the Air: Asthma and Indoor Air Exposures.” Book review. The New England Journal of Medicine 343 (December 14, 2000): 24.

“Day Care, Siblings, and Asthma—Please, Sneeze on My Child.” The New England Journal of Medicine 343 (August 24, 2000): 8.

Folkerts, Gert, Gerhard Walzl, and Peter J.M. Openshaw. “Do common childhood infections ‘teach’ the immune system not to be allergic?” Immunology Today 21, no. 3 (2000): 118–120.

Gergen, Peter J. “Remembering the Patient.” Archives of

Pediatrics & Adolescent Medicine (American Medical Association) 154 (October 2000): 10.

Herz, Udo, Paige Lacy, Harald Renz, and Klaus Erb. “The influence of infections on the development and severity of allergic disorders.” Current Opinion in Immunology 12, no. 6 (2000): 632–640.

“Health: A Breath of Hope.” Berkeley Lab research review 23 (Fall 2000): 3.

Illi, S., E. von Mutius, S. Lau, R. Bergmann, B. Niggemann, C. Sommerfeld, and U. Wahn. “Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study.” British Medical Journal 322 (February 17, 2001): 390–395.

Johnston, Sebastian L., and Peter J. M. Openshaw. “The protective effect of childhood infections—The next challenge is to mimic safely this protection against allergy and asthma.” British Medical Journal 322 (February 17, 2001): 376–377.

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O’Callaghan C., and P.W. Barry. “Asthma drug delivery devices for children.” British Medical Journal 320 (March 11, 2000): 7236-664.

“Program and Abstracts from the AAAAI 57th Annual Meeting: March 16–March 21, 2001.” The Journal of Allergy and Clinical Immunology 107 (February 2001, part 2): 2.

“Siblings, Day-Care Attendance, and the Risk of Asthma and Wheezing.” The New England Journal of Medicine 343, no. 26 (December 28, 2000).

“Treatment of Allergic Asthma with Monoclonal Anti-IgE Antibody.” The New England Journal of Medicine 342 (April 27, 2000): 17.

Walker, Christoph, and Claudia Zuany-Amorim. “New trends in immunotherapy to prevent atopic diseases.” Review.

Trends in Pharmacological Sciences 22, no. 2 (2001): 84–90.

ORGANIZATIONS

Allergy and Asthma Network. Mothers of Asthmatics, Inc. 2751 Prosperity Ave., Suite 150, Fairfax, VA 22031. (800) 878-4403. Fax: (703) 573-7794.

American Academy of Allergy, Asthma & Immunology. 611 E. Wells St., Milwaukee, WI 53202. (414) 272-6071. Fax: (414) 272-6070. http://www.aaaai.org/default.stm .

American Lung Association. 1740 Broadway, New York, NY 10019. (212) 315-8700 or (800) 586-4872. http://www

.lungusa.org .

Asthma and Allergy Foundation of America (AAFA). 1233 20th St. NW, Suite 402, Washington, DC 20036. (800) 7-ASTHMA. Fax: (202) 466-8940. http://www.aafa.org .

Division of Lung Diseases, National Heart, Lung and Blood Institute. Suite 10122, 6701 Rockledge Dr. MSC 7952, Bethesda, MD 20892-7952. (301) 435-0233. http://www

.nhlbi.nih.gov/index.htm .

Global Initiative for Asthma. Prof. Tim Clark, Chairman of GINA, 0207-594-5008 Fax: (207) 594-8802. shurd @prodigy.net. http://www.ginasthma.com .

KidsHealth. Nemours Center for Children’s Health Media. PO Box 269, Wilmington, DE 19899. http://www.kidshealth

.org/teen/health_problems/diseases/asthma.html . National Asthma Education and Prevention Program (NAEPP).

School Asthma Education Subcommittee, http://www

.nih.gov/health/asthma/index.htm .

National Center for Environmental Health. Centers for Disease Control and Prevention, Mail Stop F-29, 4770 Buford Highway NE, Atlanta, GA 30341-3724. http://www.cdc

.gov/nceh/asthma/default.htm .

National Institutes of Health (NIH). PO Box 5801, Bethesda, MD 20824. (800) 352-9424. http://www.ninds.nih.gov/ health .

Pew Environmental Health Commission at the Johns Hopkins School of Public Health. 111 Market Place, Suite 850, Baltimore, MD 21202. (410) 659-2690. http://pewenvirohealth

.jhsph.edu/html/reports/PEHCAsthmaReport.pdf .

OTHER

Attack asthma: Why America Needs a Public Health Defense System to Battle Environmental Threats. http:// pewenvirohealth.jhsph.edu/html/reports/PEHCAsthma Report.pdf .

