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

Read More

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.

Read More

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.

Read More

Ehlers-Danlos syndrome is a rare disorder of connective tissue that results in unusually flexible joints, very elastic skin, and fragile tissues.

This syndrome is caused by a defect in one of the genes that controls the production of connective tissue.
Typical symptoms include flexible joints, a humpback, flat feet, and elastic skin.
The diagnosis is based on symptoms and results of a physical examination.
Most people with this syndrome have a normal life span.
There is no cure for Ehlers-Danlos syndrome.

Ehlers-Danlos syndrome is caused by an abnormality in one of the genes that controls the production of connective tissue. There are several variants (with widely varying severity) affecting different genes and causing slightly different changes. The result is abnormally fragile connective tissue, which causes problems in joints and bones and may weaken internal organs.

Children with Ehlers-Danlos syndrome usually have very flexible joints. Some develop small, hard, round lumps under the skin; a humpback with an abnormal curve of the spine (kyphoscoliosis); or flat feet. The skin can be stretched up to several inches but returns to its normal position when released.

Ehlers-Danlos syndrome may alter the body's response to injuries. Minor injuries may result in wide gaping wounds. Although these wounds usually do not bleed excessively, they leave wide scars. Sprains and dislocations develop easily.

In a small number of children with Ehlers-Danlos syndrome, the blood clots poorly. Bleeding from minor wounds may be difficult to stop.

The intestines can bulge through the abdominal wall (hernias), and abnormal outpouchings (diverticula) can develop in the intestine. Rarely, a fragile intestine bleeds or ruptures (perforates).

If a pregnant woman has Ehlers-Danlos syndrome, delivery may be premature. If the fetus has Ehlers-Danlos syndrome, its surrounding membranes may rupture early (premature rupture of membranes). A mother or baby who has Ehlers-Danlos syndrome can bleed excessively before, during, and after delivery.

A doctor bases the diagnosis on the symptoms and results of a physical examination. The doctor can try to confirm the diagnosis of some types of Ehlers-Danlos syndrome by taking a sample of skin to examine under a microscope (biopsy). Genetic and biochemical tests are available at some research centers for some types. Other tests are performed to check for conditions that are associated with complications, such as problems with the heart or blood vessels.

Prognosis and Treatment

Despite the many and varied complications people with Ehlers-Danlos syndrome may have, their life span is usually normal. However, in a few people with one specific type of Ehlers-Danlos syndrome, complications (usually bleeding) are fatal. Genetic counseling for family members is suggested.

Special precautions should be taken to prevent injuries. For example, children with severe forms of Ehlers-Danlos syndrome can wear protective clothing and padding.

There is no way to cure Ehlers-Danlos syndrome or correct the abnormalities in the connective tissue. Injuries can be treated, but it may be difficult for a doctor to stitch cuts because stitches tend to tear out of the fragile tissue. Usually, using an adhesive tape or medical skin glue closes cuts more easily and leaves less scarring.

Surgery requires special techniques that minimize injury and ensure that a large supply of blood is available for transfusion. An obstetrician must supervise pregnancy and delivery.

Last full review/revision February 2008 by Frank Pessler, MD, PhD; David D. Sherry, MD

Read More

Osteogenesis imperfecta (OI) literally means "imperfectly formed bone." People with osteogenesis imperfecta have an error (mutation) in the genetic instructions on how to make strong bones. This may cause the bones to break easily.

Causes

Osteogenesis imperfecta is relatively rare. In some cases, the parent has osteogenesis imperfecta and the condition has been genetically transmitted to the child. But, the child's symptoms and the degree of disability could be very different from that of the parent. In some children, neither parent has osteogenesis imperfecta. In these cases, the genetic defect is a spontaneous mutation.

Diagnosis/Symptoms

Osteogenesis imperfecta is a relatively rare disorder. Ultrasound can often detect severe cases of osteogenesis imperfecta during pregnancy. Genetic testing may be able to identify the mutation, particularly if the parent's mutation is also known. But in many cases, bone fractures that occur with little or no trauma are often the first indication that a person has osteogenesis imperfecta.

In people with osteogenesis imperfecta, one of the genes that tells the body how to make a specific protein is defective. This protein (type I collagen) is a major component of the connective tissues in bones. Type I collagen is also important in forming ligaments, teeth, and the white outer tissue of the eyeballs (sclera).

As a result of the defective gene, not enough type I collagen is produced, or the collagen that is produced is of poor quality. In either case, the result is fragile bones that break easily but can heal at a normal rate.

There are four recognized types of osteogenesis imperfecta, which vary in severity and characteristics. Several other findings are also associated with osteogenesis imperfecta, including short stature, a triangular face, respiratory problems, and hearing loss. Each person with osteogenesis imperfecta may have a different combination of clinical characteristics.
Type I Osteogenesis Imperfecta

Type I osteogenesis imperfecta is the most common and mildest type of this disease. While the structure of the collagen is normal, there is less collagen than there should be. There is little or no bone deformity, although the bones are fragile and easily broken. The effects of osteogenesis imperfecta may extend to the teeth, making them prone to cavities and cracking. The whites of the eyes may have a blue, purple, or gray tint.
Type II Osteogenesis Imperfecta

Type II osteogenesis imperfecta is the most severe form of the disease. The collagen does not form properly. Bones may break even while the fetus is in the womb. Many infants with type II osteogenesis imperfecta are stillborn or die shortly after birth.
Type III Osteogenesis Imperfecta

Type III osteogenesis imperfecta also has improperly formed collagen and often severe bone deformities plus additional complications. The infant is often born with fractures. The whites of the eyes may be white, blue, purple, or gray. People with type III osteogenesis imperfecta are generally shorter than average. They may have spinal deformities, respiratory complications, and brittle teeth.
Type IV Osteogenesis Imperfecta

Type IV osteogenesis imperfecta is moderately severe, with improperly formed collagen. Bones fracture easily, but the whites of the eyes are normal. Some people with type IV osteogenesis imperfecta may be shorter than average and may have brittle teeth. Bone deformities are mild to moderate.

Treatment

While there is no cure for osteogenesis imperfecta, there are opportunities to improve the child's quality of life. Treatment must be individualized and depends on the severity of the disease and the age of the patient. Care is provided by a team of health-care professionals, including several types of doctors, a physical therapist, a nurse-clinician and a social worker.

Nonsurgical Treatment

In most cases, treatment will be nonsurgical.

Medical bisphosphonates, given to the child either by mouth or intravenously, slow down bone resorption. In children with more-severe osteogenesis imperfecta, bisphosphonate treatment often decreases the number of fractures and bone pain. These medications must be administered by properly trained doctors and require close monitoring.

Casting, bracing, or splinting of fractures is necessary to immobilize the bone so that healing can occur. Movement and weight bearing are encouraged as soon as possible after fractures to increase mobility and decrease the risk of future fractures.

Precautions

Here are some tips developed by the Osteogenesis Imperfecta Foundation for dealing with children with osteogenesis imperfecta.
Don't be afraid to touch or hold an infant with osteogenesis imperfecta, but be careful. Never lift a child with osteogenesis imperfecta by holding him or her under the armpits. Do not pull on arms or legs or lift the legs by the ankles to change a diaper. To lift an infant with osteogenesis imperfecta, spread your fingers apart and put one hand between the legs and under the buttocks; place the other hand behind the shoulders, neck and head.
Do not feel guilty if a fracture does occur. Children must develop and fractures will occur no matter how careful you are.
Select an infant car seat that reclines. It should be easy to place or remove the child in the seat. Consider padding the seat with foam and using a layer of foam between the child and the harness.
Be sure your stroller is large enough to accommodate casts. Don't use a sling or umbrella-type stroller.
Follow your doctor's instructions carefully, especially with regard to cast care and mobility exercises. Swimming and walking are often recommended as safe exercises.
Avoid activities such as smoking, drinking and taking steroids because they have a negative impact on bone density.
Increasing awareness of child abuse and a lack of awareness about osteogenesis imperfecta may lead to inaccurate conclusions about a family situation. Always have a letter from your family doctor and a copy of your child's medical records handy.

Surgical Treatment

Repeated fractures of the same bone, deformity, or fractures that do not heal properly are all indications that surgery may be necessary. Metal rods may be inserted in the long bones of the arms and legs. Some rods are a fixed length and must be replaced as the child grows. Other rods are designed like telescopes so they can expand along with the bone growth. However, other complications may occur with telescoping rods. Do not hesitate to ask your orthopaedic surgeon about both options.

In many children with osteogenesis imperfecta, the number of times their bones fracture decreases significantly as they mature. However, osteogenesis imperfecta may become active again after menopause in women or after the age of 60 years in men.

Scoliosis, or curvature of the spine, is a problem for many children with osteogenesis imperfecta. Bracing is the usual treatment for scoliosis, but it is often ineffective in children with osteogenesis imperfecta. Spinal fusion, in which the vertebrae are realigned and fused together, may be recommended to prevent excessive curvature.

Read More

The neurofibromatoses are a group of three genetically distinct but related disorders of the nervous system that cause tumors to grow around the nerves. Tumors begin in the cells that make up the myelin sheath, a thin membrane that envelops and protects nerve fibers, and often spread into adjacent areas. The type of tumor that develops depends on its location in the body and the kind of cells involved. The most common tumors are neurofibromas, which develop in the tissue surrounding peripheral nerves. Most tumors are non-cancerous, although occasionally they become cancerous over time.

Why these tumors occur still isn’t completely known, but it appears to be mainly related to mutations in genes that play key roles in suppressing tumor growth in the nervous system. These mutations keep the genes – identified as NF1 and NF2 – from making specific proteins that control cell production. Without these proteins, cells multiply out of control and form tumors.

An estimated 100,000 Americans have a neurofibromatosis (the singular form of neurofibromatoses) disorder, which occurs in both sexes and in all races and ethnic groups. Scientists have classified the disorders as neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and a type that was once considered to be a variation of NF2 but is now called schwannomatosis.

What is NF1?

NF1 is the most common neurofibromatosis, occurring in 1 in 3,000 to 4,000 individuals in the United States . Although many affected people inherit the disorder, between 30 to 50 percent of new cases occur because of a spontaneous genetic mutation from unknown causes. Once this mutation has taken place, the mutant gene can be passed on to succeeding generations.

