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(1)Frafile X.

(2)PRADER-WILLI Syndrome (PWS)




(1)

Fragile X syndrome
is the leading hereditary cause of developmental disabilities in all populations. The absence of a functional fragile X gene shuts off production of a special protein in the brain needed for normal cognitive development. Without this protein, children with the syndrome will never learn normally, despite hours of therapy and rehabilitation. Visit the links at right to learn more about this common genetic condition.



What is Fragile X

In 1991, scientists discovered the gene (called FMR1) that causes Fragile X. In individuals with Fragile X Syndrome, a defect in FMR1 (a full mutation) shuts the gene down. Like a defective factory, the FMR1 gene cannot manufacture the protein that it normally makes. Some individuals are fragile X carriers; they have a small defect in the FMR1 gene (called a premutation) but do not show symptoms of Fragile X .



Fragile X is inherited. Carrier men (transmitting males) pass the premutation to all their daughters but none of their sons. Each child of a carrier woman has a 50% chance of inheriting the gene. The Fragile X premutation can be passed silently down through generations in a family before a child is affected by the syndrome. A DNA blood test identifies both carriers and affected individuals. While the exact prevalence of Fragile X is unknown, recent studies indicate the statistics below:


1 in 2000 boys and 1 in 4000 girls are estimated to be affected.

1 in 260 women are carriers.




The Effects Of Fragile X

Fragile X is the leading form of autism of known cause: 90 % of Fragile X patients have autistic features, 50% of pre-school Fragile X children meet autism diagnostic criteria, and 6% of all autistic individuals turn out to have fragile X. Fragile X also gives rise to anxiety disorders, attention deficit hyperactivity disorder, psychosis, obsessive-compulsive disorder, and many other problems.




Is There a Cure for Fragile X Syndrome?

There is currently no cure for Fragile X Syndrome, although appropriate education and medications can help maximize the potential of each child. However, most boys and many girls remain significantly affected throughout their lives. The cost to society for treatment, special education, and lost income is staggering. The need for research aimed at treatment is urgent. Recent significant progress has been made in understanding mechanisms and developing potential treatments for inherited diseases that are caused by a single gene, such as Fragile X. Current medical research focuses on: Gene Therapy - studying the gene that causes Fragile X in order to determine whether a healthy gene may be inserted into the cells of affected individuals, thereby replacing the mutated, ineffective gene. Protein Replacement Therapy - studying the protein product that is lacking due to the mutation, in hopes that the protein may be supplemented from an external source. Psychopharmacology - treating the symptoms of the disorder with medications.



Many researchers believe that medical treatment, when it becomes available, will be able to help Fragile X individuals of all ages. Experts think that the missing FMR protein has a regulatory function in the brain, rather than a structural function, and that this protein is needed throughout a person's life.





Fragile X is a hereditary/genetic condition which can impact families in many ways.
It includes fragile X syndrome (FXS), the most common cause of genetically-inherited mental impairment ranging from subtle learning disabilities and a normal IQ, to severe cognitive or intellectual challenges (often still referred to as mental retardation) including autism or "autistic-like" behavior. Symptoms often include unique physical characteristics, behavioral deficits and delays in speech and language development.

Fragile X also includes fragile X-associated tremor ataxia syndrome (FXTAS), a balance, tremor and memory condition that affects some older male carriers of the premutation. Fragile X can also include problems for female carriers such as early menopause, medically referred to as premature ovarian failure (POF).

Fragile X can be passed on in a family by individuals with no apparent sign of the condition. In some families it is a problem which has been occurring for decades, affecting numerous family members through the generations, while in others, it seems to have caused problems in only one person.


For more information, check out the following websites:

www.nfxf.org

www.fraxa.org

www.cfxf.org

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(2)

What is Prader-Willi Syndrome (PWS): ?

