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Prader WilliAngelman Syndromes

Chromosome 15 partial gene deletion or inexpressibility

by Panagiotis Koskeridis for Medical Genetics class of 2008

A project supervised by Medical Genetics Instructor Evangellos Karamberis

Prader Willi- Angelman Syndromes

Introduction
The aim of this project is to present and define Prader Willi and Angelman syndromes. Both of those syndromes represent rare genetic disorders that occur in the 15th chromosome. The cause of these disorders is the deficiency of some genes or the complete absence of a DNA sequence in either the paternal or the maternal chromosome 15. As a result, these two syndromes have major consequences (with varying effects - from mental disorders to extreme obesity-). This report contains all of the crucial information needed to understand the origin and the physiology of these syndromes. Finally, there will be an attempt to further investigate how these syndromes affect the patients and the ways to prevent or reduce the frequency and volume of the problems caused by these particular genetic disorders (such as testing and experimental treatment of manifestations).

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PRADER – WILLI SYNDROME History and introduction
Prader-Willi syndrome is a very rare genetic disorder, in which seven genes (or some subset thereof) on chromosome 15 are missing or unexpressed (chromosome 15q partial deletion) on the paternal chromosome. 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 sex 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
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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. 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.

Genetics of PWS (Prader –Willi syndrome)
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
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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. 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. In medical practice there have been discovered (throughout testing) three forms of PWS: • 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
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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 . 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, 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
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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 sex 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.
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Concerns and common issues encountered because of PWS
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. • 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, smallappearing 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
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• • • • • • • •

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

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 dec reased 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
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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.
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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 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
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• 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. The following table shows Sensitivities and the Percentages of Documentation of the Published Criteria
% Affected

Major criteria 
Neonatal hypotonia  Feeding problems in infancy  Excessive weight gain  88 79 67
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Facial features  Hypogonadism  Developmental delay  Hyperphagia 

88 51 99 84

Minor criteria 
Decreased fetal activity  Behavior problems  Sleep disturbance/sleep apnea  Short stature  Hypopigmentation  Small hands and/or feet  Narrow hands/straight  ulnar borders  Eye abnormalities  Thick viscous saliva  Articulation defects  Skin­picking  68 89 80 83 62 87 76 63 73 88 82

Diagnosis
Clinical Diagnosis Consensus diagnostic criteria for Prader-Willi syndrome (PWS) developed in 1993 [Holm et al 1993] have proven to be accurate [Gunay-Aygun et al 2001]. However, confirmation of diagnosis requires molecular genetic testing. Major criteria are weighted at one point each; minor criteria are one-half point each. Supportive findings only increase or decrease the level of suspicion of the diagnosis. • For children under age three years, five points are required for diagnosis, four of which must be major criteria.