What are the signs and symptoms of NF1?

To diagnose NF1, a doctor looks for two or more of the following:
six or more light brown spots on the skin (often called “cafe-au-lait” spots), measuring more than 5 millimeters in diameter in children, or more than 15 millimeters across in adolescents and adults;
two or more neurofibromas, or one plexiform neurofibroma (a neurofibroma that involves many nerves);
freckling in the area of the armpit or the groin;
two or more growths on the iris of the eye (known as Lisch nodules or iris hamartomas);
a tumor on the optic nerve (optic glioma);
abnormal development of the spine (scoliosis), the temple (sphenoid) bone of the skull, or the tibia (one of the long bones of the shin);
a first degree relative (parent, sibling, or child) with NF1.

What other symptoms or conditions are associated with NF1?

Many children with NF1 have larger than normal head circumference and are shorter than average. Hydrocephalus, the abnormal buildup of fluid in the brain, is a possible complication of the disorder. Headache and epilepsy are also more likely in individuals with NF1 than in the normal population. Cardiovascular complications are associated with NF1, including congenital heart defects, high blood pressure (hypertension), and constricted, blocked, or damaged blood vessels (vasculopathy). Children with NF1 may have poor linguistic and visual-spatial skills, and perform less well on academic achievement tests, including those that measure reading, spelling, and math skills. Learning disabilities, such as attention deficit hyperactivity disorder (ADHD), are common in children with NF1.

When do symptoms appear?

Symptoms, particularly the most common skin abnormalities -- café-au-lait spots, neurofibromas, Lisch nodules, and freckling in the armpit and groin -- are often evident at birth or shortly afterwards, and almost always by the time a child is 10 years old. Because many features of these disorders are age dependent, a definitive diagnosis may take several years.

What is the prognosis for someone with NF1?

NF1 is a progressive disorder, which means most symptoms will worsen over time, although a small number of people may have symptoms that stay the same and never get any worse. It isn’t possible to predict the course of any individual’s disorder. In general, most people with NF1 will develop mild to moderate symptoms, and if complications arise they will not be life-threatening. Most people with NF1 have a normal life expectancy.

How is NF1 treated?

Since doctors don’t know how to prevent or stop neurofibromas from growing, surgery is often recommended to remove them. Several surgical options exist, but there is no general agreement among doctors about when surgery should be performed or which surgical option is best. Individuals considering surgery should carefully weigh the risks and benefits of all their options to determine which surgical treatment is right for them. There are also surgical and chemical techniques that can reduce the size of eye tumors (optic gliomas) when vision is threatened. In addition, some bone malformations, such as scoliosis, can be surgically corrected. In the rare instances when tumors become malignant (3 to 5 percent of all cases), treatment may include surgery, radiation, or chemotherapy.

Treatments for other conditions associated with NF1 are aimed at controlling or relieving symptoms. Headache and epileptic seizures are treated with medications. Since there is a higher than average risk for learning disabilities, children with NF1 should undergo a detailed neurological exam before they enter school. Once these children enter school, if teachers or parents suspect there is evidence of a learning disability (or disabilities), they should request an evaluation that includes an IQ test and the standard range of tests to evaluate verbal and spatial skills. Children with learning disabilities are eligible for special education services under the provisions of the Individuals with Disabilities Education Act (IDEA).

What is NF2?

This rare disorder affects about 1 in 40,000 people. NF2 is characterized by slow-growing tumors on the eighth cranial nerve. This nerve has two branches: the acoustic branch helps people hear by transmitting sound sensations to the brain; the vestibular branch helps people maintain their balance. The tumors of NF2, called vestibular schwannomas because of their location and the types of cells that compose them (Schwann cells, which form the myelin sheath around nerves), press against and sometimes even damage the nerves they surround. In some cases they will also damage nearby vital structures such as other cranial nerves and the brainstem, leading to a potentially life-threatening situation.

Individuals with NF2 are at risk for developing other types of nervous system tumors such as spinal schwannomas, which grow within the spinal cord and between the vertebrae, and meningiomas, which are tumors that grow along the membranes covering the brain and spinal cord.

What are the signs and symptoms of NF2?

To diagnose NF2, a doctor looks for the following:
bilateral vestibular schwannomas, or
a family history of NF2 (parent, sibling, or child) plus a unilateral vestibular schwannoma before age 30

or any two of the following:
glioma,
meningioma,
schwannoma,
juvenile posterior subcapsular lenticular opacity (juvenile cortical cataract).

When do symptoms appear?

Signs of NF2 may be present in childhood but are so subtle that they can be overlooked, especially in children who don’t have a family history of the disorder. Typically, symptoms of NF2 are noticed between 18 and 22 years of age. The most frequent first symptom is hearing loss or ringing in the ears (tinnitus). Less often, the first visit to a doctor will be because of disturbances in balance, vision impairment (such as vision loss from cataracts), weakness in an arm or leg, seizures, or skin tumors.

What is the prognosis for someone with NF2?

Because NF2 is so rare, few studies have been done to look at the natural progression of the disorder. The course of NF2 varies greatly among individuals, although inherited NF2 appears to run a similar course among affected family members. Generally, vestibular schwannomas grow slowly, and balance and hearing deteriorate over a period of years. A recent study suggests that an earlier age of onset is associated with faster tumor growth and a greater mortality risk.

How is NF2 treated?

NF2 is best managed at a specialty clinic with an initial screening and annual follow-up evaluations. Improved diagnostic technologies, such as MRI (magnetic resonance imaging), can reveal tumors as small as a few millimeters in diameter, which allows for early treatment. Vestibular schwannomas grow slowly, but they can grow large enough to completely engulf the eighth cranial nerve. Early surgery, to completely remove the tumor while it’s still small, might be advisable to preserve hearing and balance. There are several surgical options, depending on tumor size and the extent of hearing loss. Some techniques preserve the auditory nerve and enable individuals to retain some hearing; other techniques may involve removing the nerve and replacing it with an electronic auditory implant in the brainstem to restore hearing.
Surgery is available to correct cataracts and retinal abnormalities. A strategy of watchful waiting might be more appropriate for slowly growing brain and spinal tumors, which have higher risks of surgical complications.

What is schwannomatosis?

Schwannomatosis is a newly recognized neurofibromatosis that is genetically and clinically distinct from NF1 and NF2. Like NF2 it occurs rarely. Inherited forms of the disorder account for only 15 percent of all cases. Researchers still don’t fully understand what causes the tumors and the intense pain that are characteristics of the disorder.

What are the signs and symptoms of schwannomatosis?

The distinguishing feature of schwannomatosis is the development of multiple schwannomas everywhere in the body except on the vestibular nerve. The dominant symptom is excruciatingly intense pain, which develops when a schwannoma enlarges, compresses nerves, or presses on adjacent tissue. Some people experience additional neurological symptoms, such as numbness, tingling, or weakness in the fingers and toes. Patients with schwannomatosis never have neurofibromas.

About one-third of those with schwannomatosis have tumors limited to a single part of the body, such as an arm, a leg, or a segment of the spine. Some people develop many schwannomas; others develop only a few.

What is the prognosis for someone with schwannomatosis?

Anyone with schwannomatosis experiences some degree of pain, but the intensity varies. A small number of people have such mild pain that they are never diagnosed with the disorder. Most people have significant pain, which can be managed with medications or surgery. In some extreme cases, pain will be so severe and disabling it will keep people from working or leaving the house.

How is schwannomatosis treated?

There is no currently accepted medical treatment or drug for schwannomatosis, but surgical management is often effective. When tumors are completely removed pain usually subsides, although it may recur if new tumors form. When surgery isn’t possible, ongoing monitoring and management of pain in a multidisciplinary pain clinic is advisable.

Are there prenatal tests for the neurofibromatoses?

Clinical genetic testing can confirm the presence of a mutation in the NF1 gene with an accuracy of 95 percent. Some families and doctors may choose to use a genetic test to confirm an uncertain diagnosis when there is no family history of the disorder and when waiting for additional symptoms to appear would put an unnecessary emotional burden on the family. Prenatal testing for the NF1 mutation is also possible using amniocentesis or chorionic villus sampling procedures. Genetic testing for the NF2 mutation is sometimes available but is accurate in only 65 percent of those tested. Genetic counselors can provide information about these procedures and help families cope with the results.

What research is being done on the neurofibromatoses?

The National Institute of Neurological Disorders and Stroke (NINDS), one of the National Institutes of Health (NIH), is the leader in federal funding of research studying neurological diseases. The Institute sponsors basic studies aimed at understanding normal and abnormal development of the brain and nervous system, as well as clinical trials to improve the diagnosis and treatment of neurological disorders. In conjunction with the NIH's National Cancer Institute (NCI), the NINDS supports research focused on finding better ways to prevent, treat, and ultimately cure the neurofibromatosis disorders.

In the mid-1990s, research teams supported by the NINDS located the exact position of the NF1 gene on chromosome 17. The gene has been cloned and its structure continues to be analyzed. The NF1 gene makes a large and complex protein called neurofibromin, which is primarily active in nervous system cells as a regulator of cell division, functioning as a kind of molecular brake to keep cells from over-multiplying. In addition to work on NF1, intensive efforts have led to the identification of the NF2 gene on chromosome 22. As in NF1, the NF2 gene product is a tumor-suppressor protein (termed merlin or schwannomin).

Ongoing NINDS-sponsored research continues to discover additional genes that appear to play a role in tumor suppression or growth. Continuing research on these genes and their proteins is beginning to reveal how this novel family of growth regulators controls how and where tumors form and grow. Understanding the molecular pathways and mechanisms that govern these key proteins and their activities will offer scientists exciting opportunities to design drugs that could replace the missing proteins in people who have the neurofibromatoses and return their cell production to normal.

The NINDS currently supports basic and clinical research to understand how the genetic mutations that cause the benign tumors of NF1 can also cause abnormal development of neurons and neural networks during fetal development. This abnormal development can lead to the learning disabilities and cognitive deficits of children with the disorder.

