Prader Willi Syndrome

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Prader Willi Syndrome

Postby patoco » Sat Feb 03, 2007 7:37 pm

Prader Willi Syndrome

*** An uncommon disorder that can effect the lymphatics and there are a number of reported cases of Prader Willi patients with severe leg lymphedema.**

History

Prader-Willi Syndrome first appeared in the medical literature when endocrinologists Prader, Labhart, and Willi published a report describing an unusual pattern of abnormalities. These abnormalities included diminished fetal activity, profound poor muscle tone, feeding problems in infancy, underdeveloped not allowed organs, short stature and retarded bone age, small hands and feet, delayed developmental milestones, characteristic faces, cognitive impairment, onset of gross obesity in early childhood due to insatiable hunger, and a tendency to develop diabetes in adolescence and adulthood when weight was not controlled. Further studies in the late 1960’s followed up on these cases, and added more. Orthopedic, dental and developmental characteristics that could assist in differential diagnosis of PWS were identified, and two clearly identifiable phases of the disorder were described (Phase I, the prenatal, neonatal, and early infancy period, in which the child shows diminished fetal activity, poor muscle tone, and failure to thrive after birth, and Phase II, in which the uncontrollable hunger drive emerges between ages 2 and 3).. Behavioral, personality and medical problems associated with PWS were described in literature in the 1970’s and 80’s. A study published by Greenswag in 1987of 232 individuals with PWS, age 16 and over, indicated that with appropriate nutritional control, the life expectancy of this population could be extended. The study also showed that emotional liability increases with age and is independent of the presence of adult obesity, that psychosocial adaptation to adulthood requires special management, and that the presence of PWS has a profound impact on family life.

The Genetics of Prader-Willi Syndrome:

An Explanation for the Rest of Us

Chromosome 15

Originally published in PWSA’s The Gathered View by Linda Keder, former editor, March-May 2000. Revised and updated in July 2004 with the assistance of Merlin G. Butler, M.D. Ph.D., Chair, PWSA-USA Scientific Advisory Board.)

When the medical world first learned about Prader-Willi syndrome in 1956, doctors had no idea what caused people to have this collection of features and problems that we now know as PWS. In 1981, Dr. David Ledbetter and his colleagues reported a first breakthrough discovery: Many people with PWS that they studied had the same segment of genes missing from one of their chromosomes. They had discovered the deletion on chromosome 15 that accounts for about 70 percent of the cases of PWS. Since then, researchers have made a series of other important discoveries about the genes involved in Prader-Willi syndrome. Thanks to their perseverance, we now know much more about the several genetic forms of this complex disorder, and we have genetic tests that can confirm nearly every case.

Originally published in PWSA’s The Gathered View by Linda Keder, former editor, March-May 2000. Revised and updated in July 2004 with the assistance of Merlin G. Butler, M.D. Ph.D., Chair, PWSA-USA Scientific Advisory Board.)

When the medical world first learned about Prader-Willi syndrome in 1956, doctors had no idea what caused people to have this collection of features and problems that we now know as PWS. In 1981, Dr. David Ledbetter and his colleagues reported a first breakthrough discovery: Many people with PWS that they studied had the same segment of genes missing from one of their chromosomes. They had discovered the deletion on chromosome 15 that accounts for about 70 percent of the cases of PWS. Since then, researchers have made a series of other important discoveries about the genes involved in Prader-Willi syndrome. Thanks to their perseverance, we now know much more about the several genetic forms of this complex disorder, and we have genetic tests that can confirm nearly every case.

Chromosomes and Genes: The Basics

To understand the genetics of PWS, it helps to have a basic understanding of chromosomes and genes. Chromosomes are tiny structures that are present in nearly every cell of our bodies. They are the packages of genes we inherit from our parents. Genes contain all the detailed instructions our bodies need to grow, develop, and function properly—our DNA. Specific genes direct our cells to produce proteins, enzymes, and other essential substances. Each of our many genes is located on a specific chromosome. Most of our body’s cells contain 46 chromosomes—23 inherited from our mother and 23 from our father. (Egg and sperm cells normally contain just 23 chromosomes, because those are the cells that join in conception and provide the baby the right number of chromosomes.) Twenty-two of the chromosome pairs are labeled with a number based on their size (chromosome 1 is the largest pair, and chromosome 22 is nearly the smallest), and the two chromosomes in each numbered pair contain the same genes (one set from mother and one from father). The changes that cause Prader-Willi syndrome occur on the pair known as chromosome 15. The 23rd chromosome pair is designated as the not allowed chromosome pair This pair determines the baby’s not allowed: XX for a girl, XY for a boy.

Changes or errors in genes and chromosomes are common in the formation of egg and sperm cells. Some of these genetic changes will have no effect when a baby is conceived; some will cause a miscarriage; and some, like those in Prader-Willi syndrome, will cause significant differences in how the baby develops and functions. While many genetic disorders are caused by a change in a single gene and can be passed down from parent to child, PWS is more complicated.

Some of the important genetic characteristics of PWS identified through research are:

More than one gene is involved in PWS, and these genes are near each other in a small area of what is called the “long arm” of chromosome 15—in a region labeled 15q11-q13. Scientists still don’t know exactly how many genes and which specific ones are involved.

The critical genes must come from the baby’s father in order to function properly; the mother’s genes in this area are “turned off” through a rare phenomenon called “genomic imprinting.”

There are at least three different chromosome errors that can keep these key genes from working normally, and all result in the child having Prader-Willi syndrome.

The two most common errors that cause PWS can occur in any conception—in other words, PWS is not usually an inherited condition; it just happens. In very rare cases, however, parents may have a 50-percent chance of having another child with PWS.

The Role of Genomic Imprinting

During the early 1980s, scientists puzzled over why some people who seemed to have PWS did not have the chromosome 15 deletion, and why some people with the chromosome 15 deletion seemed to have a different condition from PWS. Dr. Merlin Butler and colleagues began unraveling the puzzle when they reported in 1983 that the chromosome 15 deletion in PWS was on the father’s chromosome.

The next breakthrough came in 1989, when Dr. Robert Nicholls and fellow researchers announced their discovery that PWS is an example of genetic or genomic imprinting, a process well known in plant genetics but not previously identified in humans. This means that some of our genes have to come from a particular parent to work normally. These rare genes are said to be “imprinted,” or have the ability to be turned off or on, depending on which parent contributed the gene. In what scientists call the “Prader-Willi region” of chromosome 15 (the area where the deletion occurs), there are genes that must come from the baby’s father that are active, or “expressed,” in order to work. These genes are not active or expressed on the chromosome 15 inherited from the mother because the mother’s imprint turns them off. In Prader-Willi syndrome, these critical genes are either missing (deleted) from the father’s chromosome 15, functioning improperly because of an imprinting defect, or the entire chromosome 15 from the father is missing and both chromosome 15s come from the mother. (See The Three Genetic Forms of PWS for more detail on each of these errors.)