Breath of Life Exhibition. National Library of Medicine.http://www.nlm.nih.gov/hmd/breath/breath_exhibit/ mainframe.html .

Becker, Jack Michael, M.D. Genetics of asthma. October 25, 2000. DNA Sciences, Inc. http://www.dna.com/ .

“What Makes Asthma Worse?” medfacts 2000. Lung Line, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. Phone: 303-388-4461 (7700).http://www.nationaljewish.org/medfacts/worse.html .

Marshall G. Letcher, MA

I Ataxia-telangiectasia

Definition

Ataxia-telangiectasia (A-T) is a rare, genetic neurological disorder that progressively affects various systems in the body. Children affected with A-T appear normal at birth; however, the first signs of the disease— usually a lack of balance and slurred speech—often appear between one and two years of age.

Description

The onset of cerebellar ataxia (unsteadiness and lack of coordination) marks the beginning of progressive degeneration of the cerebellum, the part of the brain responsible for motor control (movement). This degeneration gradually leads to a general lack of muscle control, and eventually confines the patient to a wheelchair. Children with A-T become unable to feed or dress themselves without assistance. Because of the worsening ataxia, children with A-T lose their ability to write, and speech also becomes slowed and slurred. Even reading eventually becomes impossible, as eye movements become difficult to control.

Soon after the onset of the ataxia, an individual usually exhibits another symptom of the disease: telangiectases, or tiny red spider veins (dilated blood vessels). These telangiectases appear in the corners of the eyes— giving the eyes a blood-shot appearance—or on the surfaces of the ears and cheeks exposed to sunlight.

In about 70% of children with A-T, another symptom of the disease is present: an immune system deficiency that usually leads to recurrent respiratory infections. In many patients, these infections can become life threatening. Due to deficient levels of IgA and IgE immunoglob- ulins—the natural infection-fighting agents in the

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blood—children with A-T are highly susceptible to lung infections that are resistant to the standard antibiotic treatment. For these patients, the combination of a weakened immune system and progressive ataxia can ultimately lead to pneumonia as a cause of death.

Children with A-T tend to develop malignancies of the blood circulatory system almost 1,000 times more frequently than the general population. Lymphomas (malignant tumors of lymphoid tissues) and leukemias (abnormal overgrowth of white blood cells, causing tumor cells to grow) are particularly common types of cancer, although the risk of developing most types of cancer is high in those with A-T. Another characteristic of the disease is an increased sensitivity to ionizing radiation (high-energy radiation such as x rays), which means that patients with A-T frequently cannot tolerate the radiation treatments often given to cancer patients.

Genetic profile

Ataxia-telangiectasia is called a recessive genetic disorder because parents do not exhibit symptoms; however, each parent carries a recessive (unexpressed) gene that may cause A-T in offspring. The genetic path of A-T is therefore impossible to predict. The recessive gene may lie dormant for generations until two people with the defective gene have children. When two such A-T carriers have a child together, there is a 1-in-4 chance (25% risk) of having a child with A-T. Every healthy sibling of a child with A-T has a 2-in-3 chance (66% risk) of being a carrier, like his or her parents.

The A-T gene (called ATM, or A-T Mutated) was discovered by Tel Aviv researchers in 1995. The ATM protein is thought to prevent damaged DNA from being reproduced. However, the cells of patients with A-T lack the ATM protein, although the cells of those with the mild form of the disorder contain small amounts of it. It is thought that ATM is involved in sending messages to several other regulating proteins in the body. The absence of ATM severely disrupts the transmission of these messages, thereby affecting many different systems of the body.

Scientists have found that the ATM gene is often found with the p53 gene, which is defective in the majority of cancerous tumors. Tumor biologists, therefore, view A-T as one of the most explicit human models for studying inherited cancer susceptibility. In children who have A-T, the defective A-T gene blocks the normal development of the thymus, the organ most important for the development of the immune response. Understanding how immunodeficiencies develop in children with A-T may have relevance to research on other immunodeficiency disorders.

Demographics

Both males and females are equally affected by A-T. Epidemiologists estimate the frequency of A-T as

K E Y T E R M S

Alpha-fetoprotein (AFP)—A chemical substance produced by the fetus and found in the fetal circulation. AFP is also found in abnormally high concentrations in most patients with primary liver cancer.

Atrophy—Wasting away of normal tissue or an organ due to degeneration of the cells.

Cerebellar ataxia—Unsteadiness and lack of coordination caused by a progressive degeneration of the part of the brain known as the cerebellum.

Dysarthria—Slurred speech.

Dysplasia—The abnormal growth or development of a tissue or organ.

