Fitness training balances five elements of good health. Make sure your routine includes aerobic fitness, muscular fitness, stretching, core exercise and balance training.

By Mayo Clinic staff

Whether you're a novice taking the first steps toward fitness or an exercise fanatic hoping to optimize your results, a well-rounded fitness training program is essential. Include these five elements to create a balanced routine.

Aerobic fitness

Aerobic exercise, also known as cardio or endurance activity, is the cornerstone of most fitness training programs. Aerobic exercise causes you to breathe faster and more deeply, which maximizes the amount of oxygen in your blood. The better your aerobic fitness, the more efficiently your heart, lungs and blood vessels transport oxygen throughout your body — and the easier it is to complete routine physical tasks and rise to unexpected challenges, such as running to your car in the pouring rain.

Aerobic exercise includes any physical activity that uses large muscle groups and increases your heart rate. Try walking, jogging, biking, swimming, dancing, water aerobics — even leaf raking, snow shoveling and vacuuming. Aim for at least two hours and 30 minutes a week of moderate aerobic activity or one hour and 15 minutes a week of vigorous aerobic activity — preferably spread throughout the week.

Strength training

Muscular fitness is another key component of a fitness training program. Strength training at least twice a week can help you increase bone strength and muscular fitness. It can also help you maintain muscle mass during a weight-loss program.

Most fitness centers offer various resistance machines, free weights and other tools for strength training. But you don't need to invest in a gym membership or expensive equipment to reap the benefits of strength training. Hand-held weights or homemade weights — such as plastic soft drink bottles filled with water or sand — may work just as well. Resistance bands are another inexpensive option. Your own body weight counts, too. Try push-ups, abdominal crunches and leg squats.

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Anxiety disorders range from feelings of uneasiness to immobilizing bouts of terror. This fact sheet briefly describes the different types of anxiety disorders. This fact sheet is not exhaustive, nor does it include the full range of symptoms and treatments. Keep in mind that new research can yield rapid and dramatic changes in our understanding of and approaches to mental disorders. If you believe you or a loved one has an anxiety disorder, seek competent, professional advice or another form of support.

Generalized Anxiety Disorder: Most people experience anxiety at some point in their lives and some nervousness in anticipation of a real situation. However if a person cannot shake unwarranted worries, or if the feelings are jarring to the point of avoiding everyday activities, he or she most likely has an anxiety disorder.
Symptoms: Chronic, exaggerated worry, tension, and irritability that appear to have no cause or are more intense than the situation warrants. Physical signs, such as restlessness, trouble falling or staying asleep, headaches, trembling, twitching, muscle tension, or sweating, often accompany these psychological symptoms.
Formal diagnosis: When someone spends at least six months worried excessively about everyday problems. However, incapacitating or troublesome symptoms warranting treatment may exist for shorter periods of time.
Treatment: Anxiety is among the most common, most treatable mental disorders. Effective treatments include cognitive behavioral therapy, relaxation techniques, and biofeedback to control muscle tension. Medication, most commonly anti-anxiety drugs, such as benzodiazepine and its derivatives, also may be required in some cases. Some commonly prescribed anti-anxiety medications are diazepam, alprazolam, and lorazepam. The non-benzodiazepine anti-anxiety medication buspirone can be helpful for some individuals.

Panic Disorder: People with panic disorder experience white-knuckled, heart-pounding terror that strikes suddenly and without warning. Since they cannot predict when a panic attack will seize them, many people live in persistent worry that another one could overcome them at any moment.
Symptoms: Pounding heart, chest pains, lightheadedness or dizziness, nausea, shortness of breath, shaking or trembling, choking, fear of dying, sweating, feelings of unreality, numbness or tingling, hot flashes or chills, and a feeling of going out of control or going crazy.
Formal Diagnosis: Either four attacks within four weeks or one or more attacks followed by at least a month of persistent fear of having another attack. A minimum of four of the symptoms listed above developed during at least one of the attacks. Most panic attacks last only a few minutes, but they occasionally go on for ten minutes, and, in rare cases, have been known to last for as long as an hour. They can occur at any time, even during sleep.
Treatment: Cognitive behavioral therapy and medications such as high-potency anti-anxiety drugs like alprazolam. Several classes of antidepressants (such as paroxetine, one of the newer selective serotonin reuptake inhibitors) and the older tricyclics and monoamine oxidase inhibitors (MAO inhibitors) are considered "gold standards" for treating panic disorder. Sometimes a combination of therapy and medication is the most effective approach to helping people manage their symptoms. Proper treatment helps 70 to 90 percent of people with panic disorder, usually within six to eight weeks.

Phobias: Most of us steer clear of certain, hazardous things. Phobias however, are irrational fears that lead people to altogether avoid specific things or situations that trigger intense anxiety. Phobias occur in several forms, for example, agoraphobia is the fear of being in any situation that might trigger a panic attack and from which escape might be difficult. Social phobia is a fear of being extremely embarrassed in front of other people. The most common social phobia is fear of public speaking.
Symptoms: Many of the physical symptoms that accompany panic attacks - such as sweating, racing heart, and trembling - also occur with phobias.
Formal Diagnosis: The person experiences extreme anxiety with exposure to the object or situation; recognizes that his or her fear is excessive or unreasonable; and finds that normal routines, social activities, or relationships are significantly impaired as a result of these fears.
Treatment: Cognitive behavioral therapy has the best track record for helping people overcome most phobic disorders. The goals of this therapy are to desensitize a person to feared situations or to teach a person how to recognize, relax, and cope with anxious thoughts and feelings. Medications, such as anti-anxiety agents or antidepressants, can also help relieve symptoms. Sometimes therapy and medication are combined to treat phobias.

Post-traumatic Stress Disorder: Researchers now know that anyone, even children, can develop PTSD if they have experienced, witnessed, or participated in a traumatic occurrence-especially if the event was life threatening. PTSD can result from terrifying experiences such as rape, kidnapping, natural disasters, or war or serious accidents such as airplane crashes. The psychological damage such incidents cause can interfere with a person's ability to hold a job or to develop intimate relationships with others.
Symptoms: The symptoms of PTSD can range from constantly reliving the event to a general emotional numbing. Persistent anxiety, exaggerated startle reactions, difficulty concentrating, nightmares, and insomnia are common. People with PTSD typically avoid situations that remind them of the traumatic event, because they provoke intense distress or even panic attacks.
Formal Diagnosis: Although the symptoms of PTSD may be an appropriate initial response to a traumatic event, they are considered part of a disorder when they persist beyond three months.
Treatment: Psychotherapy can help people who have PTSD regain a sense of control over their lives. They also may need cognitive behavior therapy to change painful and intrusive patterns of behavior and thought and to learn relaxation techniques. Support from family and friends can help speed recovery and healing. Medications, such as antidepressants and anti-anxiety agents to reduce anxiety, can ease the symptoms of depression and sleep problems. Treatment for PTSD often includes both psychotherapy and medication.

For more information, as well as referrals to specialists and self-help groups in your State, contact:
Anxiety Disorders Association of America
8730 Georgia Avenue - Suite 600
Silver Spring, MD 20910
Telephone: 240-485-1001
Fax: 240-485-1035
www.adaa.org

Mental Help Net
CenterSite, LLC
570 Metro Place
Dublin, OH 43017
http://mentalhelp.net/poc/center_index.php?id=1

National Mental Health Association
2001 Beauregard Street, 12th Floor
Alexandria, VA 22311
Telephone: 800-969-6642
Fax: 703-684-5968
(TDD): 800-433-5959
www.nmha.org/infoctr/factsheets/index.cfm

The National Institute of Mental Health's toll-free information line is
1-866-615-6464; their web address is

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Hodgkin disease (or Hodgkin lymphoma) is a type of lymphoma. There are 2 kinds of lymphoma:

Hodgkin disease (named after Dr. Thomas Hodgkin, who recognized it in 1832)

non-Hodgkin lymphoma

Non-Hodgkin lymphoma is covered in a separate American Cancer Society document.


The Lymph System and Lymphoid Tissue

To better understand Hodgkin disease, it helps to know about the body's lymph (pronounced "limf") system. The lymph system is made up of lymphoid tissue, lymph vessels, and a clear fluid called lymph.

Lymphatic tissue includes the lymph nodes and other organs that are part of the body’s immune and blood-forming systems. Lymph nodes are small, bean-shaped organs found in many places throughout the body. Other parts of the lymphatic system include the spleen, the bone marrow, and the thymus gland.

The lymph nodes make and store lymphocytes, which are special white blood cells that fight infection. There are 2 types of lymphocytes: B lymphocytes (or B cells) and T lymphocytes (or T cells). Most cases of Hodgkin disease start in B lymphocytes.


Start and Spread of Hodgkin Disease

Because lymphatic tissue is found in many parts of the body, Hodgkin disease can start almost anywhere. Most often it starts in lymph nodes in the upper part of the body. (Those in the chest, neck, or under the arms.) This disease causes the lymphatic tissue to become enlarged and press on nearby structures. But lymph nodes can become swollen for many reasons. Most often it happens when the body is fighting an infection.