When a deletion of chromosome 15q11-q13 region is found on the mother’s chromosome 15, the result is an entirely different syndrome called Angelman syndrome (AS). That is because there is also one gene in the Prader-Willi region that is imprinted, or turned off, on the father’s chromosome 15; people who lack this gene from their mother have AS rather than PWS. This discovery explained the mysterious cases of people who had a chromosome 15 deletion but did not have the characteristics of PWS—their deletion was on the chromosome 15 that came from the mother. Because the genetic errors happen in the same section of chromosome 15, PWS and AS are sometimes called “sister” syndromes even though the disorders have few features in common.

The Three Genetic Forms of PWS

Although every case of Prader-Willi syndrome is due to the baby failing to receive active genes from a specific section of the father’s chromosome 15, there are three different ways that this can happen:

Paternal deletion — about 70% of all cases of PWS
In the most common form of PWS, part of the chromosome 15 inherited from the child’s father—the part containing the PWS critical genes—is missing. In some cases, the section that has disappeared (called a “deletion” or sometimes a “microdeletion”) is large enough to be identified with high resolution chromosome studies done with a microscope; in other cases, it is too small but it can be detected with another chromosome test called FISH (see Tests Used To Diagnose Prader-Willi Syndrome). Typical or common deletions are now classified as Class/Type 1 or Class/Type 2, based on the size of the deletion. Usually a deletion happens for no known reason, and it is not likely to happen again in another pregnancy (less than 1% chance of recurrence). There is nothing the father did (or did not do) to cause it and no way to prevent it.

Note: In rare cases of atypical deletions, imprinting defects (see below), or when a chromosome change such as a “translocation” caused the PWS genes to not function normally , the family could have another child with the same condition. (In a translocation, part of one chromosome is broken off and attached to a different chromosome.) It is especially important for these families to have further testing and genetic counseling.

Maternal uniparental disomy (UPD) — about 25% of cases
In this less common form of PWS, the baby inherits both copies of chromosome 15 from one parent—the mother. (Maternal means mother; uniparental means one parent; and disomy means two chromosome bodies). In these cases, the developing baby usually starts out with three copies of chromosome 15 (a condition called trisomy 15) because there was an extra chromosome 15 in the mother’s egg. Later, one of the three is lost—the chromosome 15 that came from the father’s sperm. The result has the same effect as a deletion. The child does not have active genes on chromosome 15 that must come from the father in order to be expressed (to function). Even though there are two complete copies of the mother’s chromosome 15, the key genes in the PWS region are imprinted, or turned off, in the mother’s copies. Because the error in this form of PWS starts with an extra chromosome in the mother’s egg, and older eggs are more likely to have errors of this type, older mothers are more likely than younger mothers to have a baby with this form of PWS. Even so, it is not likely to happen (and hasn’t yet) to a second child in the same family. When a baby inherits two identical chromosome 15s from the mother (isodisomy, or two copies of the same one rather than one of each of the mother’s own chromosomes), there is a chance of having additional genetic problems or conditions.

Imprinting defect — less than 5% of cases
In very rare cases, the PWS genes on the father’s chromosome are present but do not work because the imprinting process is faulty. The activity of the genes is controlled by a tiny imprinting center on chromosome 15 in the same area as the PWS critical genes. Normally, when genes are passed down to a child, the prior imprints are cleared away, and new imprints are made according to the not allowed of the parent. When there is a microdeletion or other defect in the imprinting control center, gene function on the father’s chromosome 15 may not be set to work normally. An imprinting defect can appear suddenly, or it can be present in the father’s chromosome that he received from his mother. If he received the defect from his mother, the father would not have PWS himself (because it’s on his maternal chromosome 15), but he could pass it on to his child (it would be the child’s paternal chromosome 15). There is a 50-50 chance that any child he has will receive the chromosome with the defect instead of the one that’s working correctly. Likewise, the father’s siblings could carry and pass on the mutation to their children. Further testing and genetic counseling are especially important for families who have a child with an imprinting defect.

Which genetic tests should be done and in what order?

The approach to testing for PWS in any given case will depend on a number of considerations—what tests have already been done, what expertise and laboratories are available, whether both parents are available for blood samples, and so forth. Chromosome studies are typically done in any case, but the order of the other tests—and their results—will determine how many need to be done. In 1996, two national genetics groups worked together to develop guidelines on testing for Prader-Willi and Angelman syndromes. Their recommendations have been published and are available on the Internet at www.faseb.org/genetics/acmg/pol-22htm. In most cases, they recommend continued testing until the genetic cause of PWS is known.

Some testing scenarios:

If an experienced diagnostician suspects Prader-Willi syndrome in an older child or adult who meets the Diagnostic Criteria for PWS, the FISH test might be the first test of choice because it is widely available and will detect the majority of cases of PWS. If the FISH test is positive (a deletion is found), the diagnosis of PWS is confirmed and no further testing is needed. If the FISH test comes back negative (detecting no deletion), the next step would be the DNA methylation test. A relatively new test, DNA methylation can diagnose more than 99 percent of people with PWS, but it does not tell whether the cause of PWS is deletion, uniparental disomy (UPD), or an imprinting defect. If, after the negative FISH test, the methylation test confirms that the person has PWS, more testing is needed to find out whether the cause is UPD or an imprinting defect. If the UPD test is negative in this case, the cause must be an imprinting defect. At this time, imprinting defects are diagnosed by process of elimination—positive methylation test, but negative FISH and UPD tests--However, to confirm a suspected defect may require testing in genetics laboratories specializing in PWS research.

In cases where the suspicion of PWS is not as strong, or where the diagnosing physician is not as familiar with PWS, the DNA methylation test might be the best place to start. The test is becoming more widely available and can confirm or rule out PWS at the first step. If the methylation test is positive, then additional testing can be done at the same lab to determine the specific form of PWS. Even experienced diagnosticians have sometimes misdiagnosed infants as having PWS when in fact they had Angelman syndrome. (Both syndromes can cause hypotonia in the newborn baby, and both will show a chromosome 15 deletion on the FISH test.) Starting with the methylation test avoids this problem.

In cases of an imprinting defect or other rare test findings, families may need further testing through a research laboratory, both to get an accurate diagnosis and to learn about their risks of having another child with PWS.

What about prenatal testing?

Prenatal testing for PWS is now available. An expectant family might wonder whether to have testing done if they have had a child with PWS previously. Although the risk of having a second baby with PWS is very low in most cases, prenatal testing can provide important reassurance to the family that the new baby will not be affected. Counseling by a genetics professional can help a family understand their specific risks and whether testing of the fetus is important in their situation.

