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

Epilepsy

I Epilepsy

Definition

Epilepsy is a chronic (persistent) disorder of the nervous system. The primary symptoms of this disease are periodic or recurring seizures that are triggered by sudden episodes of abnormal electrical activity in the brain. The term “seizure” refers to any unusual body functions or activities that are under the control of the nervous system.

Description

The word epilepsy is derived from the Greek term for seizure. Seizures can involve a combination of sensations, muscle contractions, and other abnormal body functions. Seizures may appear spontaneously—without any apparent cause—or can be triggered by a specific type of stimulus such as a flashing light. Specific cases of epilepsy may result from known causes, such as brain injury, or may have no apparent cause (referred to as ideopathic epilepsy). Ideopathic epilepsy may be initiated by a combination of genetic and environmental factors.

An epileptic seizure involves a transient (temporary) episode of abnormal electrical activity in the brain. During a seizure, many nerve cells within a specific region of the brain may begin to fire at the same time. This activity may then spread out over other parts of the brain. In addition to abnormal physical symptoms, seizures can bring on emotions ranging from fear, anger, and rage, to joy or happiness. During a seizure, patients may experience disorientation, spontaneous sensations of sounds, smells, visions, and distorted visual perception— such as misshapen objects and places.

Epilepsy can be caused by some event or condition that results in damage to the brain such as strokes, tumors, abscesses, trauma (physical injury), or infections such as meningitis. Epilepsy can also be triggered by inherited (genetic) factors or some form of injury or trauma at birth. Epilepsy cases that seem to have no readily identifiable cause are referred to as “idiopathic” cases in medical terminology. Symptoms of this disease can appear at any age. Seizures can damage and destroy brain cells and scar tissue can develop in the section of brain tissue where seizures originate.

There are many forms of epileptic seizures. The parts of the body that are affected by a seizure and the distinctive characteristics, duration, and severity of the symptoms can distinguish each type of epilepsy. Patients can experience more than one type of seizure. The nature of the symptoms depends on where in the brain the

seizure originated and how much of the brain is involved. Seizures can be classified as either “generalized” or “partial”. Partial seizures involve abnormal activity in a specific region of the brain.

Generalized (also called tonic-clonic) seizures last about two minutes and are the result of abnormal electrical activity that spreads out over both sides or hemispheres of the brain. They were formerly referred to as grand mal seizures. The patient will usually lose consciousness and fall during the episode. The term “tonic” refers to the first phase of a generalized seizure in which the body muscles become taunt or stiff. This is followed by strong, rhythmic muscular contractions (convulsions) of the “clonic” phase. Sometimes a patient’s breathing may be hampered by a brief stoppage of the respiratory muscles, causing the skin to develop a bluish tinge due to lack of oxygen.

Epileptic seizures can also be classified as “complex” or “simple.” Complex seizures generally involve a loss of consciousness, whereas simple seizures do not. Simple partial seizures can begin as a localized (focal) seizure and then evolve into a “secondary generalized” episode in which the initial abnormal electrical activity spreads to involve other parts of the brain. Patients may actually remember the physical and psychological events that occur during a simple seizure, such as the types of movement, emotions, and sensations, but frequently are completely unaware of the event. Partial seizures are more common in adults.

An “absence seizure” (once called petit mal) typically results in brief periods of “lack of awareness” and some abnormal muscle movement. The patient generally remains conscious during the seizure episode, but may become absent-minded and unresponsive. They may also appear to be “starring”. Absence seizures last about 5–10 seconds.

How seizures affect a person’s memory depends where in the brain seizures occur. Seizures can interfere with learning, storage, and retrieval of new information. For example, a form of epilepsy that produces seizures in the temporal lobe of the brain can cause a serious deterioration (loss) of memory function. Early treatment can help prevent or reduce memory loss.

In some forms of epilepsy, seizures can be triggered by a particular mental—or cognitive—activity. For example, the simple activity of reading aloud can trigger a seizure in patients with reading epilepsy. Symptoms include face muscle spasms. In medical terms, this type of epilepsy is referred to as “idiopathic localizationrelated epilepsy”. This means that seizures occur in one part of the brain (in this case, the temporal lobes) and that there is no apparent cause that brought on the disease.

Genetic profile

Genetic factors contribute to about 40% of all epilepsy cases. Most of the generalized epilepsy syndromes and some of the partial epilepsy syndromes have an inherited component. Medical researchers suggest that at least 500 genes may somehow be involved in the development of various forms of epilepsy. It is believed that some of these genes can make people with epilepsy more susceptible or sensitive to environmental factors that initiate or start seizures. Only a few types of epilepsy are thought to be caused by just one type of gene.