The NINDS also encourages research aimed at developing improved methods of diagnosing the neurofibromatoses and at identifying factors that contribute to the wide variations of symptoms and severity of the disorders.

Just as important, the NINDS is supporting ongoing research with a large group of children with NF1 to help doctors answer the question that most parents ask when their child is diagnosed with the disorder: “What can we expect when our child goes to school?” Using MRI, which shows brain structure, functional MRI, which shows areas of the brain at work, and neuropsychological tests that measure specific cognitive skills, researchers are looking for associations between brain abnormalities and specific cognitive disabilities. Finding these links would give doctors an indication of the kinds of learning disabilities parents and their children could anticipate in the future and help them develop early intervention programs.

How can I help research?

The NINDS contributes to the support of the Human Brain and Spinal Fluid Resource Center in Los Angeles. This tissue bank supplies investigators around the world with tissue from patients with neurological and other disorders. Tissue from individuals with NF1 or NF2 is needed to enable scientists to study these disorders more intensely. Prospective donors may contact:

Human Brain and Spinal Fluid Resource Center
Neurology Research (127A)
W. Los Angeles Healthcare Center
11301 Wilshire Blvd., Bldg. 212
Los Angeles, CA 90073
310-268-3536
24-hour pager: 310-636-5199
Email: RMNbbank@ucla.edu
http://www.loni.ucla.edu/~nnrsb/NNRSB
top
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:Children's Tumor Foundation
95 Pine Street
16th Floor
New York, NY 10005
info@ctf.org
http://www.ctf.org
Tel: 800-323-7938 212-344-6633
Fax: 212-747-0004

National Cancer Institute (NCI)
National Institutes of Health, DHHS
6116 Executive Boulevard, Ste. 3036A, MSC 8322
Bethesda, MD 20892-8322
cancergovstaff@mail.nih.gov
http://cancer.gov
Tel: 800-4-CANCER (422-6237) 800-332-8615 (TTY)

Neurofibromatosis, Inc. (NF Inc.)
P.O. Box 18246
Minneapolis, MN 55418
nfinfo@nfinc.org
http://www.nfinc.org
Tel: 301-918-4600 800-942-6825
Acoustic Neuroma Association
600 Peachtree Parkway
Suite 108
Cumming, GA 30041
info@anausa.org
http://www.anausa.org
Tel: 770-205-8211 877-200-8211
Fax: 770-205-0239/877-202-0239

International RadioSurgery Association
3002 N. Second Street
Harrisburg, PA 17110
office1@irsa.org
http://www.irsa.org
Tel: 717-260-9808
Fax: 717-260-9809

"Neurofibromatosis Fact Sheet," NINDS.

NIH Publication No. 06-2126

Back to Neurofibromatosis Information Page

See a list of all NINDS Disorders

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

Read More

Marfan syndrome is a genetic disorder that affects connective tissue. Connective tissue holds other tissues together throughout the body. Individuals with Marfan syndrome can have signs and symptoms involving the heart, blood vessels, bones and joints, and eyes. Sometimes the lungs and skin are also affected. Marfan syndrome does not affect intelligence. Signs and symptoms of Marfan syndrome can be mild or severe. They may be present at birth or become apparent in childhood or in adult life.

How common is Marfan syndrome?
Marfan syndrome affects about 1 in 5,000 Americans (1, 2). The disorder affects males and females of all races and ethnic groups. The condition is named for Dr. Antoine Marfan who, in 1896, described a 5-year-old girl with unusually long, slender fingers and limbs, and other skeletal abnormalities.

How are individuals with Marfan syndrome affected?
Affected individuals are tall, slender and loose-jointed. Arms, legs, fingers and toes often are unusually long. Some people with Marfan syndrome have low foot arches (flat feet), and others have high arches. Individuals with Marfan syndrome usually have long narrow faces, and their teeth are generally crowded.

Individuals with Marfan syndrome can have one or more of the following problems:
Heart and blood vessel problems: The most serious problem associated with Marfan syndrome is weakness of the wall of the aorta. The aorta is the body's largest artery, which carries oxygen-rich blood from the left side of the heart to the rest of the body. In Marfan syndrome, the wall of the aorta gradually weakens and stretches (aortic dilation) over time. Eventually, this can cause a tear (dissection) in the lining of the aorta. Blood can leak out through the tear into the aortic wall, sometimes resulting in a rupture, allowing blood to leak into the chest or abdomen. These complications, if not detected, can result in sudden death.
Abnormal heart valves: The heart's mitral valve tends to be floppy and billowing (mitral valve prolapse). Heart valves are tiny flaps or gates that keep the blood flowing in one direction through the heart. Differences in the mitral valve can allow blood to briefly flow backwards during a heartbeat (regurgitation). Sometimes this creates an abnormal sound that a health care provider may hear through a stethoscope. Mitral valve prolapse can sometimes be associated with irregular or rapid heartbeat and shortness of breath.
Skeletal abnormalities: Many individuals have a lateral (sideways) curvature of the spine (scoliosis). Sometimes there is a sharp forward curvature (kyphosis). Many individuals have deformities of their breastbone (sternum). These are called pectus deformities. Pectus deformities can sometimes protrude outward and/or inward. Sometimes the connective tissue which surrounds the spinal cord loosens and stretches out (dural ectasia) causing back pain.
Lung problems: Persons with Marfan syndrome are more prone than others to sudden collapse of their lungs (spontaneous pneumothorax). They also may develop respiratory problems and shortness of breath. Respiratory problems can worsen if the individual has severe skeletal abnormalities, which do not allow the chest to fully expand, or emphysema (a breathing disorder usually associated with smoking). Adults with Marfan syndrome are at increased risk of early emphysema, even if they don't smoke.
Eye problems: The lens of one or both eyes is off-center in about 60 percent of persons with Marfan syndrome (1, 2). This is called ectopia lentis. Most affected individuals also are nearsighted and have astigmatism (eyes cannot focus clearly). Individuals with Marfan syndrome are at increased risk of developing cataracts (clouding of the lens of the eye) and glaucoma (an increase of pressure in the eye) at an earlier age than individuals in the general population. Severe nearsightedness can lead to detachment of the retina (the light-sensing lining at the back of the eye). Retinal detachment and glaucoma can lead to vision loss.

Most individuals with Marfan syndrome have one or two of these problems. The severity of effects of Marfan syndrome varies greatly, even within the same family.

How is Marfan syndrome diagnosed?
An evaluation for Marfan syndrome generally includes:
A complete physical examination.
Eye examination by an ophthalmologist (eye doctor). The ophthalmologist uses eye drops to fully dilate the pupils of the eyes and examines them with a slit-lamp (a microscope with a light attached) to look for lens dislocation.
Heart tests, including an electrocardiogram (EKG), which measures electrical activity in the heart, and an echocardiogram. An echocardiogram is a special noninvasive ultrasound examination that lets doctors look for involvement of the heart and blood vessels, which often can't be determined by a physical examination.
Family history, in order to determine if there are other family members known or suspected to have Marfan syndrome, and/or who died early due to an unexplained heart disorder or an aneurysm (bulging of a blood vessel, such as the aorta, sometimes leading to rupture of the blood vessel).
Genetic testing of a blood sample to help confirm the diagnosis, in some cases.
Magnetic resonance imaging (MRI) of the lower spine to look for dural ectasia.

How is Marfan syndrome treated?
Advances in treatment have greatly improved the outlook for children and adults with Marfan syndrome. Today, the life expectancy of individuals with the disorder who receive proper treatment is about 70 years (1).

Most of the problems associated with Marfan syndrome can be managed effectively, as long as they are diagnosed early. The disorder usually is treated by a team of experienced physicians and health care professionals, overseen by a single doctor who knows all of its aspects.

The team of physicians should include a cardiologist (heart doctor). Affected individuals need to have serial (repeated periodically) echocardiograms to measure the dimensions of their aorta and the condition of their heart valves. These and other tests help the doctors determine whether or not treatment is needed, and when intervention should take place.

To help prevent or reduce heart problems, doctors often recommend treatment with high blood pressure medications called beta blockers. These medications reduce the strength and frequency of heartbeats, reducing stress on the wall of the aorta. Studies suggest that beta blockers may slow down the rate of dilation of the aorta and help prevent it from tearing (1, 2).

Strenuous exercise also can place stress on the aorta. Children and adults with Marfan syndrome should avoid strenuous exercise, including collision and contact sports (1, 2). Heavy lifting should be prohibited. With their doctor's guidance, many can still participate in less vigorous activities, such as walking, playing golf, bicycle riding and swimming.

In spite of the use of medication, the aorta sometimes continues to dilate. Doctors will recommend surgery to repair the aorta before there is a danger of its tearing or dissecting. Doctors evaluate information from several sources when considering surgery and planning the timing of surgery.

For example, doctors use accurate measurements of the aorta to help determine the rate at which the aorta is dilating. Family history of others with aortic dilation/dissection also may influence the timing of surgery. Aortic repair also is considered when there is significant leaking of the aortic valve or worsening of the leak over time.

There are a few surgical options for repairing the aorta. In one operation, the surgeon replaces a section of the aorta with a synthetic tube (composite graft) and sometimes repairs or replaces the aortic valve. More recently, some individuals with Marfan syndrome have had what is called a valve-sparing procedure, in which the aortic valve is retained, and a portion of the aorta closest to the heart is replaced. Individuals with Marfan syndrome should have aortic surgery performed at a hospital where the surgeons are experienced with Marfan syndrome. The individuals should discuss the pros and cons of the various surgical options with their surgeon.

Early preventive surgery for aortic dilation is far safer than waiting until emergency surgery is needed. A 1999 study showed that with preventive surgery, the death rate was 1.5 percent vs. 12 percent for patients who had emergency surgery (3).

When necessary, other faulty heart valves also can be surgically repaired or replaced. After any valve replacement surgery, the individual must take anti-clotting medication for life, because blood tends to clot when it comes in contact with artificial valves.

Individuals with heart valve abnormalities, including most people with Marfan syndrome, and those who have had surgery to replace a heart valve or part of the aorta, are prone to heart valve infections. They must be treated with oral antibiotics to prevent infection of the valves before any procedure that may release bacteria into the blood stream. These procedures include dental work such as cleaning, filling and extractions, as well as other kinds of surgery. Individuals with Marfan syndrome should check with the cardiologist before dental procedures to see if additional treatment is recommended, such as a higher dose of antibiotics given by injection.