Hodgkin disease can spread through the lymphatic vessels in a stepwise fashion from lymph node to lymph node. Rarely, and late in the disease, it gets into the blood vessels and can then spread to almost any other place in the body.


The Hodgkin Disease Cell

The cancer cells in Hodgkin disease are unique. They are called Reed-Sternberg cells (or Hodgkin cells). They are an abnormal type of B lymphocyte that is much larger than normal lymphocytes.

The 2 main types are classical Hodgkin disease (which has several subtypes) and nodular lymphocyte predominance Hodgkin disease. The types differ in the way the cancer cells look under a microscope. The types are important because each grows and spreads in a different way. Often they are treated differently. Ask your doctor about the exact type of Hodgkin disease you (or your loved one) has.


Classical Hodgkin Disease

Classical Hodgkin disease (HD) accounts for about 95% of all cases of Hodgkin disease in developed countries. It has 4 subtypes, all of which have Reed-Sternberg cells that can be seen under the microscope.


Nodular Lymphocyte Predominant Hodgkin Disease

Nodular lymphocyte predominant Hodgkin disease (NLPHD) accounts for about 5% of Hodgkin disease. This type mostly involves lymph nodes in the neck and under the arm.

All types of Hodgkin disease are cancerous (malignant) because as they grow they may compress, invade, and destroy normal tissue and spread to other tissues. Hodgkin disease occurs in both children and adults. Because Hodgkin disease is similar in both children and adults, this document covers treatment in both groups.

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The immune system is the body's means of protection against microorganisms and other "foreign" substances. It is composed of two major parts. One component, B lymphocytes, produces antibodies, proteins that attack "foreign" substances and cause them to be removed from the body; this is sometimes called the humoral immune system. The other component consists of special white blood cells called T lymphocytes, which can attack "foreign" substances directly; this is sometimes called the cellular immune system. It takes time for both components of the immune system to develop. The only protections a newborn will have are the antibodies that have transferred from the mother to the baby before birth. T lymphocytes become protective, and antibodies are developed after a person is exposed to specific "foreign" threats. Over a lifetime, the immune system develops an extensive library of identified substances and microorganisms that are cataloged as “threat” or “not threat.” Vaccinations utilize this process to add to the library. They expose a person’s immune system to weakened or inactivated forms of bacteria and viruses that can no longer cause disease, so that the person’s immune system will recognize them and create antibodies that will be ready to protect against the infectious forms of these microorganisms if the person comes in contact with them in the future.

Normally, the immune system can distinguish between “self” and “not self” and only attacks those tissues that it recognizes as “not self.” This is usually the desired response, but not always. When a person is given an organ transplant, the immune system will correctly recognize the new organ as “not self” (unless it is from an identical twin) and will attack it in a process called rejection. To prevent rejection, the transplant patient must take drugs that reduce the activity of the immune system (immunosuppressants) for the rest of his life.

What are autoimmune disorders?
Autoimmune disorders are diseases caused by the body producing an inappropriate immune response against its own tissues. Sometimes the immune system will cease to recognize one or more of the body’s normal constituents as “self” and will create autoantibodies – antibodies that attack its own cells, tissues, and/or organs. This causes inflammation and damage and it leads to autoimmune disorders.

The cause of autoimmune diseases is unknown, but it appears that there is an inherited predisposition to develop autoimmune disease in many cases. In a few types of autoimmune disease (such as rheumatic fever), a bacteria or virus triggers an immune response, and the antibodies or T-cells attack normal cells because they have some part of their structure that resembles a part of the structure of the infecting microorganism.

Autoimmune disorders fall into two general types: those that damage many organs (systemic autoimmune diseases) and those where only a single organ or tissue is directly damaged by the autoimmune process (localized). However, the distinctions become blurred as the effect of localized autoimmune disorders frequently extends beyond the targeted tissues, indirectly affecting other body organs and systems. Some of the most common types of autoimmune disorders include:
Systemic Autoimmune Diseases Localized Autoimmune Diseases

Rheumatoid arthritis (RA) and Juvenile RA (JRA) (joints; less commonly lung, skin)
Type 1 Diabetes Mellitus (pancreas islets)

Lupus [Systemic Lupus Erythematosus] (skin, joints, kidneys, heart, brain, red blood cells, other)
Hashimoto's thyroiditis, Graves' disease (thyroid)

Scleroderma (skin, intestine, less commonly lung)
Celiac disease, Crohn's disease, Ulcerative colitis (GI tract)

Sjogren's syndrome (salivary glands, tear glands, joints)
Multiple sclerosis*

Goodpasture's syndrome (lungs, kidneys)
Addison's disease (adrenal)


Wegener's granulomatosis (blood vessels, sinuses, lungs, kidneys)
Primary biliary cirrhosis, Sclerosing cholangitis, Autoimmune hepatitis (liver)

Polymyalgia Rheumatica (large muscle groups)
Temporal Arteritis / Giant Cell Arteritis (arteries of the head and neck)

Guillain-Barre syndrome (nervous system)




* There is still some debate as to whether MS is an autoimmune disease

For a more complete list of autoimmune conditions, visit the Patient Information page of the American Autoimmune Related Diseases Association, Inc.

In some cases, a person may have more than one autoimmune disease; for example, persons with Addison's disease often have type 1 diabetes, while persons with sclerosing cholangitis often have ulcerative colitis.

In some cases, the antibodies may not be directed at a specific tissue or organ; for example, antiphospholipid antibodies can react with clotting proteins in the blood, leading to formation of blood clots within the blood vessels (thrombosis).

Autoimmune disorders are diagnosed, evaluated, and monitored through a combination of autoantibody blood tests, blood tests to measure inflammation and organ function, clinical presentation, and through non-laboratory examinations such as X-rays. There is currently no cure for autoimmune disorders, although in rare cases they may disappear on their own. Many people may experience flare-ups and temporary remissions in symptoms, others chronic symptoms or a progressive worsening. Treatment of autoimmune disorders is tailored to the individual and may change over time. The goal is to relieve symptoms, minimize organ and tissue damage, and preserve organ function. New treatments and a greater understanding of autoimmune disorders are being researched. Patients should talk to their doctors and to any specialists they are referred to about their treatment options.

For more information on specific autoimmune disorders, see the related condition pages and web sites listed below.

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Millions of Americans have found relief from depression and other emotional difficulties through psychotherapy. Even so, some people find it hard to get started or stay in psychotherapy. This brief question-and-answer guide provides some basic information to help individuals take advantage of outpatient (non-hospital) psychotherapy.

Why do people consider using psychotherapy?

Psychotherapy is a partnership between an individual and a professional such as a psychologist who is licensed and trained to help people understand their feelings and assist them with changing their behavior. According to the National Institute of Mental Health, one-third of adults in the United States experience an emotional or substance abuse problem. Nearly 25 percent of the adult population suffers at some point from depression or anxiety.

People often consider psychotherapy, also known simply as therapy, under the following circumstances:

- They feel an overwhelming and prolonged sense of sadness and helplessness, and they lack hope in their lives.
- Their emotional difficulties make it hard for them to function from day to day. For example, they are unable to concentrate on assignments and their job performance suffers as a result.
- Their actions are harmful to themselves or to others. For instance, they drink too much alcohol and become overly aggressive.
- They are troubled by emotional difficulties facing family members or close friends.

What does research show about the effectiveness of psychotherapy?

Research suggests that therapy effectively decreases patients' depression and anxiety and related symptoms- such as pain, fatigue and nausea. Psychotherapy has also been found to increase survival time for heart surgery and cancer patients, and it can have a positive effect on the body's immune system. Research increasingly supports the idea that emotional and physical health are very closely linked and that therapy can improve a person's overall health status.

There is convincing evidence that most people who have at least several sessions of psychotherapy are far better off than untreated individuals with emotional difficulties. One major study showed that 50 percent of patients noticeably improved after eight sessions while 75 percent of individuals in therapy improved by the end of six months. Psychotherapy with children is similar in effectiveness to psychotherapy with adults.

How do I find a qualified therapist?

Selecting a therapist is a highly personal matter. A professional who works very well with one individual may not be a good choice for another person. There are several ways to get referrals to qualified therapists, such as licensed psychologists, including the following:

- Talk to close family members and friends for their recommendations, especially if they have had a good experience with psychotherapy.
- Many state psychological associations operate referral services which put individuals in touch with licensed and competent mental health providers. (Call the American Psychological Association's consumer information line at 800-964-2000 to be connected to the appropriate state organization.)
- Ask your primary care physician (or other health professional) for a referral. Tell the doctor what's important to you in choosing a therapist so he or she can make appropriate suggestions.
- Inquire at your church or synagogue.
- Look in the phone book for the listing of a local mental health association or community mental health center and check these sources for possible referrals.