Gene mutations can cause a variety of nervous system abnormalities that are associated with epilepsy. Different mutations may lead to abnormal brain development or progressive degeneration of brain tissue. Some gene mutations make nerve cells “hyperexcitable.” These abnormal nerve cells can trigger outbursts of abnormal patterns of electrical activity that can initiate an epileptic seizure.

Specific gene locations (called gene markers) have been linked to various forms of the disease, such as juvenile myoclonic epilepsy. However, researchers have discovered that some individuals who possess this gene do not develop symptoms of this disease. In some pairs of identical twins with this gene, one twin may appear normal while the other develops typical symptoms of epilepsy. Thus, genetic inheritance seems to be just one of many factors that influence the possibility of developing epilepsy symptoms.

Some genetic mutations may also reduce the effectiveness of antiepileptic medication. One of the major goals of epilepsy research is to determine how a patient’s genetic makeup can influence their drug therapy.

Demographics

Epilepsy affects about one percent of the population. Approximately 2.3 million Americans and 40 million people throughout the world have epilepsy. It is the sec- ond-most common neurological disorder. The highest incidence is in children under 10 and elderly over 70.

Signs and symptoms

Patients have little warning that they are about to experience an epileptic seizure. Some unusual feeling or “aura” which can act as a warning that an episode is about to start generally precedes actual seizures. An “aura” may take the form of an unusual sensation such as a fearful feeling, a mental image, or an unusual taste, smell, or sound. Some patients who do not experience seizures during the day or who have prolonged “auras” or

KEY TERMS

Convulsion—Involuntary contractions of body muscles that accompany a seizure episode.

Ideopathic—Of unknown origin.

Lesion—A defective or injured section or region of the brain (or other body organ).

Magnetic resonance imaging (MRI)—A technique that employs magnetic fields and radio waves to create detailed images of internal body structures and organs, including the brain.

Seizure—Any unusual body functions or activity that is under the control of the nervous system.

warnings of an impending seizure can be permitted to drive. Getting a good night’s sleep is a common problem for young children with epilepsy. Lack of sleep can then lead to behavior problems and constant drowsiness during the daytime. A stupor may follow a seizure.

Diagnosis

Early symptoms of epilepsy include excessive staring, easy distraction, and difficulty in maintaining attention. To confirm the diagnosis, doctors look for neurological (nervous system) abnormalities such as speech or vision defects, defects in brain structure or other parts of the nervous system. The goal of the diagnositic testing is to identify where the seizures are originating. EEGs (electroencephalographs) are used to monitor electric activity— patterns of nerve impulses in the brain. A type of “brain scan” called MRI is also used extensively to try to pinpoint the location and type of abnormalities (referred to as lesions) in brain structure, which cause episodes of epileptic seizures. Idiopathic epilepsy—those cases for which no specific cause can be identified—are presumed to have a genetic basis.

Treatment and management

Currently, no cure exists for epilepsy. However, a wide range of treatment programs are available that provide varying degrees of success in controlling the symptoms of epilepsy.

Medication is the most effective and widely used treatment for the symptoms of epilepsy. Most medications work by interfering with or stopping the abnormal electrical activity in nerve cells that cause seizures. This form of treatment is generally referred to as anticonvul-

Epilepsy

Epilepsy

sant therapy. Medication is considered effective if the patient is free of seizures for at least one year.

Anticonvulsants are powerful drugs that can produce a variety of side effects, including nausea, fatigue, dizziness, and weight change. They can also increase the risk of birth defects, especially involving the early stages of embryonic development of the nervous system if taken during pregnancy.

Doctors prefer to put their patients on just one type of anticonvulsant drug. Some patients, however, experience more effective relief from their epilepsy symptoms by taking a combination of two different but “complementary” forms of medication. The choice of medication depends on the type of seizure that affects a patient, the patient’s medical history—including response to other drug therapies, their age, and gender. For example, the drug Carbamazepine is one of the most effective medications and has little impact on important cognitive functions such as thinking, memory and learning.

Newer medications generally produce fewer side effects than their predecessors. Research into gene therapy may ultimately be the most effective form of epilepsy treatment, but is still in the very early stages.

Unfortunately, medication is ineffective for more than one third of known cases of epilepsy. More than 30% of patients with epilepsy cannot maintain adequate control of their seizures. Some genetic mutations may reduce the effectiveness of antiepileptic medications.

Surgery is recommended for some patients for whom medication cannot effectively control the frequency or severity of their seizures. Surgery is a treatment option only in extreme cases where doctors can identify the specific site in the brain where seizures originate. The most promising candidates for surgery are those with a single lesion on the temporal, frontal, or occipital lobes of the brain.