Sometimes individuals with Marfan syndrome who have had repair of the upper portion of the aorta have enlargement of other parts of their aortas. These individuals need to be followed with serial echocardiograms and a CT scan or MRI scan of the chest, abdomen and pelvis at least yearly. In some cases, surgical repair may be needed.

Children and adolescents with Marfan syndrome are monitored yearly for signs of scoliosis. Many develop mild scoliosis, which may not require treatment. In more severe or progressive cases, scoliosis can cause back pain and shortness of breath. In these cases, a brace or surgery is recommended. Bracing can sometimes halt the progression of scoliosis, although sometimes surgery is needed to correct the deformity. Pectus deformities also can interfere with breathing. Corrective surgery can be performed to alleviate these symptoms.

Children with Marfan syndrome should have a yearly eye examination by an ophthalmologist. Most eye problems, such as nearsightedness, can be corrected with glasses or contact lenses. Early treatment for cataracts and glaucoma usually can prevent or lessen vision problems. Detached retinas can be treated with lasers.

What causes Marfan syndrome?
Marfan syndrome is caused by mutations (changes) in one member of a pair of genes called the fibrillin genes. These genes are located on chromosome 15, one of the 23 pairs of human chromosomes. Normally, the fibrillin gene enables the body to produce fibrillin, a protein that is a crucial component of connective tissue. Fibrillin normally is an abundant component of the connective tissue found in the aorta, in the ligaments that hold the eye's lenses in place, in bones and in the lung. The mutated fibrillin gene, in combination with the action of other genes, leads to the formation of faulty fibrillin.

The mutated fibrillin gene usually is inherited from one parent who has Marfan syndrome. The mutation is a “dominant” genetic trait. This means that each child of a parent with Marfan syndrome has a 50 percent chance of inheriting the mutation, and a 50 percent chance of not inheriting it. Only those children who inherit the mutation will develop the signs and symptoms of Marfan syndrome.

About 25 percent of cases of Marfan syndrome are sporadic. This means that they are caused by a new mutation that occurred by chance in one of the fibrillin genes in a sperm or egg cell of an unaffected parent (2). Parents who themselves do not have Marfan syndrome and do not have a family history of Marfan syndrome, but have an affected child, should meet with a genetic counselor to discuss their risks in another pregnancy.

As with other inherited disorders, Marfan syndrome cannot be “caught” from another person. Although it may be diagnosed at any age, the signs and symptoms of Marfan syndrome do not occur unless the person has the mutation.

Is pregnancy risky for women with Marfan syndrome?
There are several important issues for women with Marfan syndrome who are considering pregnancy. First, there is a 50 percent chance of having a child with Marfan syndrome with each pregnancy. Second, the stress of pregnancy may cause rapid enlargement of the aorta, especially if the aorta is significantly enlarged before pregnancy. The risk of dissection (tearing) of the aorta is low, but not zero, in women with Marfan syndrome who have a normal aortic size. The risk increases during pregnancy as the aorta enlarges.

Women with Marfan syndrome should consult their primary health care providers and their cardiologist before pregnancy to discuss whether pregnancy is safe for them. The cardiologist generally recommends an echocardiogram to determine the dimensions of the aorta.

During pregnancy, an affected woman should receive prenatal care from a high-risk obstetrician who has experience with Marfan syndrome. She should also see her cardiologist regularly. She will need to have an echocardiogram repeated in the first, second and third trimesters to monitor the size of her aorta. If the aorta measures less than 4 cm., there usually is a low risk of tears during pregnancy (1, 2). Women who are taking a beta-blocker generally can safely continue taking the medication throughout pregnancy. Those who have had a valve replaced usually are on an oral blood thinner called coumadin (warfarin). Because this drug increases the risk of birth defects, pregnant women are switched to another blood thinner called heparin, which is given by injection (usually two or three times a day), during pregnancy.

Women with Marfan syndrome do not appear to have an increased risk of miscarriage (1). One study suggests that they may be more likely than unaffected women to deliver prematurely (before 37 weeks of pregnancy) (4). Premature babies are at increased risk of health problems during the newborn period, as well as lasting disabilities.

Most women with Marfan syndrome can have a vaginal delivery. The doctor will take appropriate measures to lessen the stress of labor and delivery. However, if the woman has significant aortic dilation, a cesarean delivery generally is recommended.

A woman with Marfan syndrome should have a follow-up echocardiogram at one to two months after delivery to check the size of her aorta.

Can Marfan syndrome be prevented?
At present, there is no way to prevent Marfan syndrome. Early diagnosis can help prevent serious complications. Genetic counseling enables informed decisions about childbearing and provides up-to-date information about the genetic basis of Marfan syndrome and on genetic testing for this condition.

What research is being done on Marfan syndrome?
In 1991, researchers, funded in part by the March of Dimes, discovered the gene that causes Marfan syndrome and identified the protein controlled by this gene (5).

Since then scientists have discovered more than 500 mutations within the fibrillin gene (2). Researchers are learning more about the role the fibrillin gene plays in the growth and development of connective tissue. A clinical trial that started in September 2006 is examining the effects of different medications on aortic dilation in an effort to prevent or decrease the rate of progression.

For further information:
National Marfan Foundation
22 Manhasset Ave.
Port Washington NY 11050
(800) 8-MARFAN

References
National Marfan Foundation. About Marfan Syndrome. Accessed 3/16/06.
Judge, D.P., and Dietz, H.C. Marfan's Syndrome. Lancet, volume 366, December 3, 2005, pages 1965-1976.
Gott, V.L., et al. Replacement of the Aortic Root in Patients with Marfan's Syndrome. New England Journal of Medicine, volume 340, number 17, April 29, 1999, pages 1307-1313.
Meijboom, L.J., et al. Obstetric Complications in Marfan Syndrome. International Journal of Cardiology, October 14, 2005.
Lee, B., et al. Linkage of Marfan Syndrome and a Phenotypically Related Disorder to Two Different Fibrillin Genes. Nature, volume 352, July 25, 1991, pages 330-334.

Contributor:
Jessica G. Davis, MD
Co-Director, Division of Human Genetics
Associate Professor of Clinical Pediatrics
Department of Pediatrics
New York Presbyterian Hospital
Weill Medical College of Cornell University

Read More

Klinefelter syndrome is a condition that occurs in men as a result of an extra X chromosome. The most common symptom is infertility.

Humans have 46 chromosomes, which contain all of a person's genes and DNA. Two of these chromosomes, the sex chromosomes, determine a person?s gender. Both of the sex chromosomes in females are called X chromosomes. (This is written as XX.) Males have an X and a Y chromosome (written as XY). The two sex chromosomes help a person develop fertility and the sexual characteristics of their gender.

Most often, Klinefelter syndrome is the result of one extra X (written as XXY). Occasionally, variations of the XXY chromosome count may occur, the most common being the XY/XXY mosaic. In this variation, some of the cells in the male's body have an additional X chromosome, and the rest have the normal XY chromosome count. The percentage of cells containing the extra chromosome varies from case to case. In some instances, XY/XXY mosaics may have enough normally functioning cells in the testes to allow them to father children.

Klinefelter syndrome is found in about 1 out of every 500-1,000 newborn males. The additional sex chromosome results from a random error during the formation of the egg or sperm. About half of the time the error occurs in the formation of sperm, while the remainder are due to errors in egg development. Women who have pregnancies after age 35 have a slightly increased chance of having a boy with this syndrome.

What are the symptoms of Klinefelter syndrome?

Males who have Klinefelter syndrome may have the following symptoms: small, firm testes, a small penis, sparse pubic, armpit and facial hair, enlarged breasts (called gynecomastia), tall stature, and abnormal body proportions (long legs, short trunk).

School-age children may be diagnosed if they are referred to a doctor to evaluate learning disabilities. The diagnosis may also be considered in the adolescent male when puberty is not progressing as expected. Adult males may come to the doctor because of infertility.

Klinefelter syndrome is associated with an increased risk for breast cancer, a rare tumor called extragonadal germ cell tumor, lung disease, varicose veins and osteoporosis. Men who have Klinefelter syndrome also have an increased risk for autoimmune disorders such as lupus, rheumatoid arthritis and Sjogren's syndrome.

How is Klinefelter syndrome diagnosed?

A chromosomal analysis (karyotype) is used to confirm the diagnosis. In this procedure, a small blood sample is drawn. White blood cells are then separated from the sample, mixed with tissue culture medium, incubated, and checked for chromosomal abnormalities, such as an extra X chromosome.

The chromosome analysis looks at a number of cells, usually at least 20, which allows for the diagnosis of genetic conditions in both the full and mosaic state. In some cases, low-level mosaicism may be missed. However, if mosaicism is suspected (based on hormone levels, sperm counts, or physical characteristics), additional cells can be analyzed from within the same blood draw.

How is Klinefelter syndrome treated?

Testosterone therapy is used to increase strength, promote muscular development, grow body hair, improve mood and self esteem, increase energy and improve concentration.

Most men who have Klinefelter syndrome are not able to father children. However, some men with an extra X chromosome have fathered healthy offspring, sometimes with the help of infertility specialists.

Most men who have Klinefelter syndrome can expect to have a normal and productive life. Early diagnosis, in conjunction with educational interventions, medical management, and strong social support will optimize each individual?s potential in adulthood. Top of page

NHGRI Clinical Research on Klinefelter Syndrome

NHGRI is not currently conducting clinical research for Klinefelter syndrome.
Search ClinicalTrials.gov [clincialtrials.gov]
Two studies are currently enrolling individuals with Klinefelter syndrome:

Androgen Effect on Klinefelter Syndrome Motor Outcome [clinicaltrials.gov]

Current NHGRI Clinical Studies
Clinical Research FAQ

Additional Resources for Klinefelter Syndrome
Klinefelter syndrome [ghr.nlm.nih.gov]
From Genetics home Reference

Klinefelter syndrome [nlm.nih.gov]
From Medline Plus.

Klinefelter's Syndrome [nlm.nih.gov]
Additional references from Medline Plus.

