Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 2 - M-Z - I

National Cancer Institute. Office of Communications, 31 Center Dr. MSC 2580, Bldg. 1 Room 10A16, Bethesda, MD 20892-2580. (800) 422-6237. http://www.nci.nih

.gov .

National Familial Pancreas Tumor Registry. Johns Hopkins Hospital, Weinberg Building, Room 2242, 401 North Broadway, Baltimore, MD 21231-2410. (410) 955-9132.http://www.path.jhu.edu/pancreas .

WEBSITES

Pancreatic Action Network (PanCan).http://www.pancan.org .

Kristin Baker Niendorf, MS, CGC

Pancreatic carcinoma see Pancreatic cancer

I Panic disorder

Definition

A panic disorder is a psychological state characterized by acute (rapid onset) feelings, which engulf a person with a deep sense of destruction, death, and imminent doom. The main feature of panic disorder (PD) is a history of previous panic attacks (PA). The PA symptoms are pronounced and the affected person will gasp for air, have increased breathing (hyperventilate), feel dizzy (light headed), and develop a loss of sensation (parasthesia). Most patients will run outside and symptoms like increased breathing will slow and the PA symptoms will subside. Most PA last three to ten minutes. It is rare for PA to extend in duration over 30 minutes.

Description

The essential characteristics of panic disorder consist of specific and common criteria. The affected person usually has recurrent and unexpected panic attacks (the active presentation of panic disorder). The PA is characterized by a discrete, rapid onset feeling of intense fear or discomfort. Affected persons have several somatic (referring to physical signs) or cognitive (thinking) symptoms. Affected persons usually react in a manner that indicates impending doom. They commonly exhibit signs of a sweating, racing heart beat, chest pain, shortness of breath, and the perception of feeling smothered. The panic attack (PA) is usually followed by one month (or more) of one or more of the following thought processes:

•Persistent concern or preoccupation about having future attacks

•Worry about the possible consequences, complications, or behavioral changes associated with attacks (e.g. losing control, going crazy, or having a serious medical condition like a heart attack).

Genetic profile

Panic disorder definitely runs in families and twin studies suggest that about 20% of patients who have the criteria for diagnosis have first-degree relatives with the disorder. In families with no history of affected firstdegree relatives the prevalence decreases to 4%. The ratio between monozygotic twins (identical) twins to dizygotic (non-identical) twins is 5:1 for PD. Recent evidence suggests that there is a genetic mutation in the SLC6A4 gene. This gene is related to a brain chemical called serotonin, a chemical in the brain, which is known to effect mood. If the transport of serotonin is imbalanced, then certain parts of the brain may not receive the correct stimulus causing alterations in mood. Some studies have demonstrated that there is no positive family history in about 50% of patients diagnosed with PD. Other possible causes of PD include social learning and autonomic responsivity (the attack will affect the body and hypersensitizes nerve cells in the brain).

Demographics

PD usually begins during the affected persons late teens or in the twenties, and is uncommon after age 35 and unusual after age 45 years. Global studies suggest that the lifetime prevalence of PD is between 1.5% and 3.5%. In the United States approximately 3–5% of the population are affected with the disorder. In any given year approximately 1.7% of the U.S. population has PD. This represents about 2.4 million Americans. PD is twice as common in females compared to males (female:male ratio is 2:1).

Agoraphobia (anxiety state about being in situations or places that might make escape embarrassing or difficult) is seen in approximately one-third to one-half of persons who meet the criteria for PD diagnosis. Other reports indicate that about 95% of persons affected with agoraphobia also have a previous history or current diagnosis of PD. In some cultures PA is believed to be associated with magic or witchcraft. Additional causes of PA may include intentional suppression of one’s freedoms or public life.

Signs and symptoms

Criteria for panic attack:

1.Cardiac palpitations (pounding, racing, or accelerated heart rate).

2.Sweating.

disorder Panic

Panic disorder

3.Shaking (trembling).

4.Breathing difficulties, including shortness of breath or perceptions of being smothered.

5.Feeling of choking.

6.Chest discomfort or pain.

7.Feeling light-headed (faint, dizzy or unsteady).

8.Stomach discomfort or nausea.

9.Affected individuals may lose contact with reality during the attack.

10.A feeling of being detached and out of contact with oneself.

11.Fear of losing control of oneself (going “crazy”).

12.Fear of dying.

13.Tingling or numbness sensations.

Criteria for panic disorder:

1.Recurrent and unexpected PA.

2.Worry about the consequences, implications, or behavioral changes associated with PA (perceptions of going “crazy,” losing control of actions, or suffering from a life threatening condition, such as a heart attack).

3.PA is not caused by or associated with a medical condition.

4.PA is not associated with another mental disorder, such as phobia (an exaggerated fear to something like spiders or heights). Exposure to a specific phobia situation or object can promote a PA.