Prior to surgery, the patient must complete extensive testing to determine the precise patterns of seizures and to locate their point of origin in the brain. Patients spend extended stays in hospital during which their seizures are recorded on video and with the aid of EEGs. This machine records patterns of electrical activity in the brain using sensors (referred to as “electrodes”) attached to various parts of the body.

The surgical procedure involves the removal of a small part of brain tissue in the “suspected” region. The anterior temporal lobe and hippocampus are the most common areas in which tissue is removed. In some studies, more than 83% of patients become free of seizures following surgery. Ninety-seven percent show significant improvement in their condition.

Vagus Nerve Stimulation (VNS) is another form of treatment for some cases of epilepsy that are unresponsive (referred to as “refractory epilepsy”) to other forms of medical therapy. VNS may also be recommended for patients who cannot tolerate the side effects of medication. This procedure involves implanting a device that stimulates the Vagus nerve, located in the left side of the neck. In one study, this treatment reduced seizures by 78%.

A special dietary program is another treatment option for patients who are not good candidates for surgery or who have had little success with anticonvulsant medication. This form of treatment called the Ketogenic Diet can be effective for many types of epilepsy. It is most appropriate for young children whose parents can follow the rigid requirements of the diet. Older children and adults tend to have greater difficulty in sticking to the dietary rules for an extended period of time. The Ketogenic Diet is a stringent diet that is very high in fat, but low in proteins, carbohydrates, and calories. The excessive fat produces high levels of a substance called ketone (which the body makes when it breaks down fat for energy). Somehow these ketones help reduce the incidence of epileptic seizures. The success of this form of treatment varies. For some patients, the high fat diet is the best form of treatment. For others, the diet is less effective.

Resources

PERIODICALS

Berkovic, S.F., and I.E. Scheffer. “Genetics of the epilepsies.”

Current Opinion in Neurobiology 12, no. 2 (April 1999): 177–82.

Farooqui S., W. Boswell, J.M. Hemphill, and E. Pearlman. “Vagus nerve stimulation in pediatric patients with intractable epilepsy: case series and operative technique.” The American Surgeon 67, no. 2 (February 2001): 119–21.

Hirose S., M. Okada, S. Kaneko, and A. Mitsudome. “Are some idiopathic epilepsies disorders of ion channels?: A working hypothesis.” Epilepsy Research 41, no. 3 (Oct 2000): 191–204.

Kwan, Patrick, and Martin J. Brodie. “Early Identification of Refractory Epilepsy.” The New England Journal of Medicine 342, no. 5 (February 3, 2000).

ORGANIZATIONS

American Epilepsy Society, 342 North Main Street, West Hartford, Connecticut 06117. (860) 586-7505. <http://www. aesnet.org>.

Epilepsy Foundation. 4351 Garden City Drive, Landover, Maryland 20785. (800) 332-1000. <http://www.epilepsyfoundation.org>.

Epilepsy and Brain Mapping Program: Huntington Memorial Hospital. 10 Congress Street, Suite 505, Pasadena, California 91105. (800) 621-2102. e-mail: info@epipro.com, <http://www.epipro.com/meds.html>.

WEBSITES

“Seizures.” MayoClinic.com.http://www.mayohealth.org/home?id=SP3.1.4.7 .

“Surgical Treatment of Epilepsy.” G. Rees Cosgrove, M.D., F.R.C.S.(C) and Andrew J. Cole M.D., FRCP(C). Department of Neurosurgery, Massachusetts General Hospital. 15 Parkman St., ACC Suite # 331, Boston, MA 02114. (617) 724-0357. Fax: (617) 726-5546. cosgrove@helix.mgh.harvard.edu.

http://neurosurgery.mgh.harvard.edu/ep-sxtre.htm .

Marshall G. Letcher, MA

I Essential hypertension

Definition

Essential or primary hypertension, the most common form of hypertension, is elevated blood pressure that develops without apparent cause. Genetic factors, however, appear to play role in increasing the risk of developing the disorder.

Normal blood pressure refers to a range of values rather than a specific set of numbers and varies with factors such as age, race, and gender. However, a blood pressure reading greater than 140/90 mm Hg (millimeters of mercury pressure) is generally considered to be elevated. In this measurement, 140 refers to the systolic pressure (the maximum pressure in the arteries when the heart contracts). The 90 refers to the diastolic pressure (the lowest pressure in the arteries when the heart is between contractions).

Description

More than 95% of all elevated blood pressure can be classified as essential hypertension. When a disease, other physical problems, medications, or even temporary physical exertion or stress cause high blood pressure, the condition is called secondary hypertension.