Immunoglobulin—A protein molecule formed by mature B cells in response to foreign proteins in the body; the building blocks for antibodies.

Ionizing radiation—High-energy radiation such as that produced by x rays.

Leukemia—Cancer of the blood forming organs which results in an overproduction of white blood cells.

Lymphoma—A malignant tumor of the lymph nodes.

Recessive gene—A type of gene that is not expressed as a trait unless inherited by both parents.

Telangiectasis—Very small arteriovenous malformations, or connections between the arteries and veins. The result is small red spots on the skin known as “spider veins”.

between 1/40,000 and 1/100,000 live births. However, it is believed that many children with A-T, particularly those who die at a young age, are never properly diagnosed. Thus, the disease may occur much more often than reported.

It is also estimated that about 1% (2.5 million) of the American population carry a copy of the defective A-T gene. According to some researchers, these gene carriers may also have an increased sensitivity to ionizing radiation and have a significantly higher risk of developing cancer—particularly breast cancer in female carriers.

Signs and symptoms

Although there is much variability in A-T symptoms among patients, the signs of A-T almost always include the appearance of ataxia between the ages of two and

telangiectasia-Ataxia

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five. Other, less consistent symptoms may include neurological, cutaneous (skin), and a variety of other conditions.

Neurological

Neurological symptoms of A-T include:

Progressive cerebellar ataxia (although ataxia may appear static between the ages of two and five)

Cerebellar dysarthria (slurred speech)

Difficulty swallowing, causing choking and drooling

Progressive apraxia (lack of control) of eye movements

Muscle weakness and poor reflexes

Initially normal intelligence, sometimes with later regression to mildly retarded range

Cutaneous

Cutaneous symptoms include:

Progressive telangiectases of the eye and skin develop between two to ten years of age

Atopic dermatitis (itchy skin)

Café au lait spots (pale brown areas of skin)

Cutaneous atrophy (wasting away)

Hypoand hyperpigmentation (underpigmented and overpigmented areas of skin)

Loss of skin elasticity

Nummular eczema (coin-shaped inflammatory skin condition)

Other symptoms

Other manifestations of A-T include:

Susceptibility to neoplasms (tumors or growths)

Endocrine abnormalities

Tendency to develop insulin-resistant diabetes in adolescence

Recurrent sinopulmonary infection (involving the sinuses and the airways of the lungs)

Characteristic loss of facial muscle tone

Absence or dysplasia (abnormal development of tissue) of thymus gland

Jerky, involuntary movements

Slowed growth

Prematurely graying hair

Diagnosis

For a doctor who is familiar with A-T, the diagnosis can usually be made on purely clinical grounds and often on inspection. But because most physicians have never

seen a case of A-T, misdiagnoses are likely to occur. For example, physicians examining ataxic children frequently rule out A-T if telangiectases are not observed. However, telangiectases often do not appear until the age of six, and sometimes appear at a much older age. In addition, a history of recurrent sinopulmonary infections might increase suspicion of A-T, but about 30% of patients with A-T exhibit no immune system deficiencies.

The most common early misdiagnosis is that of static encephalopathy—a brain dysfunction, or ataxic cerebral palsy—paralysis due to a birth defect. Ataxia involving the trunk and gait is almost always the presenting symptom of A-T. And although this ataxia is slowly and steadily progressive, it may be compensated for— and masked—by the normal development of motor skills between the ages of two and five. Thus, until the progression of the disease becomes apparent, clinical diagnosis may be imprecise or inaccurate unless the patient has an affected sibling.

Once disease progression becomes apparent, Friedreich ataxia (a degenerative disease of the spinal cord) becomes the most common misdiagnosis. However, Friedreich ataxia usually has a later onset. In addition, the spinal signs involving posterior and lateral columns along the positive Romberg’s sign (inability to maintain balance when the eyes are shut and feet are close together) distinguish this type of spinal ataxia from the cerebellar ataxia of A-T.

Distinguishing A-T from other disorders (differential diagnosis) is ultimately made on the basis of laboratory tests. The most consistent laboratory marker of A-T is an elevated level of serum alpha-fetoprotein (a protein that stimulates the production of antibodies) after the age of two years. Prenatal diagnosis is possible through the measurement of alpha-fetoprotein levels in amniotic fluid and the documentation of increased spontaneous chromosomal breakage of amniotic cell DNA. Diagnostic support may also be offered by a finding of low serum IgA, IgG and/or IgE. However, these immune system findings vary from patient to patient and are not abnormal in all individuals.

The presence of spontaneous chromosome breaks and rearrangements in lymphocytes in vitro (test tube) and in cultured skin fibroblasts (cells from which connective tissue is made) is also an important laboratory marker of A-T. And finally, reduced survival of lymphocyte (cells present in the blood and lymphatic tissues) and fibroblast cultures, after exposure to ionizing radiation, will confirm a diagnosis of A-T, although this technique is performed in specialized laboratories and is not routinely available to physicians.