Criteria for agoraphobia:

1.The essential feature of agoraphobia is anxiety about being in situations or places that make escape embarrassing or difficult. These fears usually involve characteristic clusters of situations that include being on a bridge, being in a crowd, standing in line in a department store, or traveling in a train, bus, or automobile. Elevators are another common cause promoting the occurrence of PA. These situations, which lead to the PA, are often difficult or embarrassing to abruptly flee from.

2.Avoidance of the affected person’s fear, which usually limits travel away from home, causing impaired functioning.

Criteria for PD without agoraphobia:

Recurrent unexpected PA. At least one attack followed by one month or more of one or more of the following symptoms:

•Persistent concern about having future attacks

•Worry about consequences associated with attacks

•A change in behavioral patterns related to the attacks (e.g. the affected person avoids travel).

•Absence of agoraphobia

•PA are not due to a medical condition

•PA not associated with another mental disorder (e.g. phobias).

Criteria for panic disorder with agoraphobia:

1.Criteria 1, 2, and 5 for PD without agoraphobia must be present.

2.The presence of agoraphobia.

Diagnosis

There are no specific laboratory findings associated with diagnosing PD. However, evidence suggests that some affected persons may have low levels of carbon dioxide and an important ion in the human body called bicarbonate (helps in regulating blood from becoming to acidic or alkaline). These chemical changes may hypersensitize (making cells excessively sensitive) nerve cells, which can increase the activity of other structures throughout the body, such as sweat glands (sweating) and the heart (racing, accelerated or pounding rate). Additionally, lactic acid (a chemical made in the body from sugar) plays a role in nerve cell hypersensivity. The diagnosis of PD can be made accurately if the specific symptoms and criteria are established.

Neuroimaging studies indicate that the arteries (vessels that deliver oxygen rich blood to cells and tissues) are constricted (smaller diameter) as a result of increased breathing rates during a PA.

The consulting clinician must exclude other possible causes of panic attacks such as intoxication with stimulant drugs (cocaine, caffeine, amphetamines [speed]). Withdrawal from alcohol and barbiturates can also induce panic-like behaviors. Additionally, the consulting therapist should obtain a comprehensive medical history and examination to determine if the PA is caused by a medical condition frequently observed in hormonal diseases (overactive thyroid), tumors that secrete chemicals causing a person to have pronounced “hyper” changes (racing heartbeat, sweating, shaking). Other causes include a possible cardiac (heart) disease such as an irregularly beating heart.

Treatment and management

Moderate to severe PD is characterized by frequent PA ranging from five to seven times a week or with sig-

nificant disability associated with anxiety between episodes. In addition to cognitive-behavioral therapy an affected person will usually require medications. There are three classes of medications commonly prescribed for PD patients.

Tricyclic antidepressants

Tricyclic antidepressants are a class of medications used to treat depression and other closely related mental disorders. Individuals affected with PD are usually given imipramine, which has been shown in some studies to be effective in approximately 70% of cases. Medications in this category usually have a prolonged lag time until a positive response is observed. This is primarily due to adverse side effects, which prevent rapid increases of dosage and also because they act on specific chemical imbalances in the brain, which take time to stabilize.

The first choice of medication treatment for PD is tricyclics (imipramine, desipramine, and nortriptyline). These medications require careful dosing and monitoring. The actual blood level (therapeutic level necessary to make improvements) may vary in special populations who have the disorder. Elderly patients may require a smaller dose, due to decrease in metabolism (in this context metabolism refers to the breakdown of large chemicals to smaller ones for usage) and kidney function, which are part of aging. Some patients may develop gastrointestinal (stomach) side effects, which may interfere with absorption from the gut, thereby decreasing beneficial blood levels. Furthermore, patients who receive tricyclics may develop dry mouth and low blood pressure. The heart may be adversely affected (altered rate and rhythm) especially in patients with preexisting diseases, causing direct damage or strain in the heart. Affected persons receiving tricyclics also commonly experience changes in sexual functioning, including loss of desire and ejaculation. Adverse (negative) side effects usually decrease patient compliance (the person stops taking medications to avoid side effects). Recently, a new group of tricyclics was made available. These tricyclics (fluoxetine, sertraline, paroxetine and fluvoxamine) act on specific areas in the brain to correct potential chemical imbalances.

Monoamine oxidase inhibitors (MAOIs)

A second line category of medications used to treat PD are the monoamine oxidase (a chemical that assists in storing certain chemicals in nerve cells) inhibitors (MAOI). MAOI will stop the action of MAO, thereby decreasing the amount of certain chemicals in the brain that may influence PAs. This group of medications is effective in approximately 75–80% of cases, especially for refractory (not active) depression. Affected individu-

K E Y T E R M S

Palpitation—An irregular heartbeat.

Phobia—An exaggerated fear.