A disorder of chromosome 15
Prevalence: 1:12,000- 15,000 (both sexes, all races)
Major characteristics: hypotonia, hypogonadism, hyperphagia, cognitive impairment, difficult behaviors
MAJOR MEDICAL CONCERN: MORBID OBESITY.




Cause and Diagnosis of PWS

The genetic cause is loss of yet unidentified genes normally contributed
by the father. Occurs from three main genetic errors: Approximately 70%
of cases have a non-inherited deletion in the paternally contributed
chromosome 15; approximately 25% have maternal uniparental disomy
(UPD)—two maternal 15s and no paternal chromosome 15; and 2–5 %
have an error in the "imprinting" process that renders the paternal
contribution nonfunctional.

Diagnostic testing: Individuals who have a number of the clinical
findings should be referred for genetic testing. DNA methylation
analysis confirms diagnosis of PWS. FISH and DNA techniques can identify
the specific genetic cause and associated recurrence risk. (See ASHG/ACMG
Report, Am J Hum Genet 58: 1085, 1996.) Patients who had negative
or inconclusive tests with older techniques should be retested.

Recurrence risk: Significant only for rare cases with imprinting
mutations, translocations, or inversions. All families should receive genetic counseling.





Weight and Behavior

Appetite Disorder

Hypothalamic dysfunction is thought to be the cause of the disordered appetite/satiety function characteristic of PWS. Compulsive eating and obsession with food usually begin before age 6. The urge to eat is physiological and overwhelming; it is difficult to control and requires constant vigilance.

Weight Management Challenge

Compounding the pressure of excessive appetite is a decreased calorie utilization in those with PWS (typically 1,000-1,200 kcal per day for adults), due to low muscle mass and inactivity. A balanced, low-calorie diet with vitamin and calcium supplementation is recommended. Regular weigh-ins and periodic diet review are needed. The best meal and snack plan is one the family or caregiver is able to apply routinely and consistently. Weight control depends on external food restriction and may require locking the kitchen and food storage areas. Daily exercise (at least 30 minutes) also is essential for weight control and health.

To date, no medication or surgical intervention has been found that would eliminate the need for strict dieting and supervision around food. GH treatment, because it increases muscle mass and function, may allow a higher daily calorie level.

Behavior Issues

Infants and young children with PWS are typically happy and loving, and exhibit few behavior problems. Most older children and adults with PWS, however, do have difficulties with behavior regulation, manifested as difficulties with transitions and unanticipated changes. Onset of behavioral symptoms usually coincides with onset of hyperphagia (although not all problem behaviors are food-related), and difficulties peak in adolescence or early adulthood. Daily routines and structure, firm rules and limits, "time out," and positive rewards work best for behavior management. Psychotropic medications—particularly serotonin reuptake inhibitors, such as fluoxetine and sertroline—are beneficial in treating obsessive-compulsive (OCD) symptoms, perseveration, and mood swings. Depression in adults is not uncommon. Psychotic episodes occur rarely.




Developmental Concerns

Motor Skills

Motor milestones are typically delayed one to two years; although hypotonia improves, deficits in strength, coordination, balance, and motor planning may continue. Physical and occupational therapies help promote skill development and proper function. Foot orthoses may be needed. Growth hormone treatment, by increasing muscle mass, may improve motor skills. Exercise and sports activities should be encouraged and adaptations made, as needed. Proficiency with jigsaw puzzles is frequently reported, reflecting strong visual-perceptual skills.

Oral Motor and Speech

Hypotonia may create feeding problems, poor oral-motor skills, and delayed speech. The need for speech therapy should be assessed in infancy. Sign language and picture communication boards can be used to reduce frustration and aid communication. Products to increase saliva may help articulation problems. Social skills training can improve pragmatic language use. Even with delays, verbal ability often becomes an area of strength for children with PWS. In rare cases, speech is severely affected.

Cognition

IQs range from 40 to 105, with an average of 70. Those with normal IQs typically have learning disabilities. Problem areas may include attention, short-term auditory memory, and abstract thinking. Common strengths include long-term memory, reading ability, and receptive language. Early infant stimulation should be encouraged and the need for special education services and supports assessed in preschool and beyond.