When the mutated A-T gene (ATM) has been identified by researchers, it is possible to confirm a diagnosis by screening the patient’s DNA for mutations. However,

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in most cases the large size of the ATM gene and the large number of possible mutations in patients with A-T seriously limit the usefulness of mutation analysis as a diagnostic tool or method of carrier identification.

Treatment and management

There is no specific treatment for A-T because gene therapy has not become an option as of year 2000. Also, the disease is usually not diagnosed until the individual has developed health problems. Treatment is therefore focused on the observed conditions, especially if neoplams are present. However, radiation therapy must be minimized to avoid inducing further chromosomal damage and tumor growth.

Supportive therapy is available to reduce the symptoms of drooling, twitching, and ataxia, but individual responses to specific medications vary. The use of sunscreens to retard skin changes due to premature aging can be helpful. In addition, early use of pulmonary physiotherapy, physical therapy, and speech therapy is also important to minimize muscle contractures (shortening or tightening of muscles).

Although its use has not been formally tested, some researchers recommend the use of antioxidants (such as vitamin E) in patients with A-T. Antioxidants help to reduce oxidative damage to cells.

Prognosis

A-T is an incurable disease. Most children with A-T depend on wheelchairs by the age of ten because of a lack of muscle control. Children with A-T usually die from respiratory failure or cancer by their teens or early 20s. However, some patients with A-T may live into their 40s, although they are extremely rare.

Resources

BOOKS

Vogelstein, Bert, and Kenneth E. Kinzler. The Genetic Basis of Human Cancer. New York: McGraw-Hill, 1998.

PERIODICALS

Brownlee, Shanna. “Guilty Gene.” U.S. News and World Report. (July 3, 1995): 16.

Kum Kum, Khanna. “Cancer Risk and the ATM Gene.” Journal of the American Cancer Institute 92, no. 6 (May 17, 2000): 795–802.

Stankovic, Tatjana, and Peter Weber, et al. “Inactivation of Ataxia Tlangiectasia Mutated Gene in B-cell Chronic Lymphocytic Leukaemia.” Lancet 353 (January 2, 1999): 26–29.

Wang, Jean. “New Link in a Web of Human Genes.” Nature

405, no. 6785 (May 25, 2000): 404–405.

ORGANIZATIONS

A-T Children’s Project. 668 South Military Trail, Deerfield Beach, FL 33442. (800) 5-HELP-A-T. http://www.atcp

.org .

A-T Medical Research Foundation. 5241 Round Meadow Rd., Hidden Hills, CA 91302. http://pathnet.medsch.ucla

.edu/people/faculty/gatti/gatsign.htm .

National Ataxia Foundation. 2600 Fernbrook Lane, Suite 119, Minneapolis, MN 55447. (763) 553-0020. Fax: (763) 5530167. naf@ataxia.org. http://www.ataxia.org .

National Organization to Treat A-T. 4316 Ramsey Ave., Austin, TX 78756-3207. (877) TREAT-AT. http://www. treat-at

.org .

Genevieve T. Slomski, PhD

I Attention deficit hyperactivity disorder

Definition

Attention deficit hyperactivity disorder, or ADHD, is a behavioral disorder, characterized by poor attention, inability to focus on specific tasks, and excessive activity. ADHD is thought to have a strong genetic component, although studies are still ongoing to determine what role specific genes play in ADHD.

Description

Attention deficit hyperactivity disorder (ADHD) was first described by a pediatrician, Dr. George Still, in 1902. At the time, he gave an account of 43 children who exhibited such symptoms as aggressiveness, defiance, and limited attention spans. He stated that he felt these symptoms indicated a lack of “moral control” in these children and others exhibiting similar characteristics.

Until the 1950s, it was felt that the symptoms of ADHD were caused by either infections, toxins, or trauma to the head. During that time, ADHD was referred to as “minimal brain damage,” or minimal brain dysfunction.” In the 1960s and 1970s, when more was learned about brain functioning, scientists and doctors changed the name of the disorder to “hyperkinetic reaction to childhood” in response to the recognition of the prominent role of hyperactivity with the disorder. It was also during this time that the use of stimulants such as amphetamines began to be used to treat children diagnosed with the disorder. The term “attention deficit disorder,” and finally, attention deficit hyperactivity disorder, was applied to the disorder in the 1980s and 1990s.

From the time it was first clinically described by Dr. Still, the diagnosis of ADHD has included certain basic

disorder hyperactivity deficit Attention

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