Blood pressure refers to the force exerted by blood against the interior walls of the body’s blood vessels. There are three categories of blood pressure, corresponding to the three types of blood vessels: arterial, capillary, and venous. In individuals with hypertension, arterial pressure (recorded as two numbers: systolic and diastolic pressure) is the most important measurement to obtain. The reason is that because of their relative proximity to blood flowing forcefully from the heart, arteries must withstand the highest pressures of all the body’s blood vessels.

The body requires a relatively constant blood pressure level to ensure adequate passage of nutrients and oxygen to organs and tissues. To maintain a constant level of pressure, the body must balance and react to a number of factors such as these:

•volume of blood in the circulatory system

•amount of blood ejected by the heart (stroke volume

•heart rate

•thickness of the blood (viscosity

•elasticity of the arteries

When the systolic or diastolic pressure is elevated for an extended period of time, such as months or years, the heart has to work harder and may become damaged, along with the blood vessels. If it remains untreated, high blood pressure can lead to a variety of serious health problems, including heart disease, stroke, and kidney failure.

Genetic profile

Studies suggest that some people with essential hypertension may inherit abnormalities of the sympathetic nervous system—the part of the nervous system that controls heart rate, blood pressure, and the diameter of blood vessels. It is estimated that the risk of developing essential hypertension is increased twoto four-fold if one or both parents are diagnosed with the disorder.

Researchers have identified the chromosomes (11 and 18) that house the genes responsible for blood pressure regulation, although narrowing down the range of specific genes involved in hypertension is more difficult.

Genes under intense study are those that regulate a group of hormones known as the angiotensin-renin- aldosterone system. This system influences all aspects of blood pressure control, including blood vessel contraction, sodium and water balance, and cell development in the heart.

When blood pressure drops, the kidneys release an enzyme called renin, which initiates a chain reaction to bring blood pressure back up. Renin acts on angiotensinogen (a plasma protein) to produce the hormone, angiotensin I (an inactive form), which is then converted to angiotensin II (an active form of the hormone) by the angiotensin-converting enzyme (ACE). Angiotensin II then stimulates the adrenal glands to release the hormone aldosterone, which decreases kidney sodium excretion, thereby causing blood vessels to constrict. When blood vessels constrict, blood pressure goes up.

Researchers believe that this angiotensin-renin- aldosterone system evolved millions of years ago to pro-

hypertension Essential

Essential hypertension

KEY TERMS

Angiotensinogen—A plasma globulin (protein) formed in the liver and directly involved in the regulation of blood pressure.

Diastolic blood pressure—Blood pressure when the heart is resting between beats.

Renin—An enzyme produced by the kidneys.

Sphygmomanometer—An inflatable cuff used to measure blood pressure.

Systolic blood pressure—Blood pressure when the heart contracts (beats).

Vasodilator—A drug that relaxes blood vessel walls.

tect humans. By retaining salt and water and narrowing blood vessels, the body was ensured an adequate blood flow and the ability to repair injured tissue. Over time, however, this system outlived its original protective function and led to serious health complications.

Demographics

It is estimated that one in four Americans suffer from high blood pressure; it is also estimated that one in three people who have high blood pressure are unaware of the problem. Also, hypertension is much more common among African-Americans and Mexican-Americans than in Caucasian populations. Low levels of nitric oxide, which have been observed in individuals—particularly African-Americans—with elevated blood pressure, may be an important factor in the development of essential hypertension.

The prevalence of essential hypertension increases with age until at least the age of 80. Statistics indicate that more than half of all Americans over the age of 65 have hypertension. In those under the age of 55, essential hypertension is more common in males than females. Over age 55, there is an equal distribution among males and females.

Signs and symptoms

Essential hypertension may cause no symptoms for years. For this reason, high blood pressure is often called the “silent killer.” The first symptom may be a heart attack or stroke. However, many people with hypertension may experience one or more of the following symptoms:

•headache

•dizziness

•blurred vision

•irregular or rapid heartbeat

•nosebleeds

•fatigue

Diagnosis

Although genetic studies hold hope for detecting, evaluating, and treating hypertension in the future, as of early 2001 there are no reliable genetic screening tests for the disorder. Thus, essential hypertension is a condition that cannot be diagnosed until it has developed; it is often diagnosed during a routine physical or medical examination.

Blood pressure is measured by an instrument called a sphygmomanometer. A cloth-covered rubber cuff is wrapped around the upper arm and inflated. When the cuff is inflated, an artery in the arm is squeezed to momentarily stop the flow of blood. Then the air is let out of the cuff, while a stethoscope placed over the artery is used to detect the sound of the blood spurting back through the artery. This first sound is the systolic pressure. The last sound heard as the rest of the air is released is the diastolic pressure. Both sounds are recorded on the mercury gauge of the sphygmomanometer.