Klinefelter syndrome [nlm.nih.gov]
From Genetics Home Reference.

Understanding Klinefelter Syndrome [nichd.nih.gov]
From the National Institute of Child Health & Human Development.

Klinefelter Syndrome [nichd.nih.gov]
From the National Institute of Child Health & Human Development.

Karyotyping [nlm.nih.gov]
From Medline Plus.

Karyotype
NHGRI's Talking Glossary of Genetics Terms.

American Association for Klinefelter Syndrome Information and Support [aaksis.org]
Education, support, research and understanding of 47 XXY and its variants, collectively known as Klinefelter syndrome.

K,S & A: Knowledge, Support & Action [genetic.org]
K, S & A's mission is to help individuals with one or more extra X and/or Y chromosomes and their families lead fuller and more productive lives.

Finding Reliable Health Information Online
A listing of information and links for finding comprehensive genetics health information online.

Read More

In 1872, the American physician George Huntington wrote about an illness that he called "an heirloom from generations away back in the dim past." He was not the first to describe the disorder, which has been traced back to the Middle Ages at least. One of its earliest names was chorea,* which, as in "choreography," is the Greek word for dance. The term chorea describes how people affected with the disorder writhe, twist, and turn in a constant, uncontrollable dance-like motion. Later, other descriptive names evolved. "Hereditary chorea" emphasizes how the disease is passed from parent to child. "Chronic progressive chorea" stresses how symptoms of the disease worsen over time. Today, physicians commonly use the simple term Huntington's disease (HD) to describe this highly complex disorder that causes untold suffering for thousands of families.

More than 15,000 Americans have HD. At least 150,000 others have a 50 percent risk of developing the disease and thousands more of their relatives live with the possibility that they, too, might develop HD.

Until recently, scientists understood very little about HD and could only watch as the disease continued to pass from generation to generation. Families saw the disease destroy their loved ones' ability to feel, think, and move. In the last several years, scientists working with support from the National Institute of Neurological Disorders and Stroke (NINDS) have made several breakthroughs in the area of HD research. With these advances, our understanding of the disease continues to improve.

This brochure presents information about HD, and about current research progress, to health professionals, scientists, caregivers, and, most important, to those already too familiar with the disorder: the many families who are affected by HD.

What Causes Huntington's Disease?

HD results from genetically programmed degeneration of nerve cells, called neurons,* in certain areas of the brain. This degeneration causes uncontrolled movements, loss of intellectual faculties, and emotional disturbance. Specifically affected are cells of the basal ganglia, structures deep within the brain that have many important functions, including coordinating movement. Within the basal ganglia, HD especially targets neurons of the striatum, particularly those in the caudate nuclei and the pallidum. Also affected is the brain's outer surface, or cortex, which controls thought, perception, and memory.

How is HD Inherited?

HD is found in every country of the world. It is a familial disease, passed from parent to child through a mutation or misspelling in the normal gene.

A single abnormal gene, the basic biological unit of heredity, produces HD. Genes are composed of deoxyribonucleic acid (DNA), a molecule shaped like a spiral ladder. Each rung of this ladder is composed of two paired chemicals called bases. There are four types of bases—adenine, thymine, cytosine, and guanine—each abbreviated by the first letter of its name: A, T, C, and G. Certain bases always "pair" together, and different combinations of base pairs join to form coded messages. A gene is a long string of this DNA in various combinations of A, T, C, and G. These unique combinations determine the gene's function, much like letters join together to form words. Each person has about 30,000 genes—a billion base pairs of DNA or bits of information repeated in the nuclei of human cells—which determine individual characteristics or traits.

Genes are arranged in precise locations along 23 rod-like pairs of chromosomes. One chromosome from each pair comes from an individual's mother, the other from the father. Each half of a chromosome pair is similar to the other, except for one pair, which determines the sex of the individual. This pair has two X chromosomes in females and one X and one Y chromosome in males. The gene that produces HD lies on chromosome 4, one of the 22 non-sex-linked, or "autosomal," pairs of chromosomes, placing men and women at equal risk of acquiring the disease.

The impact of a gene depends partly on whether it is dominant or recessive. If a gene is dominant, then only one of the paired chromosomes is required to produce its called-for effect. If the gene is recessive, both parents must provide chromosomal copies for the trait to be present. HD is called an autosomal dominant disorder because only one copy of the defective gene, inherited from one parent, is necessary to produce the disease.

The genetic defect responsible for HD is a small sequence of DNA on chromosome 4 in which several base pairs are repeated many, many times. The normal gene has three DNA bases, composed of the sequence CAG. In people with HD, the sequence abnormally repeats itself dozens of times. Over time—and with each successive generation—the number of CAG repeats may expand further.

Each parent has two copies of every chromosome but gives only one copy to each child. Each child of an HD parent has a 50-50 chance of inheriting the HD gene. If a child does not inherit the HD gene, he or she will not develop the disease and cannot pass it to subsequent generations. A person who inherits the HD gene, and survives long enough, will sooner or later develop the disease. In some families, all the children may inherit the HD gene; in others, none do. Whether one child inherits the gene has no bearing on whether others will or will not share the same fate.

A small number of cases of HD are sporadic, that is, they occur even though there is no family history of the disorder. These cases are thought to be caused by a new genetic mutation-an alteration in the gene that occurs during sperm development and that brings the number of CAG repeats into the range that causes disease.

What are the Major Effects of the Disease?

Early signs of the disease vary greatly from person to person. A common observation is that the earlier the symptoms appear, the faster the disease progresses.

Family members may first notice that the individual experiences mood swings or becomes uncharacteristically irritable, apathetic, passive, depressed, or angry. These symptoms may lessen as the disease progresses or, in some individuals, may continue and include hostile outbursts or deep bouts of depression.

HD may affect the individual's judgment, memory, and other cognitive functions. Early signs might include having trouble driving, learning new things, remembering a fact, answering a question, or making a decision. Some may even display changes in handwriting. As the disease progresses, concentration on intellectual tasks becomes increasingly difficult.

In some individuals, the disease may begin with uncontrolled movements in the fingers, feet, face, or trunk. These movements—which are signs of chorea—often intensify when the person is anxious. HD can also begin with mild clumsiness or problems with balance. Some people develop choreic movements later, after the disease has progressed. They may stumble or appear uncoordinated. Chorea often creates serious problems with walking, increasing the likelihood of falls.

The disease can reach the point where speech is slurred and vital functions, such as swallowing, eating, speaking, and especially walking, continue to decline. Some individuals cannot recognize other family members. Many, however, remain aware of their environment and are able to express emotions.

Some physicians have employed a recently developed Unified HD Rating Scale, or UHDRS, to assess the clinical features, stages, and course of HD. In general, the duration of the illness ranges from 10 to 30 years. The most common causes of death are infection (most often pneumonia), injuries related to a fall, or other complications.

At What Age Does HD Appear?

The rate of disease progression and the age at onset vary from person to person. Adult-onset HD, with its disabling, uncontrolled movements, most often begins in middle age. There are, however, other variations of HD distinguished not just by age at onset but by a distinct array of symptoms. For example, some persons develop the disease as adults, but without chorea. They may appear rigid and move very little, or not at all, a condition called akinesia.

Some individuals develop symptoms of HD when they are very young—before age 20. The terms "early-onset" or "juvenile" HD are often used to describe HD that appears in a young person. A common sign of HD in a younger individual is a rapid decline in school performance. Symptoms can also include subtle changes in handwriting and slight problems with movement, such as slowness, rigidity, tremor, and rapid muscular twitching, called myoclonus. Several of these symptoms are similar to those seen in Parkinson's disease, and they differ from the chorea seen in individuals who develop the disease as adults. These young individuals are said to have "akinetic-rigid" HD or the Westphal variant of HD. People with juvenile HD may also have seizures and mental disabilities. The earlier the onset, the faster the disease seems to progress. The disease progresses most rapidly in individuals with juvenile or early-onset HD, and death often follows within 10 years.

Individuals with juvenile HD usually inherit the disease from their fathers. These individuals also tend to have the largest number of CAG repeats. The reason for this may be found in the process of sperm production. Unlike eggs, sperm are produced in the millions. Because DNA is copied millions of times during this process, there is an increased possibility for genetic mistakes to occur. To verify the link between the number of CAG repeats in the HD gene and the age at onset of symptoms, scientists studied a boy who developed HD symptoms at the age of two, one of the youngest and most severe cases ever recorded. They found that he had the largest number of CAG repeats of anyone studied so far—nearly 100. The boy's case was central to the identification of the HD gene and at the same time helped confirm that juveniles with HD have the longest segments of CAG repeats, the only proven correlation between repeat length and age at onset.

A few individuals develop HD after age 55. Diagnosis in these people can be very difficult. The symptoms of HD may be masked by other health problems, or the person may not display the severity of symptoms seen in individuals with HD of earlier onset. These individuals may also show symptoms of depression rather than anger or irritability, or they may retain sharp control over their intellectual functions, such as memory, reasoning, and problem-solving.

There is also a related disorder called senile chorea. Some elderly individuals display the symptoms of HD, especially choreic movements, but do not become demented, have a normal gene, and lack a family history of the disorder. Some scientists believe that a different gene mutation may account for this small number of cases, bu this has not been proven.

How is HD Diagnosed?

The great American folk singer and composer Woody Guthrie died on October 3, 1967, after suffering from HD for 13 years. He had been misdiagnosed, considered an alcoholic, and shuttled in and out of mental institutions and hospitals for years before being properly diagnosed. His case, sadly, is not extraordinary, although the diagnosis can be made easily by experienced neurologists.

A neurologist will interview the individual intensively to obtain the medical history and rule out other conditions. A tool used by physicians to diagnose HD is to take the family history, sometimes called a pedigree or genealogy. It is extremely important for family members to be candid and truthful with a doctor who is taking a family history.

The doctor will also ask about recent intellectual or emotional problems, which may be indications of HD, and will test the person's hearing, eye movements, strength, coordination, involuntary movements (chorea), sensation, reflexes, balance, movement, and mental status, and will probably order a number of laboratory tests as well.