Ideally, you will end up with more than one lead. Call and request the opportunity, either by phone or in person, to ask the therapist some questions. You might want to inquire about his or her licensure and level of training, approach to psychotherapy, participation in insurance plans and fees. Such a discussion should help you sort through your options and choose someone with whom you believe you might interact well.

If I begin psychotherapy, how should I try to gain the most from it?

There are many approaches to outpatient psychotherapy and various formats in which it may occur, including individual, group and family psychotherapy. Despite the variations, all psychotherapy is a two-way process that works especially well when patients and their therapists communicate openly. Research has shown that the outcome of psychotherapy is improved when the therapist and patient agree early about what the major problems are and how psychotherapy can help.

You and your therapist both have responsibilities in establishing and maintaining a good working relationship. Be clear with your therapist about your expectations and share any concerns that may arise. Psychotherapy works best when you attend all scheduled sessions and give some forethought to what you want to discuss during each one.

How can I evaluate whether therapy is working well?

As you begin psychotherapy, you should establish clear goals with your therapist. Perhaps you want to overcome feelings of hopelessness associated with depression. Or maybe you would like to control a fear that disrupts your daily life. Keep in mind that certain tasks require more time to accomplish than others. You may need to adjust some of your goals depending on how long you plan to be in psychotherapy.

After a few sessions, it's a good sign if you feel the experience is truly a joint effort and that you and the therapist enjoy a good rapport. On the other hand, you should be open with your therapist if you find yourself feeling "stuck" or lacking direction once you've been in psychotherapy awhile.

There may be times when a therapist appears cold and uninterested or doesn't seem to regard you positively. Tell your therapist if this is the situation, or if you question other aspects of his or her approach. If you find yourself thinking about discontinuing psychotherapy, talk with your therapist. It might be helpful to consult another professional, provided you let your therapist know you are seeking a second opinion.

Patients often feel a wide range of emotions during psychotherapy. Some qualms about psychotherapy that people may have result from the difficulty of discussing painful and troubling experiences. When this happens, it can actually be a positive sign indicating that you are starting to explore your thoughts and behaviors.

You should spend time with your therapist periodically reviewing your progress (or your concern that you are not making sufficient headway). Although there are other considerations affecting the duration of psychotherapy, success in reaching your primary goals should be a major factor in deciding when your psychotherapy should end.

Psychotherapy isn't easy, but patients who are willing to work in close partnership with their therapists often find relief from their emotional distress and begin to lead more productive and fulfilling lives.

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Von Hippel-Lindau syndrome is an inherited disorder characterized by the formation of tumors and fluid-filled sacs (cysts) in many different parts of the body. Tumors may be either noncancerous or cancerous and usually appear during young adulthood; however, the signs and symptoms of von Hippel-Lindau syndrome can occur throughout life.

Tumors called hemangioblastomas are characteristic of von Hippel-Lindau syndrome. These growths are made of newly formed blood vessels and are typically noncancerous. Hemangioblastomas that develop in the brain and spinal cord can cause headaches, vomiting, weakness, and a loss of muscle coordination (ataxia). Hemangioblastomas can also occur in the light-sensitive tissue that lines the back of the eye (the retina). These tumors, which are also called retinal angiomas, may cause vision loss.

People with von Hippel-Lindau syndrome commonly develop cysts in the kidneys, pancreas, and male genital tract. They are also at an increased risk of developing a type of kidney cancer called clear cell renal cell carcinoma and a type of noncancerous tumor called a pheochromocytoma. Pheochromocytomas affect the adrenal glands, which are small hormone-producing glands located on top of each kidney. These tumors often cause no symptoms, but in some cases they can produce an excess of hormones that cause dangerously high blood pressure.

About 10 percent of people with von Hippel-Lindau syndrome develop endolymphatic sac tumors, which are noncancerous tumors in the inner ear. These growths can cause hearing loss in one or both ears, as well as ringing in the ears (tinnitus) and problems with balance.

Von Hippel-Lindau syndrome can be divided into two major types based on the risk of developing pheochromocytomas. Type 1 von Hippel-Lindau syndrome is associated with a low risk of these tumors, and type 2 is characterized by a much higher risk. Type 2 can be further divided into types 2A, 2B, and 2C, depending on the probability of developing renal cell carcinoma and hemangioblastomas.
How common is von Hippel-Lindau syndrome?

The incidence of von Hippel-Lindau syndrome is estimated to be 1 in 36,000 individuals.
What genes are related to von Hippel-Lindau syndrome?

Mutations in the VHL gene cause von Hippel-Lindau syndrome. The VHL gene is a tumor suppressor gene, which means it keeps cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in this gene prevent production of the VHL protein or lead to the production of an abnormal version of the protein. An altered or missing VHL protein cannot effectively regulate cell survival and division. As a result, cells grow and divide uncontrollably to form the tumors and cysts that are characteristic of von Hippel-Lindau syndrome.

Read more about the VHL gene.
How do people inherit von Hippel-Lindau syndrome?

Mutations in the VHL gene are inherited in an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to increase the risk of developing tumors and cysts. Most people with von Hippel-Lindau syndrome inherit an altered copy of the gene from an affected parent. In about 20 percent of cases, however, the altered gene is the result of a new mutation that occurred during the formation of reproductive cells (eggs or sperm) or very early in development.

Unlike most autosomal dominant conditions, in which one altered copy of a gene in each cell is sufficient to cause the disorder, two copies of the VHL gene must be altered to trigger tumor and cyst formation in von Hippel-Lindau syndrome. A mutation in the second copy of the VHL gene occurs during a person's lifetime in certain cells within organs such as the brain, retina, and kidneys. Cells with two altered copies of this gene make no functional VHL protein, which allows tumors and cysts to develop. Almost everyone who inherits one VHL mutation will eventually acquire a mutation in the second copy of the gene in some cells, leading to the features of von Hippel-Lindau syndrome.
Where can I find information about treatment for von Hippel-Lindau syndrome?

These resources address the management of von Hippel-Lindau syndrome and may include treatment providers.
Brigham and Women's Hospital
Gene Review
Genetic Alliance
M. D. Anderson Cancer Center
MedlinePlus Encyclopedia: Pheochromocytoma
MedlinePlus Encyclopedia: Renal Cell Carcinoma

You might also find information on treatment of von Hippel-Lindau syndrome in Educational resources and Patient support.
Where can I find additional information about von Hippel-Lindau syndrome?

You may find the following resources about von Hippel-Lindau syndrome helpful. These materials are written for the general public.
MedlinePlus - Health information (5 links)
Additional NIH Resources - National Institutes of Health (4 links)
Educational resources - Information pages (8 links)
Patient support - For patients and families (4 links)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.
Gene Reviews - Clinical summary
Gene Tests - DNA tests ordered by healthcare professionals
ClinicalTrials.gov - Linking patients to medical research
PubMed - Recent literature
OMIM - Genetic disorder catalog
What other names do people use for von Hippel-Lindau syndrome?
Angiomatosis retinae
Cerebelloretinal Angiomatosis, Familial
Hippel-Lindau Disease
VHL syndrome
von Hippel-Lindau Disease

See How are genetic conditions and genes named? in the Handbook.
What if I still have specific questions about von Hippel-Lindau syndrome?
See How can I find a genetics professional in my area? in the Handbook.
Ask the Genetic and Rare Diseases Information Center.
Submit your question to Ask the Geneticist.
Where can I find general information about genetic conditions?

The Handbook provides basic information about genetics in clear language.
What does it mean if a disorder seems to run in my family?
What are the different ways in which a genetic condition can be inherited?
If a genetic disorder runs in my family, what are the chances that my children will have the condition?
Why are some genetic conditions more common in particular ethnic groups?

These links provide additional genetics resources that may be useful.
Genetics and health
Resources for Patients and Families
Resources for Health Professionals
What glossary definitions help with understanding von Hippel-Lindau syndrome?

adrenal glands ; angioma ; ataxia ; autosomal ; autosomal dominant ; cancer ; carcinoma ; cell ; cysts ; egg ; familial ; gene ; hemangioblastoma ; hormone ; incidence ; kidney ; mutation ; new mutation ; pancreas ; pheochromocytoma ; probability ; protein ; renal ; reproductive cells ; retina ; sign ; sperm ; symptom ; syndrome ; tinnitus ; tissue ; tumor ; tumor suppressor gene

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.
References (7 links)

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? in the Handbook.

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Tuberous sclerosis complex (TSC) is a genetic disorder that causes tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs. You will see it referred to both as tuberous sclerosis (TS) and tuberous sclerosis complex (TSC). The term TSC is used in scientific literature to distinguish tuberous sclerosis complex from Tourette's syndrome.

The disease affects some people severely, while others are so mildly affected that it often goes undiagnosed. Some people with TSC experience developmental delay, mental retardation and autism. However, there are also many people with TSC living independent, healthy lives who enjoy challenging professions such as doctors, lawyers, educators and researchers.

How many people have TSC?