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• For individuals age three years and older, eight points are required for diagnosis, at least five of which must be major criteria. Major criteria • Neonatal and infantile central hypotonia with poor suck and improvement with age • Feeding problems and/or failure to thrive in infancy, with need for gavage feeding or other special feeding techniques • Onset of rapid weight gain between ages 12 months and six years, causing central obesity • Hyperphagia • Characteristic facial features: narrow bifrontal diameter, almond-shaped palpebral fissures, down-turned mouth • Hypogonadism manifest as: ○ Genital hypoplasia: small labia minora and clitoris in females; hypoplastic scrotum and cryptorchidism in males ○ Incomplete and delayed puberty ○ Infertility • Developmental delay / mild to moderate mental retardation / multiple learning disabilities Minor criteria • Decreased fetal movement and infantile lethargy, improving with age • Typical behavior problems, including temper tantrums, obsessive-compulsive behavior, stubbornness, rigidity, stealing, and lying • Sleep disturbance/sleep apnea • Short stature for the family by age 15 years • Hypopigmentation • Hands and feet small for height age • Narrow hands with straight ulnar border • Esotropia, myopia
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• Thick, viscous saliva • Speech articulation defects • Skin picking Supportive findings • High pain threshold • Decreased vomiting • Scoliosis and/or kyphosis • Early adrenarche • Osteoporosis • Unusual skill with jigsaw puzzles • Normal neuromuscular studies (e.g., muscle biopsy, EMG, NCV) Findings that should prompt diagnostic testing have been proposed, based on analysis of diagnostic criteria met in individuals in whom the diagnosis of PWS has been molecularly confirmed . These differ by age group. The presence of the following findings is sufficient to justify methylation analysis for PWS Birth to two years. Hypotonia with poor suck in the neonatal period Two to six years • Hypotonia with history of poor suck • Global developmental delay Six to 12 years • History of hypotonia with poor suck (hypotonia often persists) • Global developmental delay • Excessive eating with central obesity if uncontrolled 13 years to adulthood • Cognitive impairment, usually mild mental retardation • Excessive eating with central obesity if uncontrolled • Hypothalamic hypogonadism and/or typical behavior problems
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Testing Cytogenetic analysis. Approximately 70% of individuals with PWS have a deletion on one number 15 chromosome involving bands 15q11.2-q13, which can be detected using high-resolution chromosome studies and fluorescence in situ hybridization (FISH) testing. Note: The typical deletion is one of two sizes: extending from the distal breakpoint (BP3) to one of two proximal breakpoints (BP1 and BP2). Clinical FISH testing detects both of these deletions and cannot distinguish between them. Approximately 1% of affected individuals have a detectable chromosomal rearrangement resulting in a deletion of bands 15q11.2-q13. Fewer than 1% of individuals have a balanced chromosomal rearrangement breaking within 15q11.2-q13 and detectable by chromosome analysis and FISH. Gene. More than 99% of individuals with PWS have a diagnostic abnormality in the parent-specific methylation imprint within the Prader-Willi critical region (PWCR). Clinical testing

Diagnosis
○ Methylation abnormality. Abnormal parent-specific

methylation imprinting within PWCR can be detected using methylation analysis. Most laboratories utilize PCR analysis with parent-specific (methylation-sensitive) PCR primers . A methylation-specific melting analysis (MSMA) method for a rapid screening of PWS/Angelman syndrome (AS) evaluates methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) for diagnosis of PWS/AS associated with deletions, uniparental disomy 15 (UPD15), or rare duplications.

Imprinting defect. An imprinting defect is presumed to be present in individuals with an abnormality in the parentspecific methylation imprint without evidence of a deletion or UPD. ○ Imprinting defects caused by microdeletions are detected using sequence analysis or MLPA of the PWSSRO (smallest region of overlap).
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○ Most imprinting defects are epimutations (i.e.,

alterations in the imprint, not the DNA) and cannot be detected by sequence analysis.

Table 1 summarizes molecular genetic testing for this disorder. Table 1. Testing Used in Prader-Willi Syndrome Test Method Mutations Detected Mutation Test Detection Availabili Frequency by Test ty Method 99% 70%-75% 25%-29% <1% Clinical

Methylation Methylation analysis abnormality FISH/Quantitative Deletion of PCR PWCR 1 Uniparental disomy UPD of PWCR (UPD) studies Sequence analysis Imprinting 2 center defect

PWCR = Prader-Willi critical region 1. Deletion varies in size, but always includes the PWCR. 2. Sequence analysis detects small deletions that account for approximately 15% of imprinting center mutations. Most imprinting defects are epimutations (i.e., alterations in the imprint, not the DNA). Testing Strategy Testing to determine whether an individual has PWS can proceed in one of two ways: • If the individual appears to fulfill the clinical diagnostic criteria for PWS, methylation testing may be used initially. • If PWS is one of several possible diagnoses: ○ Cytogenetic analysis with FISH for 15q11.2-q13 deletion can be performed initially.
○ If neither a deletion of chromosome 15 nor any other

cytogenetic anomaly is identified, methylation testing
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should be performed. If positive, the type of mutation detected (see Table 1) should be determined. For recurrence risk assessment. If the methylation pattern is characteristic of maternal inheritance only, the underlying molecular class of the mutation (deletion, UPD, or imprinting mutation) can be determined for genetic counseling purposes. It is most efficient to begin with FISH for the 15q11.2-q13 deletion. Simultaneous cytogenetic studies allow