Because a number of factors such as pain, stress, or anxiety can cause a temporary increase in blood pressure, hypertension is not diagnosed on the basis of one elevated reading. Also, blood pressure results may be different depending on which arm is used. Thus, if a blood pressure reading is 140/90 or higher for the first time, the physician will have the individual return for another blood pressure check. Diagnosis of essential hypertension is usually made based on two or more readings after the first visit.

A typical physical examination to evaluate hypertension includes:

•medical and family history (especially important to determine a genetic contribution)

•physical examination

•examination of the blood vessels in the eye

•chest x ray

•electrocardiograph (EKG)

•blood and urine tests

Treatment and management

There is no complete cure for essential hypertension because unlike secondary hypertension, there is no single

cause of the problem; it is a complex disorder only determined, in part, by genes. Environmental (lifestyle) factors interact with genetic factors to produce hypertension.

However, essential hypertension can be treated and managed effectively, even if an individual has a genetic predisposition to the disorder. If essential hypertension is mildly or even moderately high, it may be possible to bring it down to a normal level without medication. Weight loss, changes in diet, and exercise may be the only treatment necessary. General nonpharmacologic recommendations include:

•reducing the amount of salt (sodium) and fat in the diet

•exercising regularly

•maintaining a healthy weight

•limiting alcohol and caffeine consumption

•quitting smoking

•reducing stress through stress management techniques, relaxation exercises, or counseling

If lifestyle changes are not effective in lowering blood pressure to a normal level, medication may be prescribed. There are many types of drugs available to treat essential hypertension. The main categories of drugs include:

•diuretics (help kidneys eliminate excess salt and water from the body’s tissues and blood, thereby reducing swelling and lowering blood pressure)

•beta-blockers, alpha-blockers, and alpha/beta blockers (act on nervous system to slow heart rate and reduce the force of the heart’s contractions

•angiotensin-converting enzyme (ACE) inhibitors (block the production of substances that constrict blood vessels and reduce salt and water build-up in the tissues)

•calcium channel blockers (block the entry of calcium into muscle cells in artery walls, making arteries more relaxed)

•vasodilators (relax artery walls and lower blood pressure rapidly)

•peripheral acting adrenergic antagonists (act of nervous system to relax arteries and reduce the force of the heart’s contractions)

•Centrally acting agonists (act on nervous system to relax arteries)

When a blood pressure medication is prescribed, it is important to:

•take the medication regularly, exactly as prescribed

•report any side effects immediately

•have regular follow-up visits with a physician

It may take weeks or even months to find the most effective pharmacologic treatment. Once an effective drug or combination of drugs is found, individuals with high blood pressure may require treatment for the rest of their lives.

Prognosis

The higher the blood pressure, the worse the prognosis. However, most serious complications of essential hypertension can be delayed or even avoided by getting regular blood pressure checks and by treating the disorder as soon as it is diagnosed.

Resources

BOOKS

Appel, Lawrence, Robert McNamara, and Jerilyn Allen, eds.

High Blood Pressure: What You Need to Know. New York: Time Life, 1999.

Whitaker, Julian. Hypertension: A Vital New Program to Prevent, Treat, and Reduce High Blood Pressure. New York: Warner Books, 2000.

PERIODICALS

Ambler, S. Kelly, and R. Dale Brown. “Genetic Determinants of Blood Pressure Regulation.” Journal of Cardiovascular Nursing 13, no. 4 (July 1999): 59–72.

Lifton, Richard P. “Molecular genetics of human blood pressure variation.” Science 272, no. 5262 (May 3, 1996): 676–80.

Phillips, Robert A. “Hypertension: What’s new in diagnosis?” Consultant 39, no. 8 (August 1999): 2337–41.

Rowe, Paul M. “Identification of Hypertension Genes Comes Closer.” Lancet 355, no. 9214 (April 29, 2000): 1525–28.

Seppa, N. “Male hypertension may have genetic link.” Science News 153, no. 20 (May 16, 1998): 310–12.

ORGANIZATIONS

American Heart Association. 7272 Greenville Ave., Dallas, TX 75231-4596. (214) 373-6300 or (800) 242-8721. inquire@heart.org. http://www.americanheart.org .

American Society of Hypertension. 515 Madison Ave., Suite 1212, New York, 10022. (212) 644-0600. http://www

.ash-us.org .

WEBSITES

Heart Information Network. http://www.heartinfo.org .

Genevieve T. Slomski, PhD

hypertension Essential

I Fabry disease

Definition

Fabry disease is a genetic condition that typically affects males. It is caused by deficiency of an enzyme, a chemical that speeds up another chemical reaction. Fabry disease can affect many parts of the body including the kidneys, eyes, brain, and heart. Pain in the hands and feet and a characteristic rash are classic features of this disease.