At least two children born each day will have tuberous sclerosis complex. Current estimates place tuberous sclerosis complex-affected births at one in 6,000. Nearly 1 million people worldwide are known to have TSC, with approximately 50,000 in the United States. There are many undiagnosed cases due to the obscurity of the disease and the mild form symptoms may take in some people. TSC is as common as ALS (Lou Gehrig's Disease) but virtually unknown by the general population.

How does a person develop TSC?

Tuberous sclerosis complex is transmitted either through genetic inheritance or as a spontaneous genetic mutation. Children have a 50 percent chance of inheriting TSC if one of their parents has this condition. At this point, only one-third of TSC cases are known to be inherited. The other two-thirds are believed to be a result of spontaneous mutation. The cause of these mutations is still a mystery.

If a parent has a mild form of TSC, will their child with TSC also be mildly affected?

People with mild cases of tuberous sclerosis complex can produce a child who is more severely affected. In fact, some people are so mildly affected that they may only find out they also have TSC after their more severely affected child receives a diagnosis of TSC.

How is TSC diagnosed?

Diagnosis of tuberous sclerosis complex is currently made after the following tests are preformed: a brain MRI or CT Scan, renal ultrasound, echocardiogram of the heart, EKG, eye exam and a Wood's Lamp evaluation of the skin.

What genes are responsible for TSC?

Two genes have been identified that can cause tuberous sclerosis complex. Only one of the genes needs to be affected for TSC to be present. The TSC1 gene is located on chromosome 9 and is called the hamartin gene. The other gene, TSC2, is located on chromosome 16 and is called the tuberin gene. Researchers are now trying to determine what these genes do and how a defect in these genes causes tuberous sclerosis complex.

How can so many different organs be affected by TSC?

Both the TSC1 and TSC2 genes are believed to suppress tumor growth in the body. When either of these genes are defective, tumors are not suppressed and tuberous sclerosis complex results. The genes also play a role in the early fetal development of the brain and skin.

Are the tumors cancerous?

The tumors resulting from tuberous sclerosis complex are non-cancerous, but may still cause serious problems. Tumors that grow in the brain can block the flow of cerebral spinal fluid in the spaces (ventricles) in the brain. This can lead to behavior changes, nausea, headaches or a number of other symptoms. In the heart, the tumors are usually at their largest at birth, and then decrease in size as the individual gets older. These heart tumors, called cardiac rhabdomyomas, can cause problems at birth if they are blocking the flow of blood or causing severe arrhythmia problems. The tumors in the eyes are not as common, but can present problems if they grow and block too much of the retina. The tumors in the kidney (renal angiomyolipoma) can become so large they eventually take over all of the normal kidney function. In the past, the patient was left until they developed kidney failure. Today, doctors are more aggressive and remove individual tumors before they get too large and compromise healthy kidney tissue. Very rarely (less than 2 percent of) individuals with TSC develop malignant (cancerous) kidney tumors.

What is the normal life expectancy of an individual with TSC?

Most people with TSC will live a normal life span. There can be complications in some organs such as the kidneys and brain that can lead to severe difficulties and even death if left untreated. To reduce these dangers, people with TSC should be monitored throughout their life by their physician for potential complications. Thanks to research findings and improved medical therapies, people with tuberous sclerosis complex can expect improved health care.

Since there is no cure, what can be done?

Early intervention is helping to overcome developmental delays. Advancements in research are bringing new and improved therapeutic options. Surgery to remove tumors or stop tumor growth is helping to preserve the function of affected organs. Technology is pinpointing the exact portions of the brain stimulating seizures and creating new therapies to help control seizures. With every new day we are one step closer to finding improved treatments.

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1. What is Tourette Syndrome?

Tourette Syndrome TS) is a neurological disorder characterized by tics -- involuntary, rapid, sudden movements or vocalizations that occur repeatedly in the same way. The symptoms include:
Both multiple motor and one or more vocal tics present at some time during the illness although not necessarily simultaneously;

The occurrence of tics many times a day (usually in bouts) nearly every day or intermittently throughout a span of more than one year; and

Periodic changes in the number, freency, type and location of the tics, and waxing and waning of their severity. Symptoms can sometimes disappear for weeks or months at a time.

Onset before the age of 18.

The term, "involuntary," used to describe TS tics is sometimes confusing since it is known that most people with TS do have some control over their symptoms. What is not recognized is that the control, which can be exercised anywhere from seconds to hours at a time, may merely postpone more severe outbursts of symptoms. Tics are experienced as irresistible and (as with the urge to sneeze) eventually must be expressed. People with TS often seek a secluded spot to release their symptoms after delaying them in school or at work. Typically, tics increase as a result of tension or stress, and decrease with relaxation or when focusing on an absorbing task.


2. How would a typical case of TS be described?

The term typical cannot be applied to TS. The expression of symptoms covers a spectrum from very mild to quite severe. However, the majority of cases can be categorized as mild.


3. Is obscene language (coprolalia) a typical symptom of TS?

Definitely not. The fact is that cursing, uttering obscenities, and ethnic slurs are manifested by fewer than 15% of people with TS. Too often, however, the media seize upon this symptom for its sensational effect. Because milder cases are being diagnosed, the incidence of coprolalia will probably decrease.


4. What causes the symptoms?

The cause has not been established, although current research presents considerable evidence that the disorder stems from the abnormal activity of at least one brain chemical (neurotransmitter) called dopamine. There may be abnormal activity of the receptor for this chemical as well. Undoubtedly, other neurotransmitters, e.g. serotonin, may involved as well.


5. How is TS diagnosed?

A diagnosis is made by observing symptoms and by evaluating the history of their onset. No blood analysis or other type of neurological testing exists to diagnose TS. However, some physicians may wish to order an EEG, MRI, CAT scan, or certain blood tests to rule out other ailments that might be confused with TS. Rating scales are available for assessment of tic severity.


6. What are the first symptoms?

The most common first symptom is a facial tic such as rapidly blinking eyes or twitches of the mouth. Involuntary sounds such as throat clearing and sniffing, or tics of the limbs may be initial signs. For a minority, the disorder begins abruptly with multiple symptoms of movements and sounds.


7. How are tics classified?

Two categories of tics and several other examples are:

Simple:

Motor -- Eye blinking, head jerking, shoulder shrugging and facial grimacing.

Vocal -- Throat clearing, yelping and other noises, sniffing and tongue clicking.

Complex:

Motor -- Jumping, touching other people or things, smelling, twirling about, and only rarely, self-injurious actions including hitting or biting oneself.

Vocal -- Uttering words or phrases out of context and coprolalia (vocalizing socially unacceptable words).

The range of tics or tic-like symptoms that can be seen in TS is very broad. The complexity of some symptoms is often perplexing to family members, friends, teachers and employers who may find it hard to believe that the actions or vocal utterances are involuntary.


8. How is TS treated?

The majority of people with TS are not significantly disabled by their tics or behavioral symptoms, and therefore do not require medication. However, there are medications available to help control the symptoms when they interfere with functioning. The drugs include haloperidol (Haldol), clonidine (Catapres), pimozide (Orap), risperidone (Risperdal), fluphenazine (Prolixin, Permitil), and clonazepam (Klonopin). Drugs such as methylphenidate (Ritalin) and related drugs, and dextroamphetamine (Dexedrine) that are prescribed for ADHD have been described as increasing tics; this is controversial. Recent studies have not found a correlation with the use of these medication and an increase in tics. For obsessive compulsive traits that interfere significantly with daily functioning, fluoxetine (Prozac), clomipramine (Anafranil), sertraline (Zoloft) and paroxetine (Paxil) may be prescribed.

Dosages which achieve maximum control of symptoms vary for each patient and must be gauged carefully by a doctor. The medicine is administered in small doses with gradual increases to the point where there is maximum alleviation of symptoms with minimal side effects. Some of the undesirable reactions to medications are weight gain, muscular rigidity, fatigue, motor restlessness and social withdrawal, most of which can be reduced with specific medications. Some side effects such as depression and cognitive impairment can be alleviated with dosage reduction or a change of medication.

Other types of therapy may also be helpful. Psychotherapy and counseling can assist a person with TS and help his/her family cope, and some behavior therapies can teach the substitution of one tic for another that is more acceptable. The use of relaxation techniques and/or biofeedback may serve to alleviate stress reactions that cause tics to increase.


9. Is it important to treat Tourette Syndrome early?

Yes, especially in those instances when the symptoms are viewed by some people as bizarre, disruptive and frightening. It is also important to consider therapy when the child is concerned over her/his acceptance to peers. Sometimes TS symptoms provoke ridicule and rejection by peers, neighbors, teachers and even casual observers. Parents may be overwhelmed by the strangeness of their child's behavior. The child may be threatened, excluded from activities and prevented from enjoying normal interpersonal relationships. These difficulties may become greater during adolescence -- an especially trying period for young people and even more so for a person coping with a neurological problem. To avoid psychological harm, early diagnosis and treatment are crucial. Moreover, in more serious cases, it is possible to control many of the symptoms with medication.