Prenatal testing for PWS might also be done in cases where a genetic study of the fetus (through chorionic villus sampling—CVS—or amniocentesis) shows abnormalities that raise suspicion of PWS. In one case, for example, a routine chromosome test done through CVS early in a woman’s pregnancy found that some of the baby’s cells had three chromosome 15s (called mosaic trisomy 15). This led the doctor to order a molecular test for maternal uniparental disomy (UPD) in the remaining cells. The test results showed that the baby would have PWS due to UPD.

Who should do the testing?
Families who are seeking a diagnosis or who have concerns about their risks should work with a genetics specialist who is knowledgeable about PWS and the latest in testing. The geneticist will arrange to have blood samples sent to an appropriate laboratory for testing.

There is available on the Internet a free, searchable database of genetics laboratories and the tests they offer for specific conditions such as PWS. GeneTests Laboratory Directory (formerly called Helix) is sponsored by the Children’s Health Care System, Seattle, Washington, and can be found on the Internet at www.genetests.org . Note, however, that not every laboratory that performs these tests is included in the database.

Those who need help in locating a geneticist or a testing center may contact the PWSA (USA) national office at 1-800-926-4797 or through its Website, www.pwsausa.org .

References

ASHG/ACMG Report. Diagnostic Testing for Prader-Willi and Angelman Syndromes: Report of the ASHG/ACMG Test and Technology Transfer Committee. American Journal of Human Genetics 58:1085-1088.
www.faseb.org/genetics/acmg/pol-22htm
Cassidy, S.B. and Schwartz, S. (1998) Prader-Willi and Angelman Syndromes: Disorders of Genomic Imprinting. Medicine 77: 140-151.
Butler, M.G. and Thompson, T. (2000) Prader-Willi Syndrome: Clinical and Genetic Findings. The Endocrinologist 10 (4) Suppl 1:3S-16S.
Cassidy, S.B. (1998) Prader-Willi Syndrome. GeneClinics. http://www.geneclinics.org/profiles/pws/

The author wishes to thank Drs. Suzanne Cassidy, Dan Driscoll, and David Ledbetter for editing the original article, and Dr. Merlin Butler for assisting with this latest revision, so that families and other non-geneticists might better understand this complex and evolving subject.

What is Prader-Willi Syndrome?

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.

Major Clinical Findings

The following common characteristics of individuals with PWS raise suspicion of the diagnosis. Published diagnostic criteria include supportive findings and a scoring system (Holm et al, Pediatrics 91, 2, 1993).

Neonatal and infantile central hypotonia, improving with age
Feeding problems and poor weight gain in infancy
Excessive or rapid weight gain between 1 and 6 years of age; central obesity in the absence of intervention
Distinctive facial features—dolichocephaly in infants, narrow face/bifrontal diameter, almond-shaped eyes, small-appearing mouth with thin upper lip and down-turned corners of mouth
Hypogonadism—genital hypoplasia, including undescended testes
and small penis in males; delayed or incomplete gonadal maturation
and delayed pubertal signs after age 16, including scant or no
menses in women
Global developmental delay before age 6; mild to moderate mental
retardation or learning problems in older children
Hyperphagia/food foraging/obsession with food

Minor Clinical Findings:

Decreased fetal movement, infantile lethargy, weak cry
Characteristic behavior problems—temper tantrums, violent outbursts, obsessive/compulsive behavior; tendency to be argumentative, oppositional, rigid, manipulative, possessive, and stubborn; perseverating, stealing, lying
Sleep disturbance or sleep apnea
Short stature for genetic background by age 15
Hypopigmentation—fair skin and hair compared with family
Small hands and/or feet for height age
Narrow hands with straight ulnar border
Eye abnormalities (esotropia, myopia)
Thick, viscous saliva with crusting at corners of the mouth
Speech articulation defects
Skin picking

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

not allowed 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 not allowed education is important in all cases to promote good health and protect against abuse

Other Common Concerns

Strabismus—esotropia is common; requires early intervention, possibly surgery
Scoliosis—can occur unusually early; may be difficult to detect without X-ray; curve may progress with GH treatment. Kyphosis is also common in teens and adults
Osteoporosis—can occur much earlier than usual and may cause fractures; ensure adequate calcium, vitamin D, and weight-bearing exercise; bone density test recommended
Diabetes mellitus, type II—secondary to obesity; responds well to weight loss; screen obese patients regularly
Other obesity-related problems—include hypoventilation, hypertension, right-sided heart failure, stasis ulcers, cellulitis, and skin problems in fat folds
Sleep disturbances—hypoventilation and desaturation during sleep are common, as is daytime sleepiness; sleep apnea may develop with or without obesity; sleep studies may be needed
Nighttime enuresis—common at all ages; desmopressin acetate should be used in lower than normal doses
Skin picking—a common, sometimes severe habit; usually in response to an existing lesion or itch on face, arms, legs, or rectum. Best managed by ignoring behavior, treating and bandaging sores, and providing substitute activities for the hands.
Dental problems—may include soft tooth enamel, thick sticky saliva, poor oral hygiene, teeth grinding, and infrequently rumination. Special toothbrushes can improve hygiene. Products to increase saliva flow are helpful.

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

"Health Care Guidelines for Individuals with PWS"

http://www.pwsausa.org/postion/HCGuide/HCG.htm

and the book

Management of Prader-Willi Syndrome

http://www.pwsausa.org/merchand/mgmtPWS.htm

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

http://www.geneclinics.org/profiles/pws/

This information is from the Prader Willi Syndrome Association

http://www.pwsausa.org/index.html

Please visit and support their association and endeavors

.............

Pat O'Connor
Lymphedema People
http://www.lymphedemapeople.com
patoco
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Re: Prader Willi Syndrome

Postby patoco » Fri Mar 12, 2010 9:30 am

Body composition, endocrine and metabolic profiles in adults with Prader-Willi syndrome.

Growth Horm IGF Res. 2010 Mar 2

Sode-Carlsen R, Farholt S, Rabben KF, Bollerslev J, Schreiner T, Jurik AG, Christiansen JS, Höybye C.

Centre for Rare Diseases, Department of Paediatrics, Aarhus University Hospital Skejby, DK-8200 Aarhus N, Denmark.

Keywords: PWS; Adults; Body composition; Metabolism

OBJECTIVE: Prader-Willi syndrome (PWS) is a complex genetic disease associated with hypothalamic-pituitary dysfunction and severe obesity. The aim of the present study was to describe the relationships between body composition, metabolic and hormonal profiles in PWS adults.

METHOD: Forty six adults with genetically verified PWS, 25 women and 21 men, median age 28years were studied. Body composition was evaluated by standard anthropometric procedures and with computed tomography (CT) of the abdomen and at the mid-femur level. CT of abdomen was compared to 22 healthy, unmatched adults. Circulating lipids were measured and oral glucose tolerance test (OGTT) and hormonal screening including GH secretory capacity (GHRH/arginine test) was carried out.