Description

The symptoms of Fabry disease were first described by Dr. Johann Fabry and Dr. William Anderson in 1898. The enzyme deficiency that leads to the disease was identified in the 1960s. Fabry disease is caused by a change (mutation) in the GLA gene. This gene is responsible for the production of the enzyme alpha-galactosidase A. Alpha-galactosidase A normally breaks down globotriaosylceramide. Globotriaosylceramide is a natural substance in the body, made of sugar and fat. A mutation in the GLA gene leads to a decrease in alpha-galactosidase A activity which, in turn, leads to an excess of globotriaosylceramide. The excess globotriaosylceramide builds up in blood vessels (veins, arteries, and capillaries) and obstructs normal blood flow. It also builds up in parts of the skin, kidneys, heart, and brain. It is this build-up that inhibits normal function and leads to the symptoms associated with the disease.

The symptoms of Fabry disease are variable. Some individuals with Fabry disease have severe complications, while others have very mild symptoms. The first sign of the disease may be a painful burning sensation in the hands and feet (acroparesthesias). A red rash, most commonly between the belly button and the knees (angiokeratoma) is also common. The outer portion of the eye (cornea) may also become clouded in individuals with Fabry disease. The progressive buildup of globo-

triaosylceramide can also lead to kidney problems and heart disease in adulthood.

Genetic profile

The gene that produces alpha-galactosidase A is located on the X chromosome. It is called the GLA gene. Since the GLA gene is located on the X chromosome, Fabry disease is considered to be X-linked. This means that it generally affects males.

A person’s sex is determined by his or her chromosomes. Males have one X chromosome and one Y chromosome. Females, on the other hand, have two X chromosomes. Males who possess a mutation or change in their GLA gene will develop Fabry disease. Females who possess a mutation in one of their GLA genes typically do not develop many of the symptoms associated with Fabry disease. This is because a female’s other X chromosome does not have the mutation, and the normal chromosome can take over the function of the abnormal chromosome and keep her from getting the disease. These women are considered to be carriers. If a woman is a carrier, she has a 50% risk with any pregnancy to pass on her X chromosome with the mutation. Therefore, with every male pregnancy she has a 50% risk of having an affected son, and with every female pregnancy she has a 50% risk of having a daughter who is a carrier.

Demographics

Fabry disease affects approximately one in 40,000 live births. It occurs evenly among all ethnic groups. Almost always, only male children are affected. Although female carriers of the disease occasionally develop symptoms of the disease, it is rare for a female carrier to be severely affected.

Signs and symptoms

The signs and symptoms of Fabry disease vary. Some individuals with Fabry disease have many severe

Fabry disease

K E Y T E R M S

Acroparesthesias—Painful burning sensation in hands and feet.

Amniocentesis—A procedure performed at 16-18 weeks of pregnancy in which a needle is inserted through a woman’s abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus.

Angiokeratoma—Skin rash comprised of red bumps. Rash most commonly occurs between the navel and the knees.

Blood vessels—General term for arteries, veins, and capillaries that transport blood throughout the body.

Chorionic villus sampling (CVS)—A procedure used for prenatal diagnosis at 10-12 weeks gestation. Under ultrasound guidance a needle is inserted either through the mother’s vagina or abdominal wall and a sample of cells is collected from around the fetus. These cells are then tested for chromosome abnormalities or other genetic diseases.

Cornea—The transparent structure of the eye over the lens that is continous with the sclera in forming the outermost protective layer of the eye.

Dialysis—Process by which special equipment purifies the blood of a patient whose kidneys have failed.

Enzyme replacement therapy—Giving an enzyme to a person who needs it for normal body function. It is given through a needle that is inserted into the body.

Left ventricular enlargement—Abnormal enlargement of the left lower chamber of the heart.

Mitral valve prolapse—A heart defect in which one of the valves of the heart (which normally controls blood flow) becomes floppy. Mitral valve prolapse may be detected as a heart murmur, but there are usually no symptoms.

Mutation—A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring.

Proteinuria—Excess protein in the urine.

symptoms, while other individuals’ symptoms may be few and mild. The symptoms typically increase or intensify over time. This progression is caused by the slow buildup of globotriaosylceramide as the person ages.

A painful burning sensation in the hands and feet (acroparesthesias) is one of the first symptoms of Fabry disease. This pain can be severe and may grow worse with exercise, stress, illness, extreme heat, or extreme cold. Another symptom of Fabry disease typically present during childhood is a red rash (angiokeratoma). This rash typically develops between the navel and the knees. Children with Fabry disease may also have a clouding of the outer most portion of the eye (cornea). This symptom is usually diagnosed by an eye doctor (ophthalmologist). The cloudiness may increase with time. A decreased ability to sweat is another common symptom of Fabry disease.