People with HD commonly have impairments in the way the eye follows or fixes on a moving target. Abnormalities of eye movements vary from person to person and differ, depending on the stage and duration of the illness.

The discovery of the HD gene in 1993 resulted in a direct genetic test to make or confirm a diagnosis of HD in an individual who is exhibiting HD-like symptoms. Using a blood sample, the genetic test analyzes DNA for the HD mutation by counting the number of repeats in the HD gene region. Individuals who do not have HD usually have 28 or fewer CAG repeats. Individuals with HD usually have 40 or more repeats. A small percentage of individuals, however, have a number of repeats that fall within a borderline region (see table 1).

Table 1
No. of CAG repeats
Outcome
<28>40

Individual will develop HD

The physician may ask the individual to undergo a brain imaging test. Computed tomography (CT) and magnetic resonance imaging (MRI) provide excellent images of brain structures with little if any discomfort. Those with HD may show shrinkage of some parts of the brain—particularly two areas known as the caudate nuclei and putamen—and enlargement of fluid-filled cavities within the brain called ventricles. These changes do not definitely indicate HD, however, because they can also occur in other disorders. In addition, a person can have early symptoms of HD and still have a normal CT scan. When used in conjunction with a family history and record of clinical symptoms, however, CT can be an important diagnostic tool.

Another technology for brain imaging includes positron emission tomography (PET,) which is important in HD research efforts but is not often needed for diagnosis.

What is Presymptomatic Testing?

Presymptomatic testing is used for people who have a family history of HD but have no symptoms themselves. If either parent had HD, the person's chance would be 50-50. In the past, no laboratory test could positively identify people carrying the HD gene—or those fated to develop HD—before the onset of symptoms. That situation changed in 1983, when a team of scientists supported by the NINDS located the first genetic marker for HD—the initial step in developing a laboratory test for the disease.

A marker is a piece of DNA that lies near a gene and is usually inherited with it. Discovery of the first HD marker allowed scientists to locate the HD gene on chromosome 4. The marker discovery quickly led to the development of a presymptomatic test for some individuals, but this test required blood or tissue samples from both affected and unaffected family members in order to identify markers unique to that particular family. For this reason, adopted individuals, orphans, and people who had few living family members were unable to use the test.

Discovery of the HD gene has led to a less expensive, scientifically simpler, and far more accurate presymptomatic test that is applicable to the majority of at-risk people. The new test uses CAG repeat length to detect the presence of the HD mutation in blood. This is discussed further in the next section.

There are many complicating factors that reflect the complexity of diagnosing HD. In a small number of individuals with HD—1 to 3 percent—no family history of HD can be found. Some individuals may not be aware of their genetic legacy, or a family member may conceal a genetic disorder from fear of social stigma. A parent may not want to worry children, scare them, or deter them from marrying. In other cases, a family member may die of another cause before he or she begins to show signs of HD. Sometimes, the cause of death for a relative may not be known, or the family is not aware of a relative's death. Adopted children may not know their genetic heritage, or early symptoms in an individual may be too slight to attract attention.

How is the Presymptomatic Test Conducted?

An individual who wishes to be tested should contact the nearest testing center. (A list of such centers can be obtained from the Huntington Disease Society of America at 1-800-345-HDSA.) The testing process should include several components. Most testing programs include a neurological examination, pretest counseling, and followup. The purpose of the neurological examination is to determine whether or not the person requesting testing is showing any clinical symptoms of HD. It is important to remember that if an individual is showing even slight symptoms of HD, he or she risks being diagnosed with the disease during the neurological examination, even before the genetic test. During pretest counseling, the individual will learn about HD, and about his or her own level of risk, about the testing procedure. The person will be told about the test's limitations, the accuracy of the test, and possible outcomes. He or she can then weigh the risks and benefits of testing and may even decide at that time against pursuing further testing.

If a person decides to be tested, a team of highly trained specialists will be involved, which may include neurologists, genetic counselors, social workers, psychiatrists, and psychologists. This team of professionals helps the at-risk person decide if testing is the right thing to do and carefully prepares the person for a negative, positive, or inconclusive test result.

Individuals who decide to continue the testing process should be accompanied to counseling sessions by a spouse, a friend, or a relative who is not at risk. Other interested family members may participate in the counseling sessions if the individual being tested so desires.

The genetic testing itself involves donating a small sample of blood that is screened in the laboratory for the presence or absence of the HD mutation. Testing may require a sample of DNA from a closely related affected relative, preferably a parent, for the purpose of confirming the diagnosis of HD in the family. This is especially important if the family history for HD is unclear or unusual in some way.

Results of the test should be given only in person and only to the individual being tested. Test results are confidential. Regardless of test results, followup is recommended.

In order to protect the interests of minors, including confidentiality, testing is not recommended for those under the age of 18 unless there is a compelling medical reason (for example, the child is exhibiting symptoms).

Testing of a fetus (prenatal testing) presents special challenges and risks; in fact some centers do not perform genetic testing on fetuses. Because a positive test result using direct genetic testing means the at-risk parent is also a gene carrier, at-risk individuals who are considering a pregnancy are advised to seek genetic counseling prior to conception.

Some at-risk parents may wish to know the risk to their fetus but not their own. In this situation, parents may opt for prenatal testing using linked DNA markers rather than direct gene testing. In this case, testing does not look for the HD gene itself but instead indicates whether or not the fetus has inherited a chromosome 4 from the affected grandparent or from the unaffected grandparent on the side of the family with HD. If the test shows that the fetus has inherited a chromosome 4 from the affected grandparent, the parents then learn that the fetus's risk is the same as the parent (50-50), but they learn nothing new about the parent's risk. If the test shows that the fetus has inherited a chromosome 4 from the unaffected grandparent, the risk to the fetus is very low (less than 1%) in most cases.

Another option open to parents is in vitro fertilization with preimplantation screening. In this procedure, embryos are screened to determine which ones carry the HD mutation. Embryos determined not to have the HD gene mutation are then implanted in the woman's uterus.

In terms of emotional and practical consequences, not only for the individual taking the test but for his or her entire family, testing is enormously complex and has been surrounded by considerable controversy. For example, people with a positive test result may risk losing health and life insurance, suffer loss of employment, and other liabilities. People undergoing testing may wish to cover the cost themselves, since coverage by an insurer may lead to loss of health insurance in the event of a positive result, although this may change in the future.

With the participation of health professionals and people from families with HD, scientists have developed testing guidelines. All individuals seeking a genetic test should obtain a copy of these guidelines, either from their testing center or from the organizations listed on the card in the back of this brochure. These organizations have information on sites that perform testing using the established procedures and they strongly recommend that individuals avoid testing that does not adhere to these guidelines.

How Does a Person Decide Whether to be Tested?

The anxiety that comes from living with a 50 percent risk for HD can be overwhelming. How does a young person make important choices about long-term education, marriage, and children? How do older parents of adult children cope with their fears about children and grandchildren? How do people come to terms with the ambiguity and uncertainty of living at risk?

Some individuals choose to undergo the test out of a desire for greater certainty about their genetic status. They believe the test will enable them to make more informed decisions about the future. Others choose not to take the test. They are able to make peace with the uncertainty of being at risk, preferring to forego the emotional consequences of a positive result, as well as possible losses of insurance and employment. There is no right or wrong decision, as each choice is highly individual. The guidelines for genetic testing for HD, discussed in the previous section, were developed to help people with this life-changing choice.

Whatever the results of genetic testing, the at-risk individual and family members can expect powerful and complex emotional responses. The health and happiness of spouses, brothers and sisters, children, parents, and grandparents are affected by a positive test result, as are an individual's friends, work associates, neighbors, and others. Because receiving test results may prove to be devastating, testing guidelines call for continued counseling even after the test is complete and the results are known.

Is There a Treatment for HD?

Physicians may prescribe a number of medications to help control emotional and movement problems associated with HD. It is important to remember however, that while medicines may help keep these clinical symptoms under control, there is no treatment to stop or reverse the course of the disease.

Antipsychotic drugs, such as haloperidol, or other drugs, such as clonazepam, may help to alleviate choreic movements and may also be used to help control hallucinations, delusions, and violent outbursts. Antipsychotic drugs, however, are not prescribed for another form of muscle contraction associated with HD, called dystonia, and may in fact worsen the condition, causing stiffness and rigidity. These medications may also have severe side effects, including sedation, and for that reason should be used in the lowest possible doses.

For depression, physicians may prescribe fluoxetine, sertraline, nortriptyline, or other compounds. Tranquilizers can help control anxiety and lithium may be prescribed to combat pathological excitement and severe mood swings. Medications may also be needed to treat the severe obsessive-compulsive rituals of some individuals with HD.

Most drugs used to treat the symptoms of HD have side effects such as fatigue, restlessness, or hyperexcitability. Sometimes it may be difficult to tell if a particular symptom, such as apathy or incontinence, is a sign of the disease or a reaction to medication.

What Kind of Care Does the Individual with HD Need?

Although a psychologist or psychiatrist, a genetic counselor, and other specialists may be needed at different stages of the illness, usually the first step in diagnosis and in finding treatment is to see a neurologist. While the family doctor may be able to diagnose HD, and may continue to monitor the individual's status, it is better to consult with a neurologist about management of the varied symptoms.

Problems may arise when individuals try to express complex thoughts in words they can no longer pronounce intelligibly. It can be helpful to repeat words back to the person with HD so that he or she knows that some thoughts are understood. Sometimes people mistakenly assume that if individuals do not talk, they also do not understand. Never isolate individuals by not talking, and try to keep their environment as normal as possible. Speech therapy may improve the individual's ability to communicate.

It is extremely important for the person with HD to maintain physical fitness as much as his or her condition and the course of the disease allows. Individuals who exercise and keep active tend to do better than those who do not. A daily regimen of exercise can help the person feel better physically and mentally. Although their coordination may be poor, individuals should continue walking, with assistance if necessary. Those who want to walk independently should be allowed to do so as long as possible, and careful attention should be given to keeping their environment free of hard, sharp objects. This will help ensure maximal independence while minimizing the risk of injury from a fall. Individuals can also wear special padding during walks to help protect against injury from falls. Some people have found that small weights around the ankles can help stability. Wearing sturdy shoes that fit well can help too, especially shoes without laces that can be slipped on or off easily.