Recurrent—Tendency to repeat.

als using MAOI must avoid specific foods to prevent a hypertensive crisis (when the blood pressure rapidly increases). These foods include cheeses (except cream cheese, cottage cheese, and fresh yogurt); liver of all types; meat and yeast extracts; fermented or aged meats (such as salami and bologna); broad and Chinese bean pods; all types of alcohol-containing products; soy sauce; shrimp and shrimp paste; and sauerkraut. Although MAOI are effective medications for treatment of PD, they are underutilized due to strict dietary limitations.

Benzodiazepines

Benzodiazepines are another class of medications used to treat PD. They include medications such as diazepam (Valium), lorazepam, and clonazepam. They have been reported to be effective in 70–90% of patients with PD. However, the effective dose is approximately two to three times higher for PD than milder forms of simple anxiety (these medications are usually indicated for mild anxiety). This increased dosing in PD patients is undesirable since there is risk of physical dependence and withdrawal (commonly exhibited when the medication is rapidly tapered down or stopped). However, they are indicated when PD affected patients respond poorly to tricyclics or have a fear of taking MAOIs due to dietary restrictions and problems associated with eating the wrong foods accidentally.

Long term management

Reassuring the patient with PD that anticipated panic attacks are unlikely while taking medication is essential for long-term maintenance. Cognitive-behavioral therapy is also important for long-term treatment. Weaning off medications must be done slowly since patients develop a sense of security that they will not have an attack while actively dosing.

Prognosis

The course of PD and agoraphobia varies considerably over time. Some cases may experience spontaneous remissions (the disorder is present but it is not active). The course can be so variable that an affected person may go on for years without a PA, then have several attacks,

disorder Panic

Parkinson disease

and then enter a second phase of remission, which may last for years. In some cases a decrease in PA may be closely related to a decrease and avoidance of anxietyassociated situations, which promote agoraphobia. Agoraphobia itself may become chronic (long term or permanent) with or without PA. In general, approximately 50–60% will recover substantially five to 20 years after the initial attack. Approximately 20% will still have long term impairment, which will stay the same or slightly worsen. Generally, the earlier treatment is sought, the better the outcome. The course in children and adolescents is chronic (long term), usually lasting about three years. Generally, PD shows the highest risk of developing new psychological disorders during follow up visits. If PA is treated early, anticipatory anxiety and phobia may be more manageable and responsive to treatment.

Resources

BOOKS

American Psychiatric Association Staff. Diagnostic and Statistical Manual of Mental Disorders. 4th ed., revised. Washington, D.C.: American Psychiatric Association, 2000.

Maxmen, J. S., and M. G. Ward. Essential Psychopathology and Its Treatment. New York: W. W. Norton & Company, 1995.

Muench, K. H. Genetic Medicine. New York: Elsevier Science Publishing Co., Inc., 1988.

PERIODICALS

Bakker, A., R. van Dyck, P. Spinhoven, and A. J. L. M van Ballrom. “Paroxetine, clomipramine, and cognitive therapy in the treatment of panic disorder.” Journal of Clinical Psychiatry 60 (1999): 831–38.

Coplan, J. D., and R. B. Lydiard. “Brain circuits in panic disorder.” Biological Psychiatry 44 (1998): 1264–76.

Masi, G., L. Favilla, and R. Romano. “Panic disorder in children and adolescents.” Panminerva medica 41 (1999): 153–56.

ORGANIZATIONS

Anxiety Disorders Association of America. 11900 Parklawn Dr., Suite 100, Rockville, MD 20852. (301) 231-9350. Fax: (301) 231-7392. anxdis@adaa.org.

Laith Farid Gulli, MD

Bilal Nasser, MS

I Parkinson disease

Definition

Parkinson disease (PD) is a progressive movement disorder marked by tremors, rigidity, slow movements

(bradykinesia), and posture instability. It occurs when cells in one of the movement-control centers of the brain begin to die for unknown reasons. PD was first noted by British physician James Parkinson in the early 1800s.

Description

Usually beginning in a person’s late fifties or early sixties, Parkinson disease causes a progressive decline in movement control, affecting the ability to control initiation, speed, and smoothness of motion. Symptoms of PD are seen in up to 15% of those ages 65–74, and almost 30% of those ages 75–84.

Genetic profile

Most cases of PD are sporadic. This means that there is a spontaneous and permanent change in nucleotide sequences (the building blocks of genes). Sporadic mutations also involve unknown environmental factors in combination with genetic abnormalities. The abnormal gene (mutated gene) will form an altered end-product or protein. This will cause abnormalities in specific areas in the body where the protein is used. Some evidence suggests that the disease is transmitted by autosomal dominant inheritance. This implies that an affected parent has a 50% chance of transmitting the disease to any child. This type of inheritance is not commonly observed. The most recent evidence is linking PD with a gene that codes for a protein called alpha-synuclein. Further research is attempting to fully understand the relationship with this protein and nerve cell degeneration.