Growth

Failure to thrive in infancy may necessitate tube feeding. Infants should be closely monitored for adequate calorie intake and appropriate weight gain. Growth hormone is typically deficient, causing short stature, lack of pubertal growth spurt, and a high body fat ratio, even in those with normal weight. The need for GH therapy should be assessed in both children and adults.

Sexual Development

Sex hormone levels (testosterone and estrogen) are typically low. Cryptorchidism in male infants may require surgery. Both sexes have good response to treatment for hormone deficiencies, although side effects have been reported. Early pubic hair is common, but puberty is usually late in onset and incomplete.

Although it is often assumed that individuals with PWS are infertile, several pregnancies have been confirmed. Sexually active individuals should be counseled regarding risk of pregnancy and of genetic error in offspring (50%, except for those with PWS due to UPD). Basic sex education is important in all cases to promote good health and protect against abuse






Quality of Life Issues

General health is usually good in individuals with PWS. If weight is controlled, life expectancy may be normal, and the individual’s health and functioning can be maximized.

The constant need for food restriction and behavior management may be stressful for family members. PWSA (USA) can provide information and support. Family counseling may also be needed.

Adolescents and adults with PWS can function well in group and supported living programs, if the necessary diet control and structured environment are provided. Employment in sheltered workshops and other highly structured and supervised settings is successful for many. Residential and vocational providers must be fully informed regarding management of PWS.

Resources for Health Care Providers

"Health Care Guidelines for Individuals with PWS" and the book Management of Prader-Willi Syndrome are available from PWSA (USA), as are other publications for professionals and parents.

For a more comprehensive medical description of PWS, see the University of Washington School of Medicine, Seattle, GeneClinics: Medical Genetics Knowledge Base






QUESTIONS AND ANSWERS ON PRADER-WILLI SYNDROME


Table of Contents
What is Prader-Willi Syndrome (PWS)?
Is PWS inherited?
How common is PWS?
How is PWS diagnosed?
What is known about the genetic abnormality?
What causes the appetite and obesity problems in PWS?
Does the overeating associated with PWS begin at birth?
Do diet medications work for the appetite problem in PWS?
What kinds of behavior problems do people with PWS have?
Does early diagnosis help?
What does the future hold for people with PWS?
How can I get more information about PWS?


Q: What is Prader-Willi syndrome (PWS)?

A: PWS is a complex genetic disorder that typically causes low muscle tone, short stature, incomplete sexual development, cognitive disabilities, problem behaviors, and a chronic feeling of hunger that can lead to excessive eating and life-threatening obesity.

Q: Is PWS inherited?

A: Most cases of PWS are attributed to a spontaneous genetic error that occurs at or near the time of conception for unknown reasons. In a very small percentage of cases (2 percent or less), a genetic mutation that does not affect the parent is passed on to the child, and in these families more than one child may be affected. A PWS-like disorder can also be acquired after birth if the hypothalamus portion of the brain is damaged through injury or surgery.



Q: How common is PWS?

A: It is estimated that one in 12,000 to 15,000 people has PWS. Although considered a "rare" disorder, Prader-Willi syndrome is one of the most common conditions seen in genetics clinics and is the most common genetic cause of obesity that has been identified. PWS is found in people of both sexes and all races.



Q: How is PWS diagnosed?

A: Suspicion of the diagnosis is first assessed clinically, then confirmed by specialized genetic testing on a blood sample. Formal diagnostic criteria for the clinical recognition of PWS have been published (Holm et al, 1993), as have laboratory testing guidelines for PWS (ASHG, 1996).



Q: What is known about the genetic abnormality?