RESULTS: Median body mass index (BMI) was 27.2kg/m(2), with women being more obese than men. Sixteen patients had dyslipidaemia, 10 impaired glucose tolerance and seven had diabetes. Fifty percent were hypogonadal and six fulfilled BMI related criteria for growth hormone deficiency (GHD). Visceral to subcutaneous abdominal fat ratio was reduced in PWS. Visceral abdominal fat fraction correlated with both subcutaneous fat, BMI and peak GH-response. Thigh muscle volume was about half of the thigh fat volume. Beneficial effects of sex-steroid replacement on body composition were not observed.

CONCLUSIONS: Body fat was primarily located subcutaneously and metabolic consequences of obesity limited. The abnormal body composition similar to that in non-PWS GHD adults increases the interest of GH treatment in the prevention of obesity in adults with PWS.

http://www.sciencedirect.com/science?_o ... d28cf6dd78

Dementia in a woman with Prader-Willi syndrome.

Eur J Med Genet. 2010 Feb 25

Sinnema M, Schrander-Stumpel CT, Verheij HE, Meeuwsen M, Maaskant MA, Curfs LM.

Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands; Governor Kremers Centre, Maastricht University, Maastricht, The Netherlands.

We report on a 58-year-old woman with Prader-Willi syndrome (PWS) and dementia. This case report illustrates a new research area in older adults with PWS. Dementia might be associated with PWS. In the case of dementia, more clinical studies are warranted to observe whether premature Alzheimer changes or indications of other dememtia forms indeed occur more prevalent in people with PWS.

http://www.ncbi.nlm.nih.gov/pubmed/20219703

Cardiovascular and Metabolic Risk Profile and Acylation-Stimulating Protein Levels in Children with Prader-Willi Syndrome and Effects of Growth Hormone Treatment.

J Clin Endocrinol Metab. 2010 Feb 19.

Roderick F. A. de Lind van Wijngaarden*, Katherine Cianflone, Y. Gao, Ralph W. J. Leunissen, and Anita C. S. Hokken-Koelega
Dutch Growth Research Foundation (R.F.A.d.L.v.W., A.C.S.H.-K.), 3016 AH Rotterdam, The Netherlands; Department of Pediatrics, Subdivision of Endocrinology (R.F.A.d.L.v.W., R.W.J.L., A.C.S.H.-K.), Erasmus University Medical Center Rotterdam/Sophia Children's Hospital, 3015 GJ Rotterdam, The Netherlands; and Centre de Recherche, Hôpital Laval (K.C., Y.G.), Université Laval, Québec, Canada G1V 0A6

* To whom correspondence should be addressed. E-mail: r.delindvanwijngaarden@erasmusmc.nl.

Dutch Growth Research Foundation (R.F.A.d.L.v.W., A.C.S.H.-K.), 3016 AH Rotterdam, The Netherlands; Department of Pediatrics, Subdivision of Endocrinology (R.F.A.d.L.v.W., R.W.J.L., A.C.S.H.-K.), Erasmus University Medical Center Rotterdam/Sophia Children's Hospital, 3015 GJ Rotterdam, The Netherlands; and Centre de Recherche, Hôpital Laval (K.C., Y.G.), Université Laval, Québec, Canada G1V 0A6.

Context: Reports on the cardiovascular and metabolic risk profile in children with Prader-Willi syndrome (PWS) and the effects of GH treatment are scarce. Acylation-stimulating protein (ASP) stimulates glucose uptake and triglyceride storage in adipose tissue.

Objectives: The aim was to study the metabolic and cardiovascular risk profile and ASP levels and to investigate the effects of GH treatment. Design: We conducted a randomized controlled GH trial. Infants and prepubertal children were assigned to receive GH (1 mg/m(2) . d) or to serve as controls for 12 and 24 months, respectively.

Patients: Eighty-five children with PWS (mean +/- SD age of 4.9 +/- 3.0 yr) participated in the study. Main Outcome Measures: We measured fat percentage (fat%) with dual-energy x-ray absorptiometry, blood pressure, fasting insulin and glucose levels, serum lipids, and ASP levels.

Results: Mean +/- SD fat% was 28.4 +/- 6.2 in infants and 36.9 +/- 8.5 in prepubertal children. Fat% SD score (SDS) was above 2 SDS in 95% of prepubertal children.

In addition, 63% of infants and 73% of prepubertal children demonstrated at least one cardiovascular risk factor, defined as hypertension or dyslipidemia. The metabolic syndrome was demonstrated in 5% of all children. Mean +/- SD baseline ASP was 107 +/- 45 nmol/liter (normal < 58 nmol/liter) and correlated with fat mass and TG levels. GH improved fat%SDS and the HDLc/LDLc ratio (P < 0.0001 and P = 0.04). GH had no effect on mean ASP levels in this population.

Conclusions: Many children with PWS had dyslipidemia and high ASP levels. GH improved fat% and high-density lipoprotein cholesterol/low-density lipoprotein cholesterol, but not ASP. High ASP levels may prevent complete normalization of fat%SDS during GH treatment but may contribute in keeping glucose and insulin levels within normal range.

http://jcem.endojournals.org/cgi/conten ... 009-0656v1

Cognitive profile in a large french cohort of adults with Prader-Willi syndrome: differences between genotypes.

J Intellect Disabil Res. 2010 Feb 2.

Copet P, Jauregi J, Laurier V, Ehlinger V, Arnaud C, Cobo AM, Molinas C, Tauber M, Thuilleaux D.

Hôpital Marin AP-HP, Unité Prader-Willi, Hendaye, France.

Abstract Background

Prader-Willi syndrome (PWS) is a rare genetic disorder characterised by developmental abnormalities leading to somatic and psychological symptoms. These include dysmorphic features, impaired growth and sexual maturation, hyperphagia, intellectual delay, learning disabilities and maladaptive behaviours. PWS is caused by a lack of expression of maternally imprinted genes situated in the 15q11-13 chromosome region. The origin is a 'de novo' deletion in the paternal chromosome in 70% of the cases and a maternal uniparental disomy in 25%. The two main genotypes show differences, notably regarding cognitive and behavioural features, but the mechanisms are not clear.