Demographics

PD affects approximately 500,000 people in the United States, both men and women, with as many as 50,000 new cases each year.

Signs and symptoms

The immediate cause of PD is degeneration of brain cells in the area known as the substantia nigra, one of the movement control centers of the brain. Damage to this area leads to the cluster of symptoms known as “parkinsonism.” In PD, degenerating brain cells contain Lewy bodies, which help identify the disease. The cell death leading to parkinsonism may be caused by a number of conditions, including infection, trauma, and poisoning. Some drugs given for psychosis, such as haloperidol (Haldol) or chlorpromazine (thorazine), may cause parkinsonism. When no cause for nigral cell degeneration can be found, the disorder is called idiopathic parkinsonism, or Parkinson disease. Parkinsonism may be seen in

other degenerative conditions, known as the “parkinsonism plus” syndromes, such as progressive supranuclear palsy.

The substantia nigra, or “black substance,” is one of the principal movement control centers in the brain. By releasing the neurotransmitter known as dopamine, it helps to refine movement patterns throughout the body. The dopamine released by nerve cells of substantia nigra stimulates another brain region, the corpus striatum. Without enough dopamine, the corpus striatum cannot control its targets, and so on down the line. Ultimately, the movement patterns of walking, writing, reaching for objects, and other basic actions cannot function properly, resulting in the symptoms of parkinsonism.

There are some known toxins that can cause parkinsonism, most notoriously a chemical called MPTP, found as an impurity in some illegal drugs. Parkinsonian symptoms appear within hours of ingestion, and are permanent. MPTP may exert its effects through generation of toxic molecular fragments called free radicals, and reducing free radicals has been a target of several experimental treatments for PD using antioxidants.

It is possible that early exposure to some as-yet- unidentified environmental toxin or virus leads to undetected nigral cell death, and PD then manifests as normal age-related decline brings the number of functioning nigral cells below the threshold needed for normal movement. It is also possible that, for genetic reasons, some people are simply born with fewer cells in their substantia nigra than others, and they develop PD as a consequence of normal decline.

Symptoms

The identifying symptoms of PD include:

•Tremors, usually beginning in the hands, often occuring on one side before the other. The classic tremor of PD is called a “pill-rolling tremor,” because the movement resembles rolling a pill between the thumb and forefinger. This tremor occurs at a frequency of about three per second.

•Slow movements (bradykinesia) occur, which may involve slowing down or stopping in the middle of familiar tasks such as walking, eating, or shaving. This may include freezing in place during movements (akinesia).

•Muscle rigidity or stiffness, occuring with jerky movements replacing smooth motion.

•Postural instability or balance difficulty occurs. This may lead to a rapid, shuffling gait (festination) to prevent falling.

K E Y T E R M S

AADC inhibitors—Drugs that block the amino acid decarboxylase; one type of enzyme that breaks down dopamine. Also called DC inhibitors, they include carbidopa and benserazide.

Akinesia—A loss of the ability to move; freezing in place.

Bradykinesia—Extremely slow movement.

COMT inhibitors—Drugs that block catechol-O- methyltransferase, an enzyme that breaks down dopamine. COMT inhibitors include entacapone and tolcapone.

Dopamine—A neurochemical made in the brain that is involved in many brain activities, including movement and emotion.

Dyskinesia—Impaired ability to make voluntary movements.

MAO-B inhibitors—Inhibitors of the enzyme monoamine oxidase B. MAO-B helps break down dopamine; inhibiting it prolongs the action of dopamine in the brain. Selegiline is an MAO-B inhibitor.

Orthostatic hypotension—A sudden decrease in blood pressure upon sitting up or standing. May be a side effect of several types of drugs.

Substantia nigra—One of the movement control centers of the brain.

•In most cases, there is a “masked face,” with little facial expression and decreased eye-blinking.

In addition, a wide range of other symptoms may often be seen, some beginning earlier than others:

•Depression

•Speech changes, including rapid speech without inflection changes

•Problems with sleep, including restlessness and nightmares

•Emotional changes, including fear, irritability, and insecurity

•Incontinence

•Constipation

•Handwriting changes, with letters becoming smaller across the page (micrographia)

•Progressive problems with intellectual function (dementia)

disease Parkinson

Parkinson disease

Diagnosis

The diagnosis of Parkinson disease involves a careful medical history and a neurological exam to look for characteristic symptoms. There are no definitive tests for PD, although a variety of lab tests may be done to rule out other causes of symptoms, especially if only some of the identifying symptoms are present. Tests for other causes of parkinsonism may include brain scans, blood tests, lumbar puncture, and x rays.

Treatment and management

There is no cure for Parkinson disease. Most drugs treat the symptoms of the disease only, although one drug, selegiline (Eldepryl), may slow degeneration of the substantia nigra.