Impaired coordination may make it difficult for people with HD to feed themselves and to swallow. As the disease progresses, persons with HD may even choke. In helping individuals to eat, caregivers should allow plenty of time for meals. Food can be cut into small pieces, softened, or pureed to ease swallowing and prevent choking. While some foods may require the addition of thickeners, other foods may need to be thinned. Dairy products, in particular, tend to increase the secretion of mucus, which in turn increases the risk of choking. Some individuals may benefit from swallowing therapy, which is especially helpful if started before serious problems arise. Suction cups for plates, special tableware designed for people with disabilities, and plastic cups with tops can help prevent spilling. The individual's physician can offer additional advice about diet and about how to handle swallowing difficulties or gastrointestinal problems that might arise, such as incontinence or constipation.

Caregivers should pay attention to proper nutrition so that the individual with HD takes in enough calories to maintain his or her body weight. Sometimes people with HD, who may burn as many as 5,000 calories a day without gaining weight, require five meals a day to take in the necessary number of calories. Physicians may recommend vitamins or other nutritional supplements. In a long-term care institution, staff will need to assist with meals in order to ensure that the individual's special caloric and nutritional requirements are met. Some individuals and their families choose to use a feeding tube; others choose not to.

Individuals with HD are at special risk for dehydration and therefore require large quantities of fluids, especially during hot weather. Bendable straws can make drinking easier for the person. In some cases, water may have to be thickened with commercial additives to give it the consistency of syrup or honey.

What Community Resources are Available?

Individuals and families affected by HD can take steps to ensure that they receive the best advice and care possible. Physicians and state and local health service agencies can provide information on community resources and family support groups that may exist. Possible types of help include:

Legal and social aid. HD affects a person's capacity to reason, make judgments, and handle responsibilities. Individuals may need help with legal affairs. Wills and other important documents should be drawn up early to avoid legal problems when the person with HD may no longer be able to represent his or her own interests. Family members should also seek out assistance if they face discrimination regarding insurance, employment, or other matters.

Home care services. Caring for a person with HD at home can be exhausting, but part-time assistance with household chores or physical care of the individual can ease this burden. Domestic help, meal programs, nursing assistance, occupational therapy, or other home services may be available from federal, state, or local health service agencies.

Recreation and work centers. Many people with HD are eager and able to participate in activities outside the home. Therapeutic work and recreation centers give individuals an opportunity to pursue hobbies and interests and to meet new people. Participation in these programs, including occupational, music, and recreational therapy, can reduce the person's dependence on family members and provides home caregivers with a temporary, much needed break.

Group housing. A few communities have group housing facilities that are supervised by a resident attendant and that provide meals, housekeeping services, social activities, and local transportation services for residents. These living arrangements are particularly suited to the needs of individuals who are alone and who, although still independent and capable, risk injury when they undertake routine chores like cooking and cleaning.

Institutional care. The individual's physical and emotional demands on the family may eventually become overwhelming. While many families may prefer to keep relatives with HD at home whenever possible, a long-term care facility may prove to be best. To hospitalize or place a family member in a care facility is a difficult decision; professional counseling can help families with this.

Finding the proper facility can itself prove difficult. Organizations such as the Huntington's Disease Society of America (see listing on the Information Resources card in the back pocket of this brochure) may be able to refer the family to facilities that have met standards set for the care of individuals with HD. Very few of these exist however, and even fewer have experience with individuals with juvenile or early-onset HD who require special care because of their age and symptoms.

What Research is Being Done?

Although HD attracted considerable attention from scientists in the early 20th century, there was little sustained research on the disease until the late 1960s when the Committee to Combat Huntington's Disease and the Huntington's Chorea Foundation, later called the Hereditary Disease Foundation, first began to fund research and to campaign for federal funding. In 1977, Congress established the Commission for the Control of Huntington's Disease and Its Consequences, which made a series of important recommendations. Since then, Congress has provided consistent support for federal research, primarily through the National Institute of Neurological Disorders and Stroke, the government's lead agency for biomedical research on disorders of the brain and nervous system. The effort to combat HD proceeds along the following lines of inquiry, each providing important information about the disease:

Basic neurobiology. Now that the HD gene has been located, investigators in the field of neurobiology-which encompasses the anatomy, physiology, and biochemistry of the nervous system-are continuing to study the HD gene with an eye toward understanding how it causes disease in the human body.

Clinical research. Neurologists, psychologists, psychiatrists, and other investigators are improving our understanding of the symptoms and progression of the disease in patients while attempting to develop new therapeutics.

Imaging. Scientific investigations using PET and other technologies are enabling scientists to see what the defective gene does to various structures in the brain and how it affects the body's chemistry and metabolism.

Animal models. Laboratory animals, such as mice, are being bred in the hope of duplicating the clinical features of HD and can soon be expected to help scientists learn more about the symptoms and progression of the disease.

Fetal tissue research. Investigators are implanting fetal tissue in rodents and nonhuman primates with the hope that success in this area will lead to understanding, restoring, or replacing functions typically lost by neuronal degeneration in individuals with HD.

These areas of research are slowly converging and, in the process, are yielding important clues about the gene's relentless destruction of mind and body. The NINDS supports much of this exciting work.

Molecular Genetics

For 10 years, scientists focused on a segment of chromosome 4 and, in 1993, finally isolated the HD gene. The process of isolating the responsible gene—motivated by the desire to find a cure—was more difficult than anticipated. Scientists now believe that identifying the location of the HD gene is the first step on the road to a cure.

Finding the HD gene involved an intense molecular genetics research effort with cooperating investigators from around the globe. In early 1993, the collaborating scientists announced they had isolated the unstable triplet repeat DNA sequence that has the HD gene. Investigators relied on the NINDS-supported Research Roster for Huntington's Disease, based at Indiana University in Indianapolis, to accomplish this work. First started in 1979, the roster contains data on many American families with HD, provides statistical and demographic data to scientists, and serves as a liaison between investigators and specific families. It provided the DNA from many families affected by HD to investigators involved in the search for the gene and was an important component in the identification of HD markers.

For several years, NINDS-supported investigators involved in the search for the HD gene made yearly visits to the largest known kindred with HD—14,000 individuals—who live on Lake Maracaibo in Venezuela. The continuing trips enable scientists to study inheritance patterns of several interrelated families.

The HD Gene and Its Product

Although scientists know that certain brain cells die in HD, the cause of their death is still unknown. Recessive diseases are usually thought to result from a gene that fails to produce adequate amounts of a substance essential to normal function. This is known as a loss-of-function gene. Some dominantly inherited disorders, such as HD, are thought to involve a gene that actively interferes with the normal function of the cell. This is known as a gain-of-function gene.

How does the defective HD gene cause harm? The HD gene encodes a protein—which has been named huntingtin—the function of which is as yet unknown. The repeated CAG sequence in the gene causes an abnormal form of huntingtin to be made, in which the amino acid glutamine is repeated. It is the presence of this abnormal form, and not the absence of the normal form, that causes harm in HD. This explains why the disease is dominant and why two copies of the defective gene—one from both the mother and the father—do not cause a more serious case than inheritance from only one parent. With the HD gene isolated, NINDS-supported investigators are now turning their attention toward discovering the normal function of huntingtin and how the altered form causes harm. Scientists hope to reproduce, study, and correct these changes in animal models of the disease.

Huntingtin is found everywhere in the body but only outside the cell's nucleus. Mice called "knockout mice" are bred in the laboratory to produce no huntingtin; they fail to develop past a very early embryo stage and quickly die. Huntingtin, scientists now know, is necessary for life. Investigators hope to learn why the abnormal version of the protein damages only certain parts of the brain. One theory is that cells in these parts of the brain may be supersensitive to this abnormal protein.

Cell Death in HD

Although the precise cause of cell death in HD is not yet known, scientists are paying close attention to the process of genetically programmed cell death that occurs deep within the brains of individuals with HD. This process involves a complex series of interlinked events leading to cellular suicide. Related areas of investigation include:
Excitotoxicity. Overstimulation of cells by natural chemicals found in the brain.
Defective energy metabolism. A defect in the power plant of the cell, called mitochondria, where energy is produced.
Oxidative stress. Normal metabolic activity in the brain that produces toxic compounds called free radicals.
Trophic factors. Natural chemical substances found in the human body that may protect against cell death.

Several HD studies are aimed at understanding losses of nerve cells and receptors in HD. Neurons in the striatum are classified both by their size (large, medium, or small) and appearance (spiny or aspiny). Each type of neuron contains combinations of neurotransmitters. Scientists know that the destructive process of HD affects different subsets of neurons to varying degrees. The hallmark of HD, they are learning, is selective degeneration of medium-sized spiny neurons in the striatum. NINDS-supported studies also suggest that losses of certain types of neurons and receptors are responsible for different symptoms and stages of HD.

What do these changes look like? In spiny neurons, investigators have observed two types of changes, each affecting the nerve cells' dendrites. Dendrites, found on every nerve cell, extend out from the cell body and are responsible for receiving messages from other nerve cells. In the intermediate stages of HD, dendrites grow out of control. New, incomplete branches form and other branches become contorted. In advanced, severe stages of HD, degenerative changes cause sections of dendrites to swell, break off, or disappear altogether. Investigators believe that these alterations may be an attempt by the cell to rebuild nerve cell contacts lost early in the disease. As the new dendrites establish connections, however, they may in fact contribute to nerve cell death. Such studies give compelling, visible evidence of the progressive nature of HD and suggest that new experimental therapies must consider the state of cellular degeneration. Scientists do not yet know exactly how these changes affect subsets of nerve cells outside the striatum.

Animal Models of HD

As more is learned about cellular degeneration in HD, investigators hope to reproduce these changes in animal models and to find a way to correct or halt the process of nerve cell death. Such models serve the scientific community in general by providing a means to test the safety of new classes of drugs in nonhuman primates. NINDS-supported scientists are currently working to develop both nonhuman primate and mouse models to investigate nerve degeneration in HD and to study the effects of excitotoxicity on nerve cells in the brain.