This study assessed cognitive impairment in a cohort of adults with genetically confirmed PWS, analysed their profiles of cognitive strengths and weaknesses, and compared the profiles in terms of genotype. Methods Ninety-nine male and female adults participated, all inpatients on a specialised unit for the multidisciplinary care of PWS. The Wechsler Adult Intelligence Scale (WAIS-III) was administered to all patients in identical conditions by the same psychologist. Eighty-five patients were able to cope with the test situation. Their scores were analysed with non-parametric statistical tools. The correlations with not allowed, age and body mass index were explored. Two genotype groups were compared: deletion (n = 57) and non-deletion (n = 27). Results The distribution of intelligence quotients in the total cohort was non-normal, with the following values (medians): Full Scale Intelligence Quotient (FSIQ): 52.0 (Q1:46.0; Q3:60.0), Verbal Intellectual Quotient (VIQ): 53.0 (Q1:48; Q3:62) and Performance Intellectual Quotient (PIQ): 52.5 (Q1:48; Q3:61). No correlation was found with not allowed, age or body mass index. Comparison between groups showed no significant difference in FSIQ or VIQ. PIQ scores were significantly better in the deletion group. The total cohort and the deletion group showed the VIQ = PIQ profile, whereas VIQ > PIQ was observed in the non-deletion group.

The subtest scores in the two groups showed significant differences, with the deletion group scoring better in three subtests: object assembly, picture arrangement and digit symbol coding. Some relative strengths and weaknesses concerned the total cohort, but others concerned only one genotype. Discussion We documented a global impairment in the intellectual abilities of a large sample of French PWS patients. The scores were slightly lower than those reported in most other studies. Our data confirmed the previously published differences in the cognitive profiles of the two main PWS genotypes and offer new evidence to support this hypothesis.

These results could guide future neuropsychological studies to determine the cognitive processing in PWS. This knowledge is essential to improve our understanding of gene-brain-behaviour relationships and to open new perspectives on therapeutic and educational programmes.

http://www.ncbi.nlm.nih.gov/pubmed/20136683

1p36 deletion syndrome associated with Prader-Willi-like phenotype.

Pediatr Int. 2010 Jan 26.

Tsuyusaki Y, Yoshihashi H, Furuya N, Adachi M, Osaka H, Yamamoto K, Kurosawa K.

Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.

Abstract Background: 1p36 deletion syndrome is one of the most common subtelomeric deletion syndromes, characterized by moderate to severe mental retardation, characteristic facial appearance, hypotonia, obesity, and seizures. The clinical features often overlap with those of Prader-Willi syndrome (PWS). To elucidate the phenotype-genotype correlation in 1p36 deletion syndrome, we analyzed two cases with a PWS-like phenotype by using molecular cytogenetic techniques.

Methods: Two patients presenting with the PWS-like phenotype but having negative results for PWS were investigated by FISH analysis. The size of the chromosome 1p36 deletions was characterized using probes of BAC clones based on the UCSC Genome Browser.

Results: PWS was excluded by FISH and methylation-specific PCR studies. Subsequent FISH using the probe D1Z2 showed deletion of the 1p36.3 region, confirming the diagnosis of 1p36 deletion syndrome. Further analysis characterized the 1p36 deletions as being located between 4.17 and 4.36 Mb in patient 1 and between 4.89 and 6.09 Mb in patient 2.

Conclusion: Patients with 1p36 deletion syndrome exhibit a PWS-like phenotype and are therefore probably underdiagnosed. The possible involvement of the terminal 4-Mb region of chromosome 1p36 in the PWS-like phenotype is hypothesized.

http://www.ncbi.nlm.nih.gov/pubmed/20113418

Behavioural and cognitive abnormalities in an imprinting centre deletion mouse model for Prader-Willi syndrome.

Eur J Neurosci. 2010 Jan;31

Relkovic D, Doe CM, Humby T, Johnstone KA, Resnick JL, Holland AJ, Hagan JJ, Wilkinson LS, Isles AR.

Laboratory of Cognitive and Behavioural Neuroscience, The Babraham Institute, Babraham Research Campus, Cambridge, UK.

Correspondence to Dr A. R. Isles, 2Behavioral Genetics Group, as above.
E-mail: ISLESAR1@cardiff.ac.uk

KEYWORDS
15q11–q13 • attention • locomotor activity • pre-pulse inhibition • startle response

The genes in the imprinted cluster on human chromosome 15q11-q13 are known to contribute to psychiatric conditions such as schizophrenia and autism. Major disruptions of this interval leading to a lack of paternal allele expression give rise to Prader-Willi syndrome (PWS), a neurodevelopmental disorder with core symptoms of a failure to thrive in infancy and, on emergence from infancy, learning disabilities and over-eating. Individuals with PWS also display a number of behavioural problems and an increased incidence of neuropsychiatric abnormalities, which recent work indicates involve aspects of frontal dysfunction.

To begin to examine the contribution of genes in this interval to relevant psychological and behavioural phenotypes, we exploited the imprinting centre (IC) deletion mouse model for PWS (PWS-IC(+/-)) and the five-choice serial reaction time task (5-CSRTT), which is primarily an assay of visuospatial attention and response control that is highly sensitive to frontal manipulations. Locomotor activity, open-field behaviour and sensorimotor gating were also assessed. PWS-IC(+/-) mice displayed reduced locomotor activity, increased acoustic startle responses and decreased prepulse inhibition of startle responses. In the 5-CSRTT, the PWS-IC(+/-) mice showed deficits in discriminative response accuracy, increased correct reaction times and increased omissions. Task manipulations confirmed that these differences were likely to be due to impaired attention.

Our data recapitulate several aspects of the PWS clinical condition, including findings consistent with frontal abnormalities, and may indicate novel contributions of the imprinted genes found in 15q11-q13 to behavioural and cognitive function generally.

http://www3.interscience.wiley.com/jour ... 1&SRETRY=0
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Re: Prader Willi Syndrome

Postby patoco » Fri Mar 12, 2010 9:47 am

Long-Term Growth Hormone Therapy Changes the Natural History of Body Composition and Motor Function in Children with Prader-Willi Syndrome

J Clin Endocrinol Metab. 2010 Mar

Aaron L. Carrel, Susan E. Myers, Barbara Y. Whitman, Jens Eickhoff and David B. Allen
Department of Pediatrics (A.L.C., D.B.A.), University of Wisconsin American Family Children’s Hospital, Madison, Wisconsin 53792; Department of Pediatrics (S.E.M., B.Y.W.), Cardinal Glennon Children’s Medical Center, St. Louis, Missouri 63104; and Colorado State University (J.E.), Ft. Collins, Colorado 80523

Address all correspondence and requests for reprints to: Aaron L. Carrel, M.D., Department of Pediatrics, University of Wisconsin, American Family Children’s Hospital, 600 Highland Avenue H4-436, Madison, Wisconsin 53792. E-mail: alcarrel@wisc.edu.

Background: Children with Prader-Willi syndrome (PWS) have decreased muscle mass, hypotonia, and impaired linear growth. Recombinant human GH (hGH) treatment reportedly improves body composition and physical function in children with PWS, but these studies lack long-term control data. To assess the impact of hGH therapy begun early in life on the natural history of PWS, we compared height, body composition, and strength in similar-age children with PWS naïve to hGH with those treated with hGH for 6 yr.