10. Do all people with TS have associated behaviors in addition to tics?

No, but many do have one or more additional problems which may include:

Obsessions which consist of repetitive thoughts which can become unwanted or bothersome.

Compulsions and Ritualistic Behaviors which occur when a person feels that something must be done over and over and/or in a certain way. Examples include touching an object with one hand after touching it with the other hand to "even things up" or repeatedly checking to see that the flame on the stove is turned off. Children sometimes beg their parents to repeat a sentence many times until it "sounds right." Repetitive copying and erasing of work in school can be quite disabling.

Attention Deficit Disorder with or without Hyperactivity
(ADD or ADHD) occurs in many people with TS. Children may show signs of hyperactivity before TS symptoms appear. Indications of ADHD may include: difficulty with concentration; failing to finish what is started; not listening; being easily distracted; often acting before thinking; shifting constantly from one activity to another; needing a great deal of supervision; and general fidgeting. Adults too may exhibit signs of ADHD such as overly impulsive behavior and concentration difficulties and the need to move constantly. ADD without hyperactivity includes all of the above symptoms except for the high level of activity. As children with ADHD mature, the need to move is more likely to be expressed by restless, fidgety behavior. Difficulties with concentration and poor impulse control may persist.

Learning Disabilities may include reading and writing difficulties, problems with mathematics, and perceptual problems.

Difficulties with impulse control which may result, in rare instances, in overly aggressive behaviors or socially inappropriate acts. Also, defiant and angry behaviors can occur.

Sleep Disorders are fairly common among people with TS. These include difficulty getting to sleep, frequent awakenings or walking or talking in one's sleep.


11. Do students with TS have special educational needs?

While school children with TS as a group have the same IQ range as the population at large, many have special educational needs. Data show that many may have some kind of learning problem. That condition, combined with attention deficits and the difficulty coping with frequent tics, often call for special educational assistance. The use of tape recorders, typewriters, or computers for reading and writing problems, un-timed exams (in a private room if vocal tics are a problem), and permission to leave the classroom when tics become overwhelming are often helpful. Some children need extra help such as access to tutoring in a resource room.

When difficulties in school cannot be resolved, an educational evaluation may be indicated. A resulting identification as "other health impaired" under federal law will entitle the student to an Individual Education Plan (IEP) which addresses specific educational problems in school. Such an approach can significantly reduce the learning difficulties that prevent the young person from performing at his/her potential. The child who cannot be adequately educated in a public school with special services geared to his/her individual needs may be best served by enrollment in a special school or home schooled.


12. Is TS inherited?

Genetic studies indicate that TS is inherited as a dominant gene (or genes) causing different symptoms in different family members. A person with TS has about a 50% chance of passing the gene to one of his/her children with each separate pregnancy. However, that genetic predisposition may express itself as TS, as a milder tic disorder or as obsessive compulsive symptoms with no tics at all. It is known that a higher than normal incidence of milder tic disorders and obsessive compulsive behaviors occur in the families of TS patients.

The sex of the offspring also influences the expression of the gene. The chance that the gene-carrying child of a person with TS will have symptoms is at least three to four times higher for a son than for a daughter. Yet only about 10% of the children who inherit the gene will have symptoms severe enough to ever require medical attention. In some cases TS may not be inherited, and cases such as these are identified as sporadic TS. The cause in these instances is unknown.


13. Is there a cure?

Not yet.


14. Is there ever a remission?

Many people experience marked improvement in their late teens or early twenties. Most people with TS get better, not worse, as they mature, and those diagnosed with TS have a normal life span. As many as 1/3 of patients experience remission of tic symptoms in adulthood.


15. How many people in the U.S. have TS?

Since many people with TS have yet to be diagnosed, there are no absolute figures. The official estimate by the National Institutes of Health is that 100,000 Americans have full-blown TS. Some genetic studies suggest that the figure may be as high as one in two hundred if those with chronic multiple tics and/or transient childhood tics are included in the count.


16. What is the history of TS?

In 1825 the first case of TS was reported in medical literature with a description of the Marquise de Dampierre, a noblewoman whose symptoms included involuntary tics of many parts of her body and various vocalizations including coprolalia and echolalia. Later, Dr. Georges Gilles de la Tourette, the French neurologist for whom the disorder is named, first described nine cases in 1885. Samuel Johnson, the lexicographer, and Andre Malraux, the French author, are among the famous people who are thought to have had TS.


17. What is the current focus of research?

Since 1984, the TSA has directly funded important research investigations in a number of scientific areas relevant to TS. Recently, studies have intensified to understand how the disorder is transmitted from one generation to the next, and researchers are working toward locating the gene marker for TS. That focus has been enhanced by the efforts of a TSA- supported international group of scientists who have formed a unique network to share what they know about the genetics of TS and to systematically cooperate to unravel the unknown. Additional insights are being obtained from studies of large families (kindreds) with numerous members who have TS. At the same time, investigators continue to study specific groups of brain chemicals to better understand the syndrome and to identify new and improved medications.


18. What type of services for families exist?

Local TSA affiliates and support groups allow families to exchange ideas and feelings about their common problems. Often family therapy is helpful. Parents of a child with TS have to walk a fine line between understanding and overprotection. They are constantly faced with deciding whether or not certain actions are the expression of TS or just poor behavior. Parents then must determine the appropriate response. For socially unacceptable behavior, a child should be encouraged to control what he/she can whenever possible, and try to substitute what is more socially acceptable. Parents are urged to give their children with TS the opportunity for as much independence as possible, while gently but firmly limiting attempts by some children to use their symptoms to control those around them.


19. What is the Tourette Syndrome Association?

TSA, founded in 1972, is the only national voluntary non-profit membership organization dedicated to:
Identifying the cause;
Finding the cure; and
Controlling the effects of TS.

Members include individuals with the disorder, their relatives and other interested, concerned people. The Association develops and disseminates educational material to individuals, professionals and to agencies in the fields of health care, education and government; coordinates support services to help people and their families cope with the problems that occur with TS; funds research that will ultimately find the cause of and cure for TS and, at the same time, lead to improved medications and treatments.

TSA also:
Offers direct help to TS families in crisis situations through its Information and Referral Service

Organizes workshops and symposiums for scientists, clinicians and others working in the field of TS

Promotes public awareness and understanding

Develops and maintains state-by-state lists of doctors who can diagnose and treat TS, as well as medical referrals in other countries; lists of allied professionals (psychologists, social workers) by state; ABA lists of pro-bono attorneys by state; advocate lists by state; and lists of health insurance resources by state.

Sponsors the Tourette Syndrome Brain Bank Program involving collection of sorely needed tissue for scientific research

Serves many thousands of members throughout the USA and abroad

Increases the knowledge and sensitivity of health care professionals to TS through exhibits at conferences, the dissemination of literature and the organization of national meetings

Organizes and assists local chapters and support groups throughout the US and around the world

Represents the interests of members to the government on critical policy issues including orphan drugs, health insurance and employment


20. Why become a member of TSA?
To help reduce stigma by supporting TSA in its efforts to increase public understanding of TS symptoms

To help bring about the early identification and proper treatment of TS

To receive the quarterly TSA Newsletter containing the latest information on treatment, research programs and scientific discoveries

To join other families at meetings to discuss common problems and offer mutual support

To obtain discounts on publications

To support TSA advocacy programs

To become eligible for discounted registration fees at TSA National Conferences

To help conquer Tourette Syndrome

The Tourette Syndrome Association has publications and videos that discuss in detail many of the topics touched upon on this page. Visit our online store

The above questions and answers are intended to provide basic information about TS. They are not intended to, nor do they constitute medical advice. Readers are warned against changing medical schedules or life activities based on this information without first consulting a physician.

Our programs of research, professional and public education, and family services are made possible through the generosity of our donors.

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A healthy baby is able to develop vision, movement, hearing, and other vital functions, in part, because enzymes clear out fatty protein and other unwanted material that can interfere with growth.

But a baby with Tay-Sachs disease is born without one of those important enzymes, called Hexosaminidase A (Hex A). So, as those fatty proteins build up in the brain, they hurt the baby's sight, hearing, movement, and mental development.

A child can only get Tay-Sachs by inheriting it. The genetic trait is relatively common among certain ethnic groups, such as Ashkenazi Jews. Because the disease can be detected before a child is born, couples in those ethnic groups who are thinking of having children may want to get a blood test to find out whether their child would be likely to have the disease.
Who Is at Risk for Tay-Sachs?

Each year, about 16 cases of Tay-Sachs are diagnosed in the United States. Although Ashkenazi Jews (Jews of central and eastern European descent) are at the highest risk for the disease, it is now also prevalent in non-Jewish populations, including people of French-Canadian/Cajun heritage.

Some people carry the genetic mutation that causes Tay-Sachs, but do not develop the full-blown disease. Among Ashkenazi Jews, one in 27 people are carriers. In the general population, one in 250 people are carriers.