Exercise, nutrition, and physical therapy

Regular, moderate exercise has been shown to improve motor function without an increase in medication for a person with PD. Exercise helps maintain range of motion in stiff muscles, improve circulation, and stimulate appetite. An exercise program designed by a physical therapist has the best chance of meeting the specific needs of the person with PD. A physical therapist may also suggest strategies for balance compensation and techniques to stimulate movement during slowdowns or freezes.

Good nutrition is important to maintenance of general health. A person with PD may lose some interest in food, especially if depressed, and may have nausea from the disease or from medications, especially those known as dopamine agonists. Slow movements may make it difficult to eat quickly, and delayed gastric emptying may lead to a feeling of fullness without having eaten much. Increasing fiber in the diet can improve constipation, soft foods can reduce the amount of needed chewing, and a prokinetic drug such as cisapride (Propulsid) can increase the movement of food through the digestive system.

People with PD may need to limit the amount of protein in their diets. The main drug used to treat PD, L- dopa, is an amino acid, and is absorbed by the digestive system by the same transporters that pick up other amino acids broken down from proteins in the diet. Limiting protein, under the direction of the physician or a nutritionist, can improve the absorption of L-dopa.

No evidence indicates that vitamin or mineral supplements can have any effect on the disease other than in the improvement of the patient’s general health. No antioxidants used to date have shown promise as a treatment except for selegiline, an MAO-B inhibitor. A large,

carefully controlled study of vitamin E demonstrated that it could not halt disease progression.

Drugs

The pharmacological treatment of Parkinson disease is complex. While there are a large number of drugs that can be effective, their effectiveness varies with the patient, disease progression, and the length of time the drug has been used. Dose-related side effects may preclude using the most effective dose, or require the introduction of a new drug to counteract them. There are five classes of drugs currently used to treat PD.

DRUGS THAT REPLACE DOPAMINE One drug that helps replace dopamine, levodopa (L-dopa), is the single most effective treatment for the symptoms of PD. L-dopa is a derivative of dopamine, and is converted into dopamine by the brain. It may be started when symptoms begin, or when they become serious enough to interfere with work or daily living.

L-dopa therapy usually remains effective for five years or longer. Following this, many patients develop motor fluctuations, including peak-dose “dyskinesias” (abnormal movements such as tics, twisting, or restlessness), rapid loss of response after dosing (known as the “on-off” phenomenon), and unpredictable drug response. Higher doses are usually tried, but may lead to an increase in dyskinesias. In addition, side effects of L- dopa include nausea and vomiting, and low blood pressure upon standing (orthostatic hypotension), which can cause dizziness. These effects usually lessen after several weeks of therapy.

ENZYME INHIBITORS Dopamine is broken down by several enzyme systems in the brain and elsewhere in the body; blocking these enzymes is a key strategy to prolonging the effect of dopamine. The two most commonly prescribed forms of L-dopa contain a drug to inhibit the amino acid decarboxylase (an AADC inhibitor), one type of enzyme that breaks down dopamine. These combination drugs are Sinemet (L-dopa plus carbidopa) and Madopar (L-dopa plus benzaseride). Controlled-release formulations also aid in prolonging the effective interval of an L-dopa dose.

The enzyme monoamine oxidase B (MAO-B) inhibitor selegiline may be given as add-on therapy for L- dopa. Research indicates selegiline may have a neuroprotective effect, sparing nigral cells from damage by free radicals. Because of this, and the fact that it has few side effects, it is also frequently prescribed early in the disease before L-dopa is begun. Entacapone and tolcapone, two inhibitors of another enzyme system called catechol-O- methyltransferase (COMT), may soon reach the market

as early studies suggest that they effectively treat PD symptoms with fewer motor fluctuations and decreased daily L-dopa requirements.

DOPAMINE AGONISTS Dopamine works by stimulating receptors on the surface of corpus striatum cells. Drugs that also stimulate these cells are called dopamine agonists, or DAs. DAs may be used before L-dopa therapy, or added on to avoid requirements for higher L-dopa doses late in the disease. DAs available in the United States as of early 1998, include bromocriptine (Permax, Parlodel), pergolide (Permax), and pramipexole (Mirapex). Two more, cabergoline (Dostinex) and ropinirole (Requip), are expected to be approved soon. Other dopamine agonists in use outside the United States include lisuride (Dopergine) and apomorphine. Side effects of all the DAs are similar to those of dopamine, plus confusion and hallucinations at higher doses.

ANTICHOLINERGIC DRUGS Anticholinergics maintain dopamine balance as levels decrease. However, the side effects of anticholinergics (dry mouth, constipation, confusion, and blurred vision) are usually too severe in older patients or in patients with dementia. In addition, anticholinergics rarely work for very long. They are often prescribed for younger patients who have predominant shaking. Trihexyphenidyl (Artane) is the drug most commonly prescribed.