Due to the progressive nature of Fabry disease, most affected individuals develop additional symptoms by 40 years of age. The buildup of globotriaosylceramide in the heart can lead to heart problems. These heart problems can include changes in the size of the heart (left ventricular enlargement), differences in the heart beat, and leaky heart valves. Mitral valve prolapse is a particular type of leaky heart valve that is common in Fabry disease, even in childhood. The excess globotriaosylceramide can also disrupt normal blood flow in the brain. In some cases this can cause dizziness, seizures, and stroke. The kidneys are other organs affected by Fabry disease. Kidney problems can lead to an abnormal amount of protein in the urine (proteinuria). Severe kidney problems can lead to kidney failure.

Although the symptoms of Fabry disease usually occur in males, female carriers may occasionally exhibit symptoms of the disease. Some carriers experience pain in their hands and feet. Carrier females may also have proteinuria and clouding of their cornea. It is rare for a female to experience all of the symptoms associated with Fabry disease.

Diagnosis

Initially, the diagnosis of Fabry disease is based on the presence of the symptoms. It should also be suspected if there is a family history of the disorder. The diagnosis of Fabry disease is definitively made by measuring the activity of the alpha-galactosidase enzyme. When the activity is very low, it is diagnostic of Fabry disease. This enzyme analysis can be performed through a blood test. Measuring the activity of the enzyme can also detect a female carrier. Women who are carriers of Fabry disease have enzyme activity that is lower than normal.

Prenatal diagnosis is possible by measuring the alpha-galactosidase A activity in fetal tissue drawn by amniocentesis or chorionic villus sampling (CVS). Fetuses should be tested if the mother is a carrier. A woman is at risk of being a carrier if she has a son with Fabry disease or someone in her family has Fabry disease.

Treatment and management

There is currently no cure for Fabry disease. However, there are clinical trials underway in which individuals with Fabry disease are being given the alphagalactosidase A enzyme as a form of enzyme replacement therapy. If successful, this enzyme replacement therapy may reduce or eliminate the symptoms associated with Fabry disease.

Until the enzyme replacement therapy is proven to be safe and effective, individuals with Fabry disease must rely on traditional treatments. Individuals with Fabry disease are recommended to have routine evaluations of the their heart and kidneys. Some individuals with kidney disease require a special diet that is low in sodium and protein. Dialysis and kidney transplantation may be necessary for patients with severe kidney disease. Certain medications may reduce the risk of stroke. Finally, individuals with Fabry disease are recommended to avoid the situations that cause the pain in their hands and feet to grow worse. In some situations medication may be required to reduce the pain.

Prognosis

The prognosis for individuals with Fabry disease is good, especially with the arrival of enzyme replacement therapy. Currently, affected individuals survive into adulthood, with the symptoms increasing over time.

Resources

BOOKS

Desnick, Robert J., Yiannis Ioannou, and Christine Eng. “Galactosidase A Deficiency: Fabry Disease.” The Molecular Bases of Inherited Disease. 8th ed. New York: McGraw Hill, 2001.

ORGANIZATIONS

Alliance of Genetic Support Groups. 4301 Connecticut Ave. NW, Suite 404, Washington, DC 20008. (202) 966-5557. Fax: (202) 966-8553. http://www.geneticalliance.org .

Deptartment of Human Genetics, International Center for Fabry Disease. Box 1497, Fifth Ave. at 100th St., New York, NY 10029. (866) 322-7963. http://www.mssm.edu/genetics/ fabry .

Fabry Support and Information Group. PO Box 510, 108 NE 2nd St., Suite C, Concordia, MO 64020. (660) 463-1355.http://www.cpgnet.com/fsig.nsf .

National Institute of Neurological Disorders and Stroke. 31 Center Drive, MSC 2540, Bldg. 31, Room 8806, Bethesda, MD 20814. (301) 496-5751 or (800) 352-9424.http://www.ninds.nih.gov .

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. http://www

.rarediseases.org .

WEBSITES

Fabry Disease Home Page.http://www.sci.ccny.cuny.edu/~fabry/ .

Online Mendelian Inheritance in Man (OMIM). http://www

.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?301500 .

Holly Ann Ishmael, MS, CGC.

Faciopalatoosseous syndrome see

Otopalatodigital syndrome

Facioscapulohumeral muscular dystrophy see FSH muscular dystrophy

Factor V deficiency see Factor V leiden thrombophilia

I Factor V Leiden

thrombophilia

Definition

Factor V Leiden thrombophilia is a common genetic disorder that leads to a predisposition or increased chance to develop blood clots in the veins (venous thrombosis).

Description

Factor V Leiden thrombophilia is a disorder caused by an inherited change or mutation in the genetic instructions for making a substance called factor V. The factor V change leads to an increased chance to develop blood clots in blood vessels.