A child can only have Tay-Sachs disease if both parents are carriers of the gene. When two carriers have a child together, there's a:
50% chance that their child will be a carrier, but not have the disease
25% chance that their child will not be a carrier and not have the disease
25% chance that their child will have the disease
Screening for Tay-Sachs Disease

Couples who are considering having children - or are already expecting - can get screened for the Tay-Sachs gene with a simple blood test. If both the mother and father carry the Tay-Sachs gene, an obstetrician/gynecologist may refer the couple to a genetic counselor for more information.
Prenatal Diagnosis of Tay-Sachs Disease

Pregnant mothers can have their unborn babies screened for the Hex A deficit that causes Tay-Sachs disease. (If the tests do not detect Hex A, the infant will have Tay-Sachs disease. If the tests do detect Hex A, the infant won't have it.)

Between the 10th and 12th weeks of pregnancy, an expectant mother can get a chorionic villus sampling, or CVS, in which a small sample of the placenta is drawn into a needle or a small tube for analysis.

Between the 15th and 18th weeks of pregnancy, the mother can also have an amniocentesis to screen for the Tay-Sachs gene. In this test, a needle is inserted into the mother's belly to draw a sample of the amniotic fluid that surrounds the fetus.
What Are the Signs and Symptoms of Tay-Sachs?

A child is usually tested for Tay-Sachs after he or she starts having hearing, sight, and movement problems. A doctor can identify the disease with a physical exam and blood tests.

A baby born with Tay-Sachs develops normally in the first 3 to 6 months of life. During the next months - or even years - the baby will progressively lose the ability to see, hear, and move. A red spot will develop in the back of the child's eyes. The child will stop smiling, crawling, turning over, and reaching out for things. By the age of 2, the child may have seizures and become completely disabled. Death usually occurs by the time the child is 5 years old.

In rare forms of the disease, a child may have the Hex A enzyme, but not enough of it to prevent developmental problems. In one of these forms, called Juvenile Hex A Deficiency, those problems may not appear until the child is 2 to 5 years old. The disease progresses more slowly, but death usually occurs by the time the child is 15 years old. In another, milder form of Tay-Sachs, the disease causes muscle weakness and slurred speech, but sight, hearing, and mental capabilities remain intact.
Helping a Child With Tay-Sachs

There is no cure for any form of Tay-Sachs disease. But doctors may be able to help your child cope with the symptoms of the disease by prescribing medication to relieve pain, manage seizures, and control muscle spasticity.

Researchers are studying ways to improve treatment for Tay-Sachs disease and screening methods for the disease.

If your child has been diagnosed with Tay-Sachs or both you and your partner are carriers of the gene, talk to your child's doctor or a genetic counselor about ongoing research. You may also want to seek support from a group such as the National Tay-Sachs and Allied Diseases Foundation or the March of Dimes Birth Defects Foundation.

Reviewed by: Louis E. Bartoshesky, MD, MPH

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Rett syndrome is a childhood neurodevelopmental disorder characterized by normal early development followed by loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, gait abnormalities, seizures, and mental retardation. It affects females almost exclusively.

The disorder was identified by Dr. Andreas Rett, an Austrian physician who first described it in a journal article in 1966. It was not until after a second article about the disorder was published in 1983 that the disorder was generally recognized.

The course of Rett syndrome, including the age of onset and the severity of symptoms, varies from child to child. Before the symptoms begin, however, the child appears to grow and develop normally. Then, gradually, mental and physical symptoms appear. Hypotonia (loss of muscle tone) is usually the first symptom. As the syndrome progresses, the child loses purposeful use of her hands and the ability to speak. Other early symptoms may include problems crawling or walking and diminished eye contact. The loss of functional use of the hands is followed by compulsive hand movements such as wringing and washing. The onset of this period of regression is sometimes sudden.

Another symptom, apraxia — the inability to perform motor functions — is perhaps the most severely disabling feature of Rett syndrome, interfering with every body movement, including eye gaze and speech.

Individuals with Rett syndrome often exhibit autistic-like behaviors in the early stages. Other symptoms may include toe walking; sleep problems; wide-based gait; teeth grinding and difficulty chewing; slowed growth; seizures; cognitive disabilities; and breathing difficulties while awake such as hyperventilation, apnea (breath holding), and air swallowing.

What are the stages of the disorder?

There are four stages of Rett syndrome. Stage I, called early onset, generally begins between 6 and 18 months of age. Quite frequently, this stage is overlooked because symptoms of the disorder may be somewhat vague, and parents and doctors may not notice the subtle slowing of development at first. The infant may begin to show less eye contact and have reduced interest in toys. There may be delays in gross motor skills such as sitting or crawling. Hand-wringing and decreasing head growth may occur, but not enough to draw attention. This stage usually lasts for a few months but can persist for more than a year.

Stage II, or the rapid destructive stage, usually begins between ages 1 and 4 and may last for weeks or months. This stage may have either a rapid or a gradual onset as purposeful hand skills and spoken language are lost. The characteristic hand movements begin to emerge during this stage and often include wringing, washing, clapping, or tapping, as well as repeatedly moving the hands to the mouth. Hands are sometimes clasped behind the back or held at the sides, with random touching, grasping, and releasing. The movements persist while the child is awake but disappear during sleep. Breathing irregularities such as episodes of apnea and hyperventilation may occur, although breathing is usually normal during sleep. Some girls also display autistic-like symptoms such as loss of social interaction and communication. General irritability and sleep irregularities may be seen. Gait patterns are unsteady and initiating motor movements can be difficult. Slowing of head growth is usually noticed during this stage.

Stage III, also called the plateau or pseudo-stationary stage, usually begins between ages 2 and 10 and can last for years. Apraxia, motor problems, and seizures are prominent during this stage. However, there may be improvement in behavior, with less irritability, crying, and autistic-like features. An individual in stage III may show more interest in her surroundings, and her alertness, attention span, and communication skills may improve. Many girls remain in this stage for most of their lives.

The last stage, stage IV — called the late motor deterioration stage — can last for years or decades and is characterized by reduced mobility. Muscle weakness, rigidity (stiffness), spasticity, dystonia (increased muscle tone with abnormal posturing of extremity or trunk), and scoliosis (curvature of the spine) are other prominent features. Girls who were previously able to walk may stop walking. Generally, there is no decline in cognition, communication, or hand skills in stage IV. Repetitive hand movements may decrease, and eye gaze usually improves.

What causes Rett syndrome?

Rett syndrome is caused by mutations (structural alterations or defects) in the MECP2 (pronounced meck-pea-two) gene, which is found on the X chromosome (see section on "Who gets Rett syndrome" for a discussion of the importance of the involvement of the X chromosome). Scientists identified the gene — which is believed to control the functions of several other genes — in 1999. The MECP2 gene contains instructions for the synthesis of a protein called methyl cytosine binding protein 2 (MeCP2), which acts as one of the many biochemical switches that tell other genes when to turn off and stop producing their own unique proteins. Because the MECP2 gene does not function properly in those with Rett syndrome, insufficient amounts or structurally abnormal forms of the protein are formed. The absence or malfunction of the protein is thought to cause other genes to be abnormally expressed, but this hypothesis has not yet been confirmed.

Seventy to 80 percent of girls given a diagnosis of Rett syndrome have the MECP2 genetic mutation detected by current diagnostic techniques. Scientists believe the remaining 20 to 30 percent of cases may be caused by partial gene deletions, by mutations in other parts of the gene, or by genes that have not yet been identified; thus, they continue to search for other mutations.

Is Rett syndrome inherited?

Although Rett syndrome is a genetic disorder — resulting from a faulty gene or genes — less than 1 percent of recorded cases are inherited or passed from one generation to the next. Most cases are sporadic, which means the mutation occurs randomly, mostly during spermatogenesis, and is not inherited.

Who gets Rett syndrome?

Rett syndrome affects one in every 10,000 to 15,000 live female births. It occurs in all racial and ethnic groups worldwide. Prenatal testing is available for families with an affected daughter who has an identified MECP2 mutation. Since the disorder occurs spontaneously in most affected individuals, however, the risk of a family having a second child with the disorder is less than 1 percent.

Genetic testing is also available for sisters of girls with Rett syndrome and an identified MECP2 mutation to determine if they are asymptomatic carriers of the disorder, which is an extremely rare possibility.

Girls have two X chromosomes, but only one is active in any given cell. This means that in a child with Rett syndrome only about half the cells in the nervous system will use the defective gene. Some of the child's brain cells use the healthy gene and express normal amounts of the proteins.

The story is different for boys who have an MECP2 mutation known to cause Rett syndrome in girls. Because boys have only one X chromosome they lack a back-up copy that could compensate for the defective one, and they have no protection from the harmful effects of the disorder. Boys with such a defect die shortly after birth.

Different types of mutations in the MECP2 gene can cause mental retardation in boys.

How is Rett syndrome diagnosed?

Doctors diagnose Rett syndrome by observing signs and symptoms during the child's early growth and development, and conducting ongoing evaluations of the child's physical and neurological status. Recently, scientists developed a genetic test to confirm the clinical diagnosis of this disorder; the test involves searching for the MECP2 mutation on the child's X chromosome. Given what we know about the genes involved in Rett syndrome, such tests are able to confirm a clinical diagnosis in up to 80 percent of all cases.