Objectives: Forty-eight children with PWS were studied: 21 subjects (aged 6-9 yr) treated with hGH for 6 yr (beginning at 4-32 months, mean 13 +/- 6 months) were compared with 27 children of similar age (5-9 yr) prior to treatment with hGH. Percent body fat, lean body mass, carbohydrate/lipid metabolism, and motor strength were compared using analysis of covariance.

Results: PWS children treated with hGH demonstrated lower body fat (mean, 36.1 +/- 2.1 vs. 44.6 +/- 1.8%, P < 0.01), greater height (131 +/- 2 vs. 114 +/- 2 cm; P < 0.001), greater motor strength [increased standing broad jump 22.9 +/- 2.1 vs. 14.6 +/- 1.9 in. (P < 0.001) and sit-ups 12.4 +/- 0.9 vs. 7.1 +/- 0.7 in 30 sec (P < 0.001)], increased high-density lipoprotein cholesterol (58.9 +/- 2.6 vs. 44.9 +/- 2.3 mg/dl, P < 0.001), decreased low-density lipoprotein (100 +/- 8 vs. 131 +/- 7 mg/dl, P < 0.01), and no difference in fasting glucose or insulin.

Conclusions: hGH treatment in children with PWS, begun prior to 2 yr of age, improves body composition, motor function, height, and lipid profiles. The magnitude of these effects suggests that long-term hGH therapy favorably alters the natural history of PWS to an extent that exceeds risks and justifies consideration for initiation during infancy.

http://jcem.endojournals.org/cgi/conten ... /95/3/1131

The transition between the phenotypes of Prader-Willi syndrome during infancy and early childhood.

Dev Med Child Neurol. 2009 Dec 23

JILL V BUTLER 1 ; JOYCE E WHITTINGTON 1 ; ANTHONY J HOLLAND 1 ; CATHERINE J McALLISTER 1 ; ANTHONY P GOLDSTONE 2
1 Department of Psychiatry, Cambridge Intellectual and Developmental Disabilities Research Group, University of Cambridge, UK . 2 Metabolic and Molecular Imaging Group, MRC Clinical Sciences Centre, Imperial College, London, UK .
Correspondence to Dr Joyce E Whittington, Department of Psychiatry, Cambridge Intellectual and Developmental Disabilities Research Group, University of Cambridge, 18b Trumpington Road, Cambridge CB2 8AH, UK. E-mail: jew1000@cam.ac.uk.

Aim Prader–Willi syndrome (PWS) is a genetic disorder historically characterized by two phenotypic stages. The early phenotype in infants is associated with hypotonia, poor suck, and failure to thrive. In later childhood, PWS is associated with intellectual disability, hyperphagia, as well as growth and not allowed hormone deficiency. Little is known about the transition between phenotypes. This study investigates the nature of the change in infancy and childhood PWS.

Method Forty-six children (22 females, 24 males; mean age 2y 9mo, SD 18.9mo; range 7mo–5y) with genetically confirmed PWS participated. Information was obtained on childhood height and weight, and eating behaviour from case notes and by parental interview.

Results Weight standard deviation scores (SDS) started to exceed height by the end of the first year. Height SDS appeared to fall from near normal at birth until stabilizing below normal around 2 years. Half of the children whose body mass index (BMI) was higher than normal at interview had food interests greater than that of their peers, and the age at which increased age-appropriate eating was first noted was later than the increase of BMI SDS.

Interpretation Obesity may develop before the increased interest in food, suggesting underlying physiological factors independent of appetite control may be important.

http://www3.interscience.wiley.com/jour ... 2/abstract
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Re: Prader Willi Syndrome

Postby patoco » Fri Mar 12, 2010 10:08 am

Perceptions of body image by persons with Prader-Willi syndrome and their parents.

Napolitano DA, Zarcone J, Nielsen S, Wang H, Caliendo JM.

Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA. deborah_napolitano@urmc.rochester.edu
Prader-Willi syndrome is a genetic disorder characterized by obesity. The Figure Rating Scale (Stunkard, Sorensen, & Schulsinger, 1983) was completed by 43 individuals with this syndrome to determine their level of dissatisfaction with their body. Their parents also completed this scale regarding their child to determine whether they were dissatisfied with their child's body status. Results showed that individuals with Prader-Willi syndrome were dissatisfied with their body. Parents also were dissatisfied with their child's body. Results of this study demonstrate that the responses of persons with Prader-Willi syndrome on the Figure Rating Scale show significant discrepancies between how they think they look and how they wished they looked.

http://www.ncbi.nlm.nih.gov/pubmed/20025358

A survey on Prader-Willi syndrome in the Italian population: prevalence of historical and clinical signs.

Pediatr Endocrinol Metab. 2009 Oct

Crinò A, Di Giorgio G, Livieri C, Grugni G, Beccaria L, Bosio L, Corrias A, Chiumello G, Trifirò G, Salvatoni A, Tonini G, Gargantini L, de Toni T, Valerio G, Ragusa L, Franzese A, Rinaldi MM, Spera S, Gattinara GC, Villani S, Iughettio L; Genetic Obesity Study Group; Italian Society of Pediatric Endocrinology and Diabetology.

Pediatric and Autoimmune Endocrine Disease Unit, Bambino Gesù Hospital, Research Institute, Via Torre di Palidoro, 00050 Palidoro, Roma, Italy. crino@opbg.net

Clinical criteria for the diagnosis of Prader-Willi Syndrome (PWS) were established by consensus in 1993 (Holm et al.). Specific molecular testing is now available and the purpose of diagnostic criteria has shifted to identify individuals to test, thus avoiding the expense of unnecessary analysis.

The aim of this study was to find clinical indicators to select patients with suspected PWS for laboratory testing. We analyzed the prevalence of clinical signs and symptoms in 147 genetically diagnosed Italian patients with PWS (67 males and 80 females), aged from 9 months to 34.6 years (13.6 +/- 8.3 years), using the consensus diagnostic criteria, and according to age, not allowed and type of genetic abnormality. The prevalence of several clinical features changed significantly with age, but very few with not allowed. According to genetic subtypes (deletion vs UPD), only hypopigmentation and acromicria were more frequent in patients with deletion. Some criteria considered as minor or supportive by Holm et al. have higher prevalence than some major criteria.

In conclusion, in order to identify patients with suspected PWS to submit to laboratory testing, we recommend a classification of clinical criteria according to age, giving more attention to those so-called minor or supportive criteria.

http://www.ncbi.nlm.nih.gov/pubmed/20020576

The C15orf2 gene in the Prader-Willi syndrome region is subject to genomic imprinting and positive selection.

Neurogenetics. 2009 Dec 19

Wawrzik M, Unmehopa UA, Swaab DF, van de Nes J, Buiting K, Horsthemke B.

Institut für Humangenetik, Universitätsklinikum Essen, Hufelandstrasse 55, 45122, Essen, Germany.