DRUGS WHOSE MODE OF ACTION IS UNCERTAIN

Amantadine (Symmetrel) is sometimes used as an early therapy before L-dopa is begun, and as an add-on later in the disease. Its anti-parkinsonian effects are mild and not seen in many patients. Clozapine (Clozaril) is effective especially against psychiatric symptoms of late PD, including psychosis and hallucinations.

Surgery

Two surgical procedures are used for treatment of PD that cannot be controlled adequately with drug therapy. In PD, a brain structure called the globus pallidus (GPi) receives excess stimulation from the corpus striatum. In a pallidotomy, the GPi is destroyed by heat, delivered by long thin needles inserted under anesthesia. Electrical stimulation of the GPi is another way to reduce its action. In this procedure, fine electrodes are inserted to deliver the stimulation, which may be adjusted or turned off as the response dictates. Other regions of the brain may also be stimulated by electrodes inserted elsewhere. In most patients, these procedures lead to significant improvement for some motor symptoms, including peak-dose dyskinesias. This allows the patient to receive more L-dopa, since these dyskinesias are usually what cause an upper limit on the L-dopa dose.

A third procedure, transplant of fetal nigral cells, is still highly experimental. Its benefits to date have been modest, although improvements in technique and patient selection are likely to change that.

Alternative treatment

Currently, the best treatments for PD involve the use of conventional drugs such as levodopa. Alternative therapies, including acupuncture, massage, and yoga, can help relieve some symptoms of the disease and loosen tight muscles. Alternative practitioners have also applied herbal and dietary therapies, including amino acid supplementation, antioxidant (vitamins A, C, E, selenium, and zinc) therapy, B vitamin supplementation, and calcium and magnesium supplementation, to the treatment of PD. Anyone using these therapies in conjunction with conventional drugs should check with their doctor to avoid the possibility of adverse interactions. For example, vitamin B6 (either as a supplement or from foods such as whole grains, bananas, beef, fish, liver, and potatoes) can interfere with the action of L-dopa when the drug is taken without carbidopa.

Prognosis

Despite medical treatment, the symptoms of Parkinson disease worsen over time, and become less responsive to drug therapy. Late-stage psychiatric symptoms are often the most troubling, including difficulty sleeping, nightmares, intellectual impairment (dementia), hallucinations, and loss of contact with reality (psychosis).

Prevention

There is no known way to prevent Parkinson disease.

Resources

BOOKS

Biziere, Kathleen, and Matthias Kurth. Living With Parkinson

Disease. New York: Demos Vermande, 1997.

PERIODICALS

“An Algorithm for the Management of Parkinson Disease.” Neurology 44/supplement 10 (December 1994): 12.http://neuro-chief-e.mgh.harvard.edu/parkinsonsweb/ Main/Drugs/ManPark1.html .

ORGANIZATIONS

National Parkinson Foundation. 1501 NW Ninth Ave., Bob Hope Road, Miami, FL 33136. http://www.parkinson

.org .

Parkinson Disease Foundation. 710 West 168th St. New York, NY 10032. (800) 457-6676. http://www.apdaparkinson

.com .

disease Parkinson

Paroxysmal nocturnal hemoglobinuria

Worldwide Education and Awareness for Movement Disorders (WE MOVE). Mt. Sinai Medical Center, 1 Gustave Levy Place, New York, NY 10029. (800) 437-MOV2.http://www.wemove.org .

WEBSITES

AWAKENINGS. http://www.parkinsonsdisease.com .

Laith Farid Gulli, MD

Parkinson disease-juvenile see Parkinson disease

Parkinsonism see Parkinson disease

I Paroxysmal nocturnal hemoglobinuria

Definition

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disease in which the bone marrow produces abnormal blood cells, including red blood cells. Such red blood cells are too easily broken, and the hemoglobin inside them is released. The disease is sometimes characterized by nighttime attacks (nocturnal paroxysms) on red blood cells, when the cells break down and spill hemoglobin into the urine (hemoglobinuria). The result is reddish-brown urine upon rising in the morning.

Description

Also known as Marchiafava-Micheli syndrome, PNH was first identified in 1882. PNH is caused by a change (mutation) in a gene that prevents it from making a fat required by the three types of blood cells: red blood cells, white blood cells, and platelets.

When the fat (glycosylphosphatidylinositol, or GPI) is missing from the outside walls of blood cells, proteins cannot stick to the cells and the cells cannot function normally. In healthy red blood cells, GPI binds proteins that protect the cells from chemical attack. In healthy white blood cells, GPI may attach to proteins that help the cells fight infections. In healthy platelets, GPI helps control the platelets clotting mechanism.

Not only are all types of blood cells abnormal in PNH, but the numbers of blood cells are decreased. The decrease in red blood cells, coupled with their destruction, causes anemia in people affected with PNH.