Investigators are working to build genetic models of HD using transgenic mice. To do this, scientists transfer the altered human HD gene into mouse embryos so that the animals will develop the anatomical and biological characteristics of HD. This genetic model of mouse HD will enable in-depth study of the disease and testing of new therapeutic compounds.

Another idea is to insert into mice a section of DNA containing CAG repeats in the abnormal, disease gene range. This mouse equivalent of HD could allow scientists to explore the basis of CAG instability and its role in the disease process.

Fetal Tissue Research

A relatively new field in biomedical research involves the use of brain tissue grafts to study, and potentially treat, neurodegenerative disorders. In this technique, tissue that has degenerated is replaced with implants of fresh, fetal tissue, taken at the very early stages of development. Investigators are interested in applying brain tissue implants to HD research. Extensive animal studies will be required to learn if this technique could be of value in patients with HD.

Clinical Studies

Scientists are pursuing clinical studies that may one day lead to the development of new drugs or other treatments to halt the disease's progression. Examples of NINDS-supported investigations, using both asymptomatic and symptomatic individuals, include:

Genetic studies on age of onset, inheritance patterns, and markers found within families. These studies may shed additional light on how HD is passed from generation to generation.

Studies of cognition, intelligence, and movement. Studies of abnormal eye movements, both horizontal and vertical, and tests of patients' skills in a number of learning, memory, neuropsychological, and motor tasks may serve to identify when the various symptoms of HD appear and to characterize their range and severity.

Clinical trials of drugs. Testing of various drugs may lead to new treatments and at the same time improve our understanding of the disease process in HD. Classes of drugs being tested include those that control symptoms, slow the rate of progression of HD, and block effects of excitotoxins, and those that might correct or replace other metabolic defects contributing to the development and progression of HD.

Imaging

NINDS-supported scientists are using positron emission tomography (PET) to learn how the gene affects the chemical systems of the body. PET visualizes metabolic or chemical abnormalities in the body, and investigators hope to ascertain if PET scans can reveal any abnormalities that signal HD. Investigators conducting HD research are also using PET to characterize neurons that have died and chemicals that are depleted in parts of the brain affected by HD.

Like PET, a form of magnetic resonance imaging (MRI) called functional MRI can measure increases or decreases in certain brain chemicals thought to play a key role in HD. Functional MRI studies are also helping investigators understand how HD kills neurons in different regions of the brain.

Imaging technologies allow investigators to view changes in the volume and structures of the brain and to pinpoint when these changes occur in HD. Scientists know that in brains affected by HD, the basal ganglia, cortex, and ventricles all show atrophy or other alterations.

How Can I Help?

In order to conduct HD research, investigators require samples of tissue or blood from families with HD. Access to individuals with HD and their families may be difficult however, because families with HD are often scattered across the country or around the world. A research project may need individuals of a particular age or gender or from a certain geographic area. Some scientists need only statistical data while others may require a sample of blood, urine, or skin from family members. All of these factors complicate the task of finding volunteers. The following NINDS-supported efforts bring together families with HD, voluntary health agencies, and scientists in an effort to advance science and speed a cure.

The NINDS-sponsored HD Research Roster at the Indiana University Medical Center in Indianapolis, which was discussed earlier, makes research possible by matching scientists with patient and family volunteers. The first DNA bank was established through the roster. Although the gene has already been located, DNA from individuals who have HD is still of great interest to investigators. Of continuing interest are twins, unaffected individuals who have affected offspring, and individuals with two defective HD genes, one from each parent-a very rare occurrence. Participation in the roster and in specific research projects is voluntary and confidential. For more information about the roster and DNA bank, contact:

Indiana University Medical Center
Department of Medical and Molecular Genetics
Medical Research and Library Building
975 W. Walnut Street
Indianapolis, IN 46202-5251
(317) 274-5744 (call collect)

The NINDS supports two national brain specimen banks. These banks supply research scientists around the world with nervous system tissue from patients with neurological and psychiatric disorders. They need tissue from patients with HD so that scientists can study and understand the disorder. Those who may be interested in donating should write to:

Human Brain and Spinal Fluid Resource Center
Neurology Research (127A)
W. Los Angeles Healthcare Center
11301 Wilshire Blvd. Bldg. 212
Los Angeles, CA 90073
310-268-3536
24-hour pager: 310-636-5199
Email: RMNbbank@ucla.edu
http://www.loni.ucla.edu/~nnrsb/NNRSB

Francine M. Benes, M.D., Ph.D., Director
Harvard Brain Tissue Resource Center
McLean Hospital
115 Mill Street
Belmont, Massachusetts 02478
800-BRAIN-BANK (800-272-4622)
(617) 855-2400
www.brainbank.mclean.org

What is the Role of Voluntary Organizations?

Private organizations have been a mainstay of support and guidance for at-risk individuals, people with HD, and their families. These organizations vary in size and emphasis, but all are concerned with helping individuals and their families, educating lay and professional audiences about HD, and promoting medical research on the disorder. Some voluntary health agencies support scientific workshops and research and some have newsletters and local chapters throughout the country. These agencies enable families, health professionals, and investigators to exchange information, learn of available services and benefits, and work toward common goals. The organizations listed on the Information Resources card in the back pocket of this brochure welcome inquiries from the public.

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:Hereditary Disease Foundation
3960 Broadway
6th Floor
New York, NY 10032
cures@hdfoundation.org
http://www.hdfoundation.org
Tel: 212-928-2121
Fax: 212-928-2172
Non-profit basic science organization dedicated to the cure of genetic disease. All publicly donated funds are directed toward the support of biomedical research.

Huntington's Disease Society of America
505 Eighth Avenue
Suite 902
New York, NY 10018
hdsainfo@hdsa.org
http://www.hdsa.org
Tel: 212-242-1968 800-345-HDSA (4372)
Fax: 212-239-3430
Dedicated to finding a cure for Huntington’s Disease while providing support and services for those with HD and their families.

Glossary
akinesia-decreased body movements.

at-risk -a description of a person whose mother or father has HD or has inherited the HD gene and who therefore has a 50-50 chance of inheriting the disorder.

autosomal dominant disorder -a non-sex-linked disorder that can be inherited even if only one parent passes on the defective gene.

basal ganglia -a region located at the base of the brain composed of four clusters of neurons, or nerve cells. This area is responsible for body movement and coordination. The neuron groups most prominently and consistently affected by HD—the pallidum and striatum—are located here. See neuron, pallidum, striatum.

caudate nuclei -part of the striatum in the basal ganglia. See basal ganglia, striatum.

chorea -uncontrolled body movements. Chorea is derived from the Greek word for dance.

chromosomes -the structures in cells that contain genes. They are composed of deoxyribonucleic acid (DNA) and proteins and, under a microscope, appear as rod-like structures. See deoxyribonucleic acid (DNA), gene.

computed tomography (CT)- a technique used for diagnosing brain disorders. CT uses a computer to produce a high-quality image of brain structures. These images are called CT scans.

cortex -part of the brain responsible for thought, perception, and memory. HD affects the basal ganglia and cortex. See basal ganglia.

deoxyribonucleic acid (DNA)- the substance of heredity containing the genetic information necessary for cells to divide and produce proteins. DNA carries the code for every inherited characteristic of an organism. See gene.

dominant -a trait that is apparent even when the gene for that disorder is inherited from only one parent. See autosomal dominant disorder, recessive, gene.

gene -the basic unit of heredity, composed of a segment of DNA containing the code for a specific trait. See deoxyribonucleic acid (DNA).

huntingtin -the protein encoded by the gene that carries the HD defect. The repeated CAG sequence in the gene causes an abnormal form of huntingtin to be formed. The function of the normal form of huntingtin is not yet known.

kindred -a group of related persons, such as a family or clan.

magnetic resonance imaging (MRI) -an imaging technique that uses radiowaves, magnetic fields, and computer analysis to create a picture of body tissues and structures.

marker -a piece of DNA that lies on the chromosome so close to a gene that the two are inherited together. Like a signpost, markers are used during genetic testing and research to locate the nearby presence of a gene. See chromosome, deoxyribonucleic acid (DNA).

mitochondria -microscopic, energy-producing bodies within cells that are the cells' "power plants."

mutation -in genetics, any defect in a gene. See gene.

myoclonus -a condition in which muscles or portions of muscles contract involuntarily in a jerky fashion.

neuron -Greek word for a nerve cell, the basic impulse-conducting unit of the nervous system. Nerve cells communicate with other cells through an electrochemical process called neurotransmission.

neurotransmitters -special chemicals that transmit nerve impulses from one cell to another.

pallidum -part of the basal ganglia of the brain. The pallidum is composed of the globus pallidus and the ventral pallidum. See basal ganglia.

positron emission tomography (PET)- a tool used to diagnose brain functions and disorders. PET produces three-dimensional, colored images of chemicals or substances functioning within the body. These images are called PET scans. PET shows brain function, in contrast to CT or MRI, which show brain structure.

prevalence -the number of cases of a disease that are present in a particular population at a given time.

putamen -an area of the brain that decreases in size as a result of the damage produced by HD.

receptor -proteins that serve as recognition sites on cells and cause a response in the body when stimulated by chemicals called neurotransmitters. They act as on-and-off switches for the next nerve cell. See neuron, neurotransmitters.

recessive -a trait that is apparent only when the gene or genes for it are inherited from both parents. See dominant, gene.

senile chorea -a relatively mild and rare disorder found in elderly adults and characterized by choreic movements. It is believed by some scientists to be caused by a different gene mutation than that causing HD.

striatum -part of the basal ganglia of the brain. The striatum is composed of the caudate nucleus, putamen, and ventral striatum. See basal ganglia, caudate nuclei.

trait -any genetically determined characteristic. See dominant, gene, recessive.

transgenic mice-mice that receive injections of foreign genes during the embryonic stage of development. Their cells then follow the "instructions" of the foreign genes, resulting in the development of a certain trait or characteristic. Transgenic mice can serve as an animal model of a certain disease, telling researchers how genes work in specific cells.

ventricles -cavities within the brain that are filled with cerebrospinal fluid. In HD, tissue loss causes enlargement of the ventricles.
top "Huntington's Disease: Hope Through Research," NINDS.

NIH Publication No. 98-49

Read More