Some children who have Rett syndrome-like characteristics or MECP2 genetic mutations do not fulfill the diagnostic criteria for the syndrome as defined below. These persons are described as having "atypical" or "variant" Rett syndrome. Atypical cases account for about 15 percent of the total number of diagnosed cases.

A pediatric neurologist or developmental pediatrician should be consulted to confirm the clinical diagnosis of Rett syndrome. The physician will use a highly specific set of guidelines that are divided into three types of clinical criteria: essential, supportive, and exclusion. The presence of any of the exclusion criteria negates a diagnosis of "classic" or "typical" Rett syndrome.

Examples of essential diagnostic criteria or symptoms include having apparently normal development until between the ages of 6 and 18 months and having normal head circumference at birth followed by a slowing of the rate of head growth with age (between 3 months and 4 years). Other essential diagnostic criteria include severely impaired expressive language, repetitive hand movements, shaking of the torso, and toe-walking or an unsteady, wide-based, stiff-legged gait.

Supportive criteria are not required for a diagnosis of Rett syndrome but may occur in some patients. In addition, these symptoms — which vary in severity from child to child — may not be observed in very young girls but may develop with age. A child with supportive criteria but none of the essential criteria does not have Rett syndrome. Supportive criteria include breathing difficulties; electroencephalogram (EEG) abnormalities; seizures; muscle rigidity, spasticity, and/or joint contracture which worsen with age; scoliosis; teeth-grinding; small feet in relation to height; growth retardation; decreased body fat and muscle mass (although there may be a tendency toward obesity in some affected adults); abnormal sleep patterns, irritability, or agitation; chewing and/or swallowing difficulties; poor circulation of the lower extremities with cold and bluish-red feet and legs; decreased mobility with age; and constipation.

In addition to the essential diagnostic criteria, a number of specific conditions enable physicians to rule out a diagnosis of Rett syndrome. These are referred to as exclusion criteria. Children with any one of the following criteria do not have Rett syndrome: enlargement of body organs or other signs of storage disease, vision loss due to retinal disorder or optic atrophy, microcephaly at birth, an identifiable metabolic disorder or other inherited degenerative disorder, an acquired neurological disorder resulting from severe infection or head trauma, evidence of growth retardation in utero, or evidence of brain damage acquired after birth.

Why are some cases more severe than others?

The course and severity of Rett syndrome vary from individual to individual. Some girls have symptoms from birth onward, while others may have late regression or milder symptoms.

Because females have two copies of the X chromosome and need only one working copy for genetic information, they turn off the extra X chromosome in a process called X inactivation. This process occurs randomly so that each cell is left with one active X chromosome. The severity of Rett syndrome in girls is in part a function of the percentage of cells with a normal copy of the MECP2 gene after X inactivation takes place: if X inactivation turns off the X chromosome that is carrying the defective gene in a large proportion of cells, the symptoms will be mild, but if a larger percentage of cells have the X chromosome with the normal MECP2 gene turned off, onset of the disorder may occur earlier and the symptoms may be more severe.

Is treatment available?

There is no cure for Rett syndrome. Treatment for the disorder is symptomatic — focusing on the management of symptoms — and supportive, requiring a multidisciplinary approach. Medication may be needed for breathing irregularities and motor difficulties, and antiepileptic drugs may be used to control seizures. There should be regular monitoring for scoliosis and possible heart abnormalities. Occupational therapy (in which therapists help children develop skills needed for performing self-directed activities — occupations — such as dressing, feeding, and practicing arts and crafts), physiotherapy, and hydrotherapy may prolong mobility. Some children may require special equipment and aids such as braces to arrest scoliosis, splints to modify hand movements, and nutritional programs to help them maintain adequate weight. Special academic, social, vocational, and support services may also be required in some cases.

What is the outlook for those with Rett syndrome?

Despite the difficulties with symptoms, most individuals with Rett syndrome continue to live well into middle age and beyond. Because the disorder is rare, very little is known about long-term prognosis and life expectancy. While it is estimated that there are many middle-aged women (in their 40s and 50s) with the disorder, not enough women have been studied to make reliable estimates about life expectancy beyond age 40.

What research is being done?

Within the Federal Government, the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Child Health and Human Development (NICHD), two of the National Institutes of Health (NIH), support clinical and basic research on Rett syndrome. Understanding the cause of this disorder is necessary for developing new therapies to manage specific symptoms, as well as for providing better methods of diagnosis. The discovery of the Rett syndrome gene in 1999 provides a basis for further genetic studies and enables the use of recently developed animal models such as transgenic mice.

One NINDS-supported study is looking for mutations in the MECP2 gene of individuals with Rett syndrome to find out how the MeCP2 protein functions. Information from this study will increase understanding of the disorder and may lead to new therapies.

Scientists know that lack of a properly functioning MeCP2 protein disturbs the function of mature brain cells but they do not know the exact mechanisms by which this happens. Investigators are also trying to find other genetic mutations that can cause Rett syndrome and other genetic switches that operate in a similar way to the MeCP2 protein. Once they discover how the protein works and locate similar switches, they may be able to devise therapies that can substitute for the malfunctioning switch. Another outcome might involve manipulating other biochemical pathways to compensate for the malfunctioning MECP2 gene, thus preventing progression of the disorder.

Where can I get more information?

For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute's Brain Resources and Information Network (BRAIN) at:

BRAIN
P.O. Box 5801
Bethesda, MD 20824
(800) 352-9424
http://www.ninds.nih.gov

Information also is available from the following organizations:International Rett Syndrome Foundation
4600 Devitt Drive
Cincinnati, OH 45246
admin@rettsyndrome.org
http://www.rettsyndrome.org
Tel: 513-874-3020

Easter Seals
230 West Monroe Street
Suite 1800
Chicago, IL 60606-4802
info@easterseals.com
http://www.easterseals.com
Tel: 312-726-6200 800-221-6827
Fax: 312-726-1494

National Institute of Child Health and Human Development (NICHD)
National Institutes of Health, DHHS
31 Center Drive, Rm. 2A32 MSC 2425
Bethesda, MD 20892-2425
http://www.nichd.nih.gov
Tel: 301-496-5133
Fax: 301-496-7101

Prepared by:
Office of Communications and Public Liaison
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, MD 20892

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Prader-Willi Syndrome is the most common genetic cause of life-threatening obesity in children.

People with Prader-Willi syndrome have a problem in their hypothalamus, a part of the brain that normally controls feelings of fullness or hunger. As a result, they never feel full and have a constant urge to eat that they cannot control.

Most cases of Prader-Willi syndrome result from a spontaneous genetic error in genes on chromosome 15 that occurs at conception. In very rare cases, the mutation is inherited.
What are the symptoms of Prader-Willi syndrome?
There are generally two stages of symptoms for people with Prader-Willi syndrome:
Stage 1--As newborns, babies with Prader-Willi can have low muscle tone, which can affect their ability to suck properly. As a result, babies may need special feeding techniques to help them eat, and infants may have problems gaining weight. As these babies grow older, their strength and muscle tone usually get better. They meet motor milestones, but are usually slower in doing so.
Stage 2--Between the ages of 1 and 6 years old, the disorder changes to one of constant hunger and food seeking. Most people with Prader-Willi syndrome have an insatiable appetite, meaning they never feel full. In fact, their brains are telling them they are starving. They may have trouble regulating their own eating and may need external restrictions on food, including locked kitchen and food storage areas.

This problem is made worse because people with Prader-Willi syndrome use fewer calories than those without the syndrome because they have less muscle mass. The combination of eating massive amounts of food and not burning enough calories can lead to life-threatening obesity if the diet is not kept under strict control.

There are other symptoms that may affect people with Prader-Willi, including:
Behavioral problems, usually during transitions and unanticipated changes, such as stubbornness or temper tantrums
Delayed motor skills and speech due to low muscle tone
Cognitive problems, ranging from near normal intelligence to mild mental retardation; learning disabilities are common
Repetitive thoughts and verbalizations
Collecting and hoarding of possessions
Picking at skin
Low sex hormone levels

Prader-Willi syndrome is considered a spectrum disorder, meaning not all symptoms will occur in everyone affected and the symptoms may range from mild to severe.

People with Prader-Willi often have some mental strengths as well, such as skills in jigsaw puzzles. If obesity is prevented, people with the syndrome can live a normal lifespan.
What are the treatments for Prader-Willi syndrome?
Prader-Willi syndrome cannot be cured. But, early intervention can help people build skills for adapting to the disorder. Early diagnosis can also help parents learn about the condition and prepare for future challenges. A health care provider can do a blood test to check for Prader-Willi syndrome.

Exercise and physical activity can help control weight and help with motor skills. Speech therapy may be needed to help with oral skills.

Human growth hormone has been found to be helpful in treating Prader-Willi syndrome. It can help to increase height, decrease body fat, and increase muscle mass. However, no medications have yet been found to control appetite in those with Prader-Willi.