The severity of PNH varies greatly from individual to individual. In some affected people, blood in the urine is barely detectable; others lose so much blood that they require repeated transfusions to stay alive. In severe cases, abnormal platelets may cause abnormal clotting, and about one-third of people with PNH die from clots in the veins of the liver, stomach, or brain.

Genetic profile

Mutations in any of 10 different genes can affect the production of GPI. Only one gene, however, is always altered in PNH. This is the PIG-A gene, located on the X chromosome. Females have two X chromosomes (only one is active) and males have one X chromosome.

People are not born with an altered PIG-A gene, probably because such an abnormality would be lethal to an unborn child. Rather, changes occur in the PIG-A gene sometime after birth, resulting in PNH. PNH is thus an acquired genetic disease, not an inherited disease.

Demographics

PNH is a rare disease. In a million people, only about two to six cases of PNH will be diagnosed. PNH is most common in adults between the ages of 30 and 50, although it has been identified in infants less than one year old and people as old as 82. The disease is slightly more common in females than in males (the ratio is 1.2- to-1). Researchers have not reported that the disease is more common in one population than others, although Asians are much less likely to have clotting problems than are Caucasians.

Signs and symptoms

Only about one-quarter of people with PNH have the telltale sign, reddish-brown urine, for which the disease is named. Other symptoms vary greatly among affected individuals. All those affected, however, have some degree of red cell breakdown that results in more or less severe anemia.

Contributing to anemia in people with PNH is the decreased production of red blood cells in the center of the bones (bone marrow). When the needed fat, GPI, is missing, the bone marrow fails to produce functioning red blood cells, white blood cells, and platelets, and the numbers of these blood cells drop dangerously low. This condition is called bone marrow failure.

Those affected with PNH may have frequent infections because their white blood cells are decreased in number and the cells that circulate in the blood are abnormal. Individuals with PNH may have stomach pain because abnormal platelets can cause clotting in liver and

stomach veins. Headaches may result when clots form in veins that pass through the brain.

Diagnosis

PNH and other types of blood diseases are usually diagnosed by examining a sample of bone marrow cells or tissue under a microscope for abnormalities. Doctors obtain the sample by performing a bone marrow aspiration or biopsy on the individual. In PNH, the bone marrow usually looks empty because so few blood cells are being produced.

Two tests that are more specific to PNH require the affected person’s blood. The Ham test, developed in 1938, has long been the standard laboratory test for confirming PNH. The test determines whether an individual’s red blood cells break down when attacked by certain chemicals. The Ham test is very sensitive and identifies minuscule levels of abnormal red blood cells, but it also identifies individuals with another disease of the red blood cells, congenital dyserythropoietic anemia. A second laboratory test, the sugar water test, works on principles similar to the Ham test. Although the sugar water test is less sensitive to low levels of abnormal red blood cells than the Ham test, it is positive only when the person has PNH.

The most sensitive and specific laboratory test for PNH is flow cytometry. In this test, the individual’s blood cells are treated with a chemical that normally binds to proteins on the cell wall. The size of the treated cells is measured to determine if the chemical is attached to the cell. In people with PNH, there are no proteins on the cell wall so the chemical does not bind and the cells appear smaller than normal cells.

Treatment and management

PNH can be treated with a bone marrow transplant, a procedure in which the diseased bone marrow is destroyed and replaced with healthy bone marrow. The operation can be risky, however, so bone marrow transplants are most often performed on children. The operation is most successful if the healthy bone marrow is donated by an identical twin of the affected child, but bone marrow from other family members can sometimes be used.

If a suitable bone marrow donor cannot be found or if the affected person is not strong enough to withstand a bone marrow transplant, PNH can be managed by supportive treatment. Those affected may take drugs to prevent clots from forming and to prevent red blood cells from breaking down. If the number of blood cells falls dangerously low, affected individuals may receive multiple transfusions of blood cells or may be given drugs. When a person has lost a lot of red blood cells, doctors

K E Y T E R M S

Anemia—A blood condition in which the level of hemoglobin or the number of red blood cells falls below normal values. Common symptoms include paleness, fatigue, and shortness of breath.

Bone marrow—A spongy tissue located in the hollow centers of certain bones, such as the skull and hip bones. Bone marrow is the site of blood cell generation.

Glycosylphosphatidylinositol (GPI)—A fat that attaches proteins to the outside walls of blood cells.

Hemoglobin—Protein-iron compound in the blood that carries oxygen to the cells and carries carbon dioxide away from the cells.

Platelets—Small disc-shaped structures that circulate in the blood stream and participate in blood clotting.

Red blood cell—Hemoglobin-containing blood cells that transport oxygen from the lungs to tissues. In the tissues, the red blood cells exchange their oxygen for carbon dioxide, which is brought back to the lungs to be exhaled.

White blood cell—A cell in the blood that helps fight infections.

may prescribe iron supplements to help build up the blood again.