Keywords Prader–Willi syndrome - Genomic imprinting - Hypothalamus - C15orf2

C15orf2 (Chromosome 15 open reading frame 2) is an intronless gene, which is located in the Prader-Willi syndrome (PWS) chromosomal region on human chromosome 15. Mice do not have an orthologous gene. Here we show that expression of C15orf2 in the fetal human brain is imprinted. Using Western blot and immunohistological studies we have obtained evidence that C15orf2 protein is present in several regions of the brain. Previously published phylogenetic studies as well as population genetic studies based on complex haplotypes as described here suggest that C15orf2 is under positive Darwinian selection.

These results indicate that C15orf2 might have an important role in human biology and that a deficiency of C15orf2 might contribute to PWS.

http://www.springerlink.com/content/jh08tm752gk8l88v/

Children with Prader-Willi syndrome exhibit more evident meal-induced responses in plasma ghrelin and peptide YY levels than obese and lean children.

Eur J Endocrinol. 2010 Mar

Carla Bizzarri, Antonello E Rigamonti1, Antonella Luce2, Marco Cappa, Silvano G Cella1, Jenny Berini2, Alessandro Sartorio3, Eugenio E Müller1 and Alessandro Salvatoni2

Unit of Endocrinology and Diabetes, Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, Rome 00165, Italy
1 Dipartimento di Farmacologia Medica, Università di Milano, Via Vanvitelli 32, Milan 20129, Italy
2 Clinica Pediatrica, Università degli Studi dell'Insubria, Via Filippo del Ponte 19, Varese 21100, Italy
3 Istituto Auxologico Italiano, Experimental Laboratory for Auxo-endocrinological Research, Via Ariosto 13, Milan 20145, Italy

(Correspondence should be addressed to A E Rigamonti; Email: antonello.rigamonti@unimi.it)

BACKGROUND AND AIMS: Ghrelin is an orexigenic 28-amino acid peptide produced by the stomach. Circulating ghrelin levels rise shortly before and fall shortly after every meal. Peptide YY (PYY), an anorexigenic 36-amino acid peptide, is secreted primarily from the intestinal mucosa of the ileum and large intestine. Plasma PYY levels begin to rise within 15 min after starting to eat and plateau within approximately 90 min, remaining elevated for up to 6 h. Recently, some studies have tried to evaluate the potential role of ghrelin and PYY in the hyperphagia of patients with Prader-Willi syndrome (PWS). While hyperghrelinemia is well characterized in PWS, conflicting results have been reported for PYY. The aim of the study was to investigate ghrelin and PYY responses to a standard liquid high-fat meal in children with PWS.

PATIENTS AND METHODS: Circulating levels of total ghrelin and PYY levels were assayed by RIA after overnight fasting and 45, 60, 90, and 180 min following a standard meal (Ensure 6 ml/kg) in 16 patients with PWS (11 boys and five girls, aged 4.6-10.7 years, including ten receiving 0.02 mg/kg per day rhGH for 2-18 months; body mass index (BMI) z-score: 0.6+/-0.2 and 1.6+/-0.5 for children treated or not treated with rhGH respectively), ten obese (eight boys and two girls, aged 9.2-15.6 years; BMI z-score: 2.4+/-0.2, i.e. BMI >97th centile for chronological age and not allowed) subjects, and 16 normal-weight controls (five boys and 11 girls, aged 5.8-17.3 years; BMI z-score: 0.6+/-0.2).

RESULTS: PWS children showed higher fasting levels of ghrelin than obese and lean controls. Postprandial ghrelin drop was more pronounced in PWS than in the other study groups. No significant difference on fasting levels of PYY was found among groups. PWS showed a higher postprandial PYY rise than obese and lean controls. PWS patients treated and not treated with GH showed similar fasting and postprandial levels of ghrelin and PYY. Fasting PYY levels correlated negatively (P<0.05; r=-0.68) with those of ghrelin only in PWS.

CONCLUSIONS: The results of this study confirm fasting hyperghrelinemia in PWS. Since in PWS adults an impaired postprandial suppression of plasma ghrelin was previously reported to be associated with a blunted postprandial PYY response, the finding of a meal-induced decrease and increase in ghrelin and PYY levels respectively in PWS children would imply that the regulation of appetite/satiety of these peptides is operative during childhood, and it progressively deteriorates and vanishes in adulthood when hyperphagia and obesity worsen.

http://eje-online.org/cgi/content/abstract/162/3/499

Excessive appetitive arousal in Prader-Willi syndrome.

Appetite. 2010 Feb

Hinton EC, Isles AR, Williams NM, Parkinson JA.

Wales Institute of Cognitive Neuroscience, School of Psychology, Cardiff University, Park Place, Cardiff CF103AT, UK. hintone@cardiff.ac.uk

Keywords: Food; Motivational arousal; Prader–Willi syndrome; Genetics; Learning; Craving

This study focused on genetic and behavioural aspects of one important component of the motivation to eat - how appetitive arousal is elicited through the presentation of food-associated stimuli. Individuals with Prader-Willi syndrome, a genetic disorder associated with hyperphagia, and control participants completed a computerised response task in the presence of motivational stimuli. In controls, appetitive arousal was specific to particular stimuli. In contrast, individuals with PWS showed a non-specific pattern of arousal. Over-activation of the anticipatory motivation system may be one consequence of the genetic disorder in PWS.

http://www.sciencedirect.com/science?_o ... 73cc583736

Sleep disordered breathing in infants with Prader-Willi syndrome during the first 6 weeks of growth hormone therapy: a pilot study.

J Clin Sleep Med. 2009 Oct

Miller JL, Shuster J, Theriaque D, Driscoll DJ, Wagner M.

Department of Pediatrics, University of Florida, College of Medicine, Gainesville, FL 32610-0296, USA. millejl@peds.ufl.edu

BACKGROUND: Sleep-related breathing disorders are common in individuals with Prader-Willi syndrome (PWS). The US Food and Drug Administration approved the use of growth hormone in PWS in 2000. Many infants with PWS are being started on growth hormone therapy, but no data exist on the respiratory effects of growth hormone treatment in this age group.

STUDY OBJECTIVES: To perform overnight polysomnographic studies to evaluate the effects of growth hormone on sleep-related breathing in infants with PWS. METHODS: Pilot study evaluating overnight polysomnography before and 6 weeks after initiation of growth hormone therapy at a dose of 1 mg/m2 per day in 20 infants from 2 to 21 months of age with genetically confirmed PWS. Polysomnography results were analyzed for frequency and severity of obstructive and central apnea and hypopnea events and the overall apnea-hypopnea index.