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KU (phenylketonuria) is an inherited disorder of body chemistry that, if untreated, causes mental retardation. Fortunately, through routine newborn screening, almost all affected newborns are diagnosed and treated early, allowing them to grow up with normal intelligence.

At least 1 baby in 25,000 is born with PKU in the United States (1). The disorder occurs in all ethnic groups, although it is more common in individuals of Northern European and Native American ancestry than in those of African-American, Hispanic and Asian ancestry.

What is PKU?
Individuals with PKU cannot process a part of protein called phenylalanine, which is present in most foods. Because of a genetic abnormality, affected individuals lack or have very low levels of an enzyme (phenylalanine hydroxylase or PAH) that converts phenylalanine to other substances the body needs. Without treatment, phenylalanine builds up in the bloodstream and causes brain damage and mental retardation.

How does PKU affect a child?
Children born with PKU appear normal for the first few months. If untreated, by 3 to 6 months they begin to lose interest in their surroundings. By the time they are 1 year old, they appear obviously developmentally delayed. Children with untreated PKU often are irritable and have behavioral problems. They may have a musty odor about them, and they may have dry skin, rashes or seizures. They usually are physically well developed and tend to have blonder hair than their siblings.

Who gets PKU?
Genes come in pairs. To inherit PKU, a child must receive two abnormal PAH genes (that regulate the production of the enzyme), one from each parent who has a mutation (change) in one PAH gene. A parent who has one abnormal PAH gene is called a "carrier." A carrier has one normal PAH gene and one PAH gene that contains a mutation. A carrier's health is not affected in any known way.

When both parents are carriers, there is:
A 1-in-4 (25 percent) chance that both will pass one abnormal PAH gene on to a child, causing the child to be born with PKU.
A 2-in-4 (50-50) chance that the baby will inherit one abnormal PAH gene from one parent and the normal gene from the other, making it a carrier like its parents.
A 1-in-4 (25 percent) chance that both parents will pass on the normal gene. The baby will neither have the disease nor be a carrier.

These chances are the same for each pregnancy.

Are all babies tested for PKU?
All states and U.S. territories screen for PKU. Babies are tested before they leave the hospital. The PKU test was the nation's first newborn screening test. Developed with the help of the March of Dimes, the test has been routinely administered since the 1960s, sparing thousands of children from mental retardation (2).

How is the test done?
The baby's heel is pricked, and a few drops of blood are taken. (The same blood sample can be used to screen for a number of other inborn errors of body chemistry.) The blood sample generally is sent to a regional medical laboratory to find out if it has more than a normal amount of phenylalanine. Findings are sent to the health care professional responsible for the baby's care. If results are abnormal, more tests are done to determine whether the baby has PKU or if there is some other cause of high phenylalanine levels.

Occasionally, a case of PKU can be missed when the test is performed before 24 hours of age. For this reason, some experts recommend that infants whose initial test was taken within the first 24 hours of life be tested again at 1-2 weeks of age (3).

Can PKU symptoms be prevented?
Yes. Mental retardation can be prevented if the baby is treated with a special diet that is low in phenylalanine. This diet should be started as soon as possible after birth, ideally within the first seven to 10 days of life (2).

At first, the baby is fed a special formula that contains protein but no phenylalanine. Breast milk or infant formula is used sparingly to supply only as much phenylalanine as the baby needs and can tolerate. Later, certain vegetables, fruits, some grain products (for example, certain cereals and noodles) and other low-phenylalanine foods are added to the diet. No regular milk, cheese, eggs, meat, fish and other high protein foods are ever allowed. Because protein is essential for normal growth and development, the child must continue to have one of the special formulas that is high in protein and essential nutrients, but contains little or no phenylalanine. Diet drinks and foods that contain the artificial sweetener aspartame (which contains phenylalanine and is sold as Nutrasweet or Equal) must be strictly avoided.

Children and adults with PKU require follow-up care at a medical center or clinic that specializes in this disorder. The diet for each person must be individualized, depending upon how much phenylalanine can be tolerated. All affected persons need regular blood tests to measure phenylalanine levels. Testing for babies may be as frequent as once a week for the first year of life, and then once or twice a month throughout childhood.

Individuals with PKU must remain on a restricted diet throughout childhood and adolescence and generally for life (although some relaxation of the diet may be possible as the person ages) (2). Until the 1980s, health care providers believed that children with PKU could safely discontinue their special diet around age 6 when brain growth was completed. However, studies since then have found that discontinuance of the diet before age 8 can lead to a decrease in IQ, and discontinuance after age 12 may lead to learning disabilities and behavioral problems (2, 4).

Parents of children with PKU and affected adults should discuss their diet and treatment questions with health care professionals at a PKU clinic.

What is maternal PKU?
There are an estimated 3,000 women of childbearing age with successfully treated PKU in the United States (5). Most discontinued their special diet in childhood because, at that time, most doctors believed it was safe to do so.

If these young women are eating a normal diet, their blood phenylalanine levels are very high when they become pregnant. During pregnancy, high blood levels of phenylalanine in the mother can cause serious problems in the fetus. About 90 percent of their babies will have mental retardation, and about 70 percent will have a small head size (microcephaly) (6). Many will have heart defects and low birthweight. Because most of these babies do not inherit PKU, but are suffering from brain damage caused by their mothers' high phenylalanine levels during pregnancy, they cannot be helped by the PKU diet.

Fortunately, there is a way to help prevent mental retardation and other problems in babies of women with PKU. Women with PKU need to resume their special diets at least three months before pregnancy and continue the diet throughout pregnancy. The Maternal PKU International Study found that women whose blood phenylalanine levels were under control before conception, or by 8 to ten weeks of pregnancy at the latest, were as likely to have healthy babies as women without PKU (7). At age 7, the IQs of their children did not differ from those of children of women without PKU (7). Women with PKU need at least weekly blood tests throughout pregnancy to make sure blood phenylalanine levels are not too high.

The March of Dimes urges all women who know or suspect that they were treated for PKU as children to contact their health care provider or clinic before they attempt to conceive, so that their blood phenylalanine levels can be measured and they can begin the special diet, if necessary.

Occasionally, a woman has undiagnosed PKU that can pose a risk to her baby. These women, who generally were not screened as newborns, usually are slightly affected, and may be diagnosed only following the birth of a baby with PKU-related birth defects. In order to help prevent these birth defects, some doctors recommend screening women who may be at risk of PKU, such as those with a family history of the disorder, so that affected women can start the PKU diet before pregnancy.

Can drugs be used to manage PKU?
In December 2007, the Food and Drug Administration (FDA) approved Kuvan (sapropterin dihydrocholoride), the first drug to help manage PKU (8). The drug helps reduce blood phenylalanine levels in individuals with PKU by increasing the activity of the PAH enzyme.

Kuvan is effective only in individuals who have some PAH activity. Individuals who take this drug must continue to follow a phenylalanine-restricted diet and have blood tests to measure phenylalanine levels.

What is new in PKU research?
Researchers continue to study the long-term outcome for children who were born from treated maternal PKU pregnancies to determine whether there is an increased risk of learning disabilities, especially among children whose mothers' blood phenylalanine levels were not well controlled in the early weeks of pregnancy.

Researchers also are studying the benefits of a nutritional supplement called BH4 in individuals with PKU. Others are developing a genetically engineered version of the missing enzyme. Both approaches eventually may allow affected individuals to eat a diet that approximates normal. Researchers also are exploring the possibility of treating PKU using gene therapy.

For more information
Children's PKU Network
3790 Via De La Valle, Suite 120
Del Mar, CA 92014
Phone: (800) 377-6677
E-mail: pkunetwork@aol.com

References
American College of Medical Genetics. Newborn Screening: Toward a Uniform Screening Panel and System. Final Report, 3/8/05.
National Institutes of Health Consensus Development Statement. Phenylketonuria: Screening and Management. Washington, D.C., October 16-18, 2000.
Kaye, C.I. and the American Academy of Pediatrics Committee on Genetics. Newborn Screening Fact Sheets. Pediatrics, volume 118, 2006, e934-963.
Mitchell, J.J. and Scriver, C.R. Phenylalanine Hydroxylase Deficiency. Gene Reviews, updated 3/29/07.
American College of Obstetricians and Gynecologists (ACOG) Committee on Genetics. Maternal Phenylketonuria. Committee Opinion, number 230, January 2000, reaffirmed 2004.
Koch, R., and de la Cruz, F. The Maternal Phenylketonuria Collaborative Study: New Developments and the Need for New Strategies—Preface. Pediatrics, volume 112, number 6, part 2, December 2003, page 1513.
Koch, R., et al. The Maternal Phenylketonuria International Study: 1984-2002. Pediatrics, volume 112, number 6, part 2, December 2003, pages 1523-1529.
Food and Drug Administration (FDA). FDA Approves Kuvan for Treatment of Phenylketonuria (PKU), December 13, 2007.

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