Gene therapy is an experimental treatment for PNH. In gene therapy, the normal PIG-A gene is inserted into the affected person’s cells, where it takes the place of the abnormal gene and begins making the missing fat. The effectiveness of gene therapy for PNH has not yet been proven in humans.

Prognosis

After an affected individual has been diagnosed with PNH, he or she usually lives for another 10 to 20 years. About 25% of people with PNH live more than 25 years after first being diagnosed. In a few people (about 15%), the disease disappears altogether and the person recovers spontaneously.

Most people who die from PNH do so because of abnormal clotting. About 10% of these individuals develop and eventually die from another disease involving red blood cells, aplastic anemia. About 5% of people with PNH develop a disease involving abnormal white blood cells, acute myelogenous leukemia.

hemoglobinuria nocturnal Paroxysmal

Patau syndrome

Resources

BOOKS

Rosse, Wendell F. “Paroxysmal Nocturnal Hemoglobinuria.” In

Hematology: Basic Principles and Practice 3rd ed. Ed. Ronald Hoffman, et al., 331–342. New York: Churchill Livingstone, 2000.

PERIODICALS

Hillmen, Peter, and Stephen J. Richards. “Implications of Recent Insights into the Pathophysiology of Paroxysmal Nocturnal Haemoglobinuria.” British Journal of Haematology 108 (2000): 470–79.

Nishimura, Jun-ichi, et al. “Paroxysmal Nocturnal Hemoglobinuria: An Acquired Genetic Disease.”

American Journal of Hematology 62 (1999): 175–82.

ORGANIZATIONS

Anemia Institute for Research and Education. 151 Bloor St. West, Suite 600, Toronto, ONT M5S 1S4. Canada (877) 99-ANEMIA. http://www.anemiainstitute.net .

Aplastic Anemia Foundation. PO Box 613, Annapolis, MD 21404-0613. (800) 747-2820. http://www.aplastic.org .

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

Paroxysmal Nocturnal Hemoglobinuria (PNH) Support Group.http://www.thegrid.net/asmaltz/Support%20Group

.htm .

Linnea E. Wahl, MS

Partial 11q monosomy syndrome see

Jacobsen syndrome

I Patau syndrome

Definition

Patau syndrome, also called trisomy 13, is a congenital (present at birth) disorder associated with the presence of an extra copy of chromosome 13. The extra chromosome 13 causes numerous physical and mental abnormalities, especially heart defects. Patau syndrome is named for Dr. Klaus Patau, who reported the syndrome and its association with trisomy in 1960.

Description

Children normally inherit 23 chromosomes from each parent, for a total of 46 chromosomes. A typical human being has 46 chromosomes: 22 pairs of non-sex linked chromosomes and one pair of sex-linked chromo-

somes that determine the child’s sex. Sometimes a child may end up with more than 46 chromosomes because of problems with the father’s sperm or the mother’s egg; or, because of mutations that occurred after the sperm and the egg fused to form the embryo (conception).

Normally, there are two copies of each of the 23 chromosomes: one from each parent. A condition called trisomy occurs when three, instead of two, copies of a chromosome are present in a developing human embryo. An extra copy of a particular chromosome can come either from the egg or sperm, or because of mutations that occur after conception.

The most well-known trisomy-related disorder is Down syndrome (trisomy 21), in which the developing embryo has an extra copy of chromosome 21. Patau syndrome is trisomy 13, in which the developing embryo has three copies of chromosome 13.

An extra copy of chromosome 13 is not the only cause of Patau syndrome. Other changes in chromosome 13, such as mispositioning (translocation), can also result in the characteristics classified as Patau syndrome. In these cases, an error occurs that causes a portion of chromosome 13 to be exchanged for a portion of another chromosome. There is no production of extra chromosomes; but a portion of each affected chromosome is “misplaced” (translocated) to another chromosome.

Patau syndrome causes serious physical and mental abnormalities including heart defects; incomplete brain development; unusual facial features such as a sloping forehead, a smaller than average head (microcephaly), small or missing eyes, low set ears, and cleft palate or hare lip; extra fingers and toes (polydactyly); abnormal genitalia; spinal abnormalities; seizures; gastrointestinal hernias, particularly at the navel (omphalocele); and mental retardation. Due to the severity of these conditions, fewer than 20% of those affected with Patau syndrome survive beyond infancy.

Genetic profile

When an extra copy (trisomy) of a chromosome is made, it may either be a total trisomy (in which an extra copy of the entire chromosome is made), or partial trisomy (in which only one part of the chromosome is made an extra time).

In most cases of trisomy, errors in chromosome duplication occur at conception because of problems with the egg or the sperm that are coming together to produce an offspring. In these cases, every cell in the body of the offspring has an extra copy of the affected chromosome. However, errors in chromosome duplication may also occur during the rapid cell division that takes place immediately after conception. In these cases,