RESULTS: When data were analyzed for the total group, there were no significant changes in sleep-related disorders before and after institution of growth hormone therapy. However, 12 infants had an increase in the frequency of obstructive events associated with either upper respiratory infections or a diagnosis of gastroesophageal reflux at the second sleep study (after institution of growth hormone therapy). Resolution of these conditions was associated with normalization of polysomnography results on follow-up studies.

CONCLUSIONS: Overall, growth hormone therapy, per se, had no significant effect on sleep related-breathing disorders in infants with PWS. Infants with upper respiratory infections of gastroesophageal reflux may be at risk for developing more obstructive events after beginning growth hormone treatment. We recommend close monitoring of infants with PWS after they begin growth hormone therapy, especially when they have upper respiratory infections.

http://www.ncbi.nlm.nih.gov/pubmed/19961030

Hypogonadism in females with Prader-Willi syndrome from infancy to adulthood: variable combinations of a primary gonadal defect and hypothalamic dysfunction

Eur J Endocrinol. 2010 Feb

Talia Eldar-Geva1, Harry J Hirsch2, Fortu Benarroch3, Orit Rubinstein2 and Varda Gross-Tsur2
1 Reproductive Endocrinology and Genetics Unit, Department of Obstetrics and Gynecology
2 Neuropediatric Unit, Department of Pediatrics, Shaare Zedek Medical Center, The Hebrew University, PO Box 3235, Jerusalem 91031, Israel
3 Child and Adolescent Psychiatry, Hadassah Mount Scopus Hospital, Jerusalem 91120, Israel

(Correspondence should be addressed to T Eldar-Geva; Email: gevat@szmc.org.il)

Design: A cross-sectional study.

OBJECTIVE: The variable hypogonadism in Prader-Willi syndrome (PWS) has generally been attributed to hypothalamic dysfunction. Recent studies have documented primary testicular dysfunction in PWS males. Our aims were to characterize sexual development and reproductive hormones in PWS females and to investigate the etiology of hypogonadism. DESIGN: A cross-sectional study.

METHODS: Physical examination was performed on 45 PWS females (aged 6 weeks to 32 years) and blood samples were obtained for hormonal analyses.

RESULTS: Age of onset and progression of puberty varied; most adults had incomplete sexual development. Spontaneous menarche was reported in four (aged 15-30 years) but all had subsequently developed secondary amenorrhea or oligomennorrhea. Anti-Mullerian hormone levels were within the normal range in all age groups. Inhibin B was consistently low or undetectable; only five women had levels in the low-normal range (20-54 pg/ml). LH was normal in most children, but low (<1.0 IU/l) in 9 of 15 adults. FSH was within the normal range for age in most children, but low (<0.5 IU/l) in 10 and high in four adults. Estradiol levels were normal-low and androgen levels were normal in the majority.

CONCLUSIONS: Pubertal development in PWS females, as in males, is characterized by normal adrenarche, pubertal arrest, and hypogonadism due to variable combinations of a unique primary gonadal defect and hypothalamic dysfunction.

http://eje-online.org/cgi/content/abstract/162/2/377

Plasma adiponectin level and sleep structures in children with Prader-Willi syndrome.

J Sleep Res. 2009 Nov 11

Joo EY, Hong SB, Sohn YB, Kwak MJ, Kim SJ, Choi YO, Kim SW, Paik KH, Jin DK.

Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Summary Adiponectin, an adipose tissue-derived hormone, has been negatively related to obstructive sleep apnea syndrome. Besides sleep apnea, children with Prader-Willi syndrome (PWS) may have excessive daytime sleepiness and rapid eye movement (REM) sleep abnormality. The aim of this study is to determine whether changes in sleep structures are related to plasma adiponectin levels in PWS. Correlations between adiponectin level and sleep variables were analyzed in 28 children with PWS and 18 controls. Overnight polysomnography was performed. The fasting plasma adiponectin levels were higher in the children with PWS than in the controls (P = 0.0006). In the PWS, Epworth sleepiness scale was significantly higher (P = 0.002); sleep latency (P = 0.003) and REM latency (P = 0.001) were significantly shortened; the apnea-hypopnea index (AHI) was significantly increased (P = 0.0001); and the duration of non-rapid eye movement (NREM) sleep stages 3 and 4 was decreased (P = 0.005). Multiple regression analysis revealed correlations between the adiponectin level and the total sleep time (beta = 0.688, P = 0.009), AHI (beta = 1.274, P = 0.010), REM latency (beta = -0.637, P = 0.021) and the percentage of NREM sleep (beta = -7.648, P = 0.002) in PWS. In children with PWS, higher plasma adiponectin levels were independently associated with several sleep variables, which was not observed in the control group. These results suggest a potential influence of elevated adiponectin level on the sleep structures in PWS

http://www.ncbi.nlm.nih.gov/pubmed/19912511
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Re: Prader Willi Syndrome

Postby patoco » Sat Sep 17, 2011 10:45 am

Physical health problems in adults with Prader-Willi syndrome.

Sinnema M, Maaskant MA, van Schrojenstein Lantman-de Valk HM, Caroline van Nieuwpoort I, Drent ML, Curfs LM, Schrander-Stumpel CT.

Source

Department of Clinical Genetics, Maastricht UMC, Maastricht University, Maastricht, The Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; Governor Kremers Centre, Maastricht University, Maastricht, The Netherlands; CAPHRI School for Public Health and Primary Care, Maastricht University, Maastricht, The Netherlands. margje.sinnema@mumc.nl.

Keywords:
Prader–Willi syndrome;physical health problems;ageing;intellectual disabilities

Abstract

Prader-Willi syndrome (PWS) is a genetic disorder which is characterized by severe hypotonia and feeding problems in early infancy. In later childhood and adolescence, this is followed by hyperphagia and extreme obesity if the diet is not strictly controlled. Data on physical health problems in adults with PWS are scarce. We report on the prevalence of physical health problems in a Dutch cohort of adults with PWS in relation to age, BMI, and genetic subtype. Participants (n = 102) were retrieved via the Dutch Prader-Willi Parent Association and through physicians specializing in persons with intellectual disabilities (ID). Details regarding physical health problem spanning the participants' lifespan were collected from caretakers through semi-structured interviews. Cardiovascular problems included diabetes mellitus, hypertension, and cerebrovascular accidents. Respiratory infections were frequent in adulthood. In males, cryptorchidism was almost universal, for which 28/48 males had a history of surgery, mostly orchidopexy. None of the women had a regular menstrual cycle. Sixteen individuals had a diagnosis of osteoporosis. Spinal deformation, hip dysplasia, and foot abnormalities were common. Skinpicking, leg edema, and erysipelas were frequent dermatological problems. The findings in our group support the notion that the prevalence of physical health problems is underestimated. This underscores the importance of developing monitoring programs which would help to recognize physical health problems at an early stage. © 2011 Wiley-Liss, Inc.

http://onlinelibrary.wiley.com/doi/10.1 ... 1/abstract
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