A: Basically, the occurrence of PWS is due to lack of several genes on one of an individual’s two chromosome 15s— the one normally contributed by the father. In the majority of cases, there is a deletion—the critical genes are somehow lost from the chromosome. In most of the remaining cases, the entire chromosome from the father is missing and there are instead two chromosome 15s from the mother (uniparental disomy). The critical paternal genes lacking in people with PWS have a role in the regulation of appetite. This is an area of active research in a number of laboratories around the world, since understanding this defect may be very helpful not only to those with PWS but to understanding obesity in otherwise normal people.



Q: What causes the appetite and obesity problems in PWS?

A: People with PWS have a flaw in the hypothalamus part of their brain, which normally registers feelings of hunger and satiety. While the problem is not yet fully understood, it is apparent that people with this flaw never feel full; they have a continuous urge to eat that they cannot learn to control. To compound this problem, people with PWS need less food than their peers without the syndrome because their bodies have less muscle and tend to burn fewer calories.



Q: Does the overeating associated with PWS begin at birth?

A: No. In fact, newborns with PWS often cannot get enough nourishment because low muscle tone impairs their sucking ability. Many require special feeding techniques or tube feeding for several months after birth, until muscle control improves. Sometime in the following years, usually before school age, children with PWS develop an intense interest in food and can quickly gain excess weight if calories are not restricted.



Q: Do diet medications work for the appetite problem in PWS?

A: Unfortunately, no appetite suppressant has worked consistently for people with PWS. Most require an extremely low-calorie diet all their lives and must have their environment designed so that they have very limited access to food. For example, many families have to lock the kitchen or the cabinets and refrigerator. As adults, most affected individuals can control their weight best in a group home designed specifically for people with PWS, where food access can be restricted without interfering with the rights of those who don't need such restriction.



Q: What kinds of behavior problems do people with PWS have?

A: In addition to their involuntary focus on food, people with PWS tend to have obsessive/compulsive behaviors that are not related to food, such as repetitive thoughts and verbalizations, collecting and hoarding of possessions, picking at skin irritations, and a strong need for routine and predictability. Frustration or changes in plans can easily set off a loss of emotional control in someone with PWS, ranging from tears to temper tantrums to physical aggression. While psychotropic medications can help some individuals, the essential strategies for minimizing difficult behaviors in PWS are careful structuring of the person's environment and consistent use of positive behavior management and supports.



Q: Does early diagnosis help?

A: While there is no medical prevention or cure, early diagnosis of Prader-Willi syndrome gives parents time to learn about and prepare for the challenges that lie ahead and to establish family routines that will support their child's diet and behavior needs from the start. Knowing the cause of their child’s developmental delays can facilitate a family's access to important early intervention services and may help program staff identify areas of specific need or risk. Additionally, a diagnosis of PWS opens the doors to a network of information and support from professionals and other families who are dealing with the syndrome.



Q: What does the future hold for people with PWS?

A: With help, people with PWS can expect to accomplish many of the things their "normal" peers do—complete school, achieve in their outside areas of interest, be successfully employed, even move away from their family home. They do, however, need a significant amount of support from their families and from school, work, and residential service providers to both achieve these goals and avoid obesity and the serious health consequences that accompany it. Even those with IQs in the normal range need lifelong diet supervision and protection from food availability.

Although in the past many people with PWS died in adolescence or young adulthood, prevention of obesity can enable those with the syndrome to live a normal lifespan. New medications, including psychotropic drugs and synthetic growth hormone, are already improving the quality of life for some people with PWS. Ongoing research offers the hope of new discoveries that will enable people affected by this unusual condition to live more independent lives.



Q: How can I get more information about PWS?

A: Contact the Prader-Willi Syndrome Association (USA) at 1-800-926-4797 or email pwsausa@pwsausa.org

A strong national organization of families and professionals, PWSA (USA) offers a toll-free helpline, a bimonthly member newsletter and numerous publications about PWS, a World Wide Web page (www.pwsausa.org), an annual family conference and scientific meeting, and chapters throughout the country to provide local family support and advocacy.
http://www.pwsausa.org/












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