Blood clots form in two steps. In the first step, the body produces platelets that are “sticky” and can form initial plugs or clots when needed. However, the first platelets only form the first temporary plugs. To form a more lasting plug or clot the platelets release chemicals to attract more platelets and other substances called clotting factors (or clotting proteins). In the second step, the platelets come together with the clotting proteins and

thrombophilia Leiden V Factor

Factor V Leiden thrombophilia

form fibers. The fibers weave together and make the clot stronger and longer lasting.

Individuals affected by factor V Leiden thrombophilia have a genetic mutation that makes a longer lasting, “stickier” form of the clotting factor or protein called factor V. This different form of factor V is called factor V Leiden. The factor V Leiden clotting protein lasts longer in the blood because a chemical produced by the body called Activated Protein C (or APC), which is supposed to help “break-down” the factor V clotting protein, cannot break down the factor V Leiden clotting protein as easily and quickly as it breaks down normal factor V. The factor V Leiden clotting protein breaks down 10 times slower than an average clotting factor V and accordingly stays in the blood longer.

Since there is longer lasting, extra sticky Factor V Leiden in the blood, individuals affected by factor V Leiden thrombophilia have an increased chance to have free-floating blood clots (thrombosis) that can get stuck in the veins and other blood vessels. An alternative name used to describe this condition is Hereditary Resistance to Activated Protein C.

Genetic profile

Factor V Leiden thrombophilia occurs when a specific gene on the long arm of chromosome one is changed or mutated. This gene is called F5. Every person has approximately 30,000–35,000 genes that tell our bodies how to form and function. Each gene is present in pairs, since one is inherited from the mother, and one is inherited from the father. Depending on the inheritance of the changed or mutated F5 gene, factor V Leiden thrombophilia runs in families in a more severe and less severe form.

The less severe form of factor V Leiden thrombophilia is called “heterozygous” and occurs when an individual inherits only one copy of the altered or mutated gene that causes factor V Leiden. The more severe form of factor V is called “homozygous” and is caused by the inheritance of two non-working or mutated copies of the gene that causes factor V Leiden thrombophilia.

Heterozygous factor V Leiden is inherited in an autosomal dominant pattern. In an autosomal dominant condition, only one changed or mutated copy of the gene for a particular condition is necessary for a person to experience symptoms of the condition. If a parent has an autosomal dominant condition, there is a 50% chance for each child to have the same or similar condition. In heterozygous factor V Leiden thrombophilia, the chance of being affected by venous blood clots is four to eight times greater than the general population.

Homozygous factor V Leiden thrombophilia is inherited in an autosomal recessive pattern. An autosomal recessive condition is caused by the inheritance of two changed or mutated copies of a gene. Individuals who are affected by heterozygous factor V Leiden thrombophilia have only one copy of the altered gene. However, when two people with heterozygous factor V Leiden thrombophilia have children together, there is a 25% chance, with each pregnancy, for the child to inherit two copies, one from each parent. That child then has two altered copies of the gene and therefore, has homozygous factor V Leiden thrombophilia. When an individual inherits two non-working copies of the gene that lead to homozygous factor V Leiden thrombophilia, there is an up to 80 times increased risk to be affected by blood clots stuck in the veins (venous thrombosis). Additionally, most individuals affected by homozygous factor V Leiden thrombophilia develop blood clots at a younger age than individuals affected by heterozygous factor V Leiden thrombophilia.

Demographics

Factor V Leiden thrombophilia is the most common inherited form of increased blood clotting in the general population. Factor V Leiden thrombophilia is more common in the Caucasian population. In the general U.S. and European population, heterozygous factor V Leiden thrombophilia occurs in approximately three to eight individuals per 100. In the same general U.S. and European population, homozygous factor V Leiden thrombophilia affects approximately one in 5,000 individuals. The frequency in African Americans, Asian Americans, Hispanic Americans, and Native Americans is smaller than that of Caucasian Americans, but is still present at approximately 0.45–2% of individuals tested. Factor V Leiden thrombophilia is very rare in individuals who have only Asian, African, and indigenous Australian descent.

Signs and symptoms

The symptoms of factor V Leiden thrombophilia vary. Some affected individuals have no physical problems. Other individuals will have complications including blood clots blocking blood vessels (thromboembolism), deep vein thrombosis, unexplained multiple miscarriages and stillborn infants, gall bladder dysfunction, strokes, and heart attacks. The most common physical sign of factor V Leiden thrombophilia is thromboembolism (a blockage in the veins caused by a free floating clot [embolus]). Venous thromboembolism is most common in the deep veins of the legs (deep venous thrombosis or DVT of the legs). Since non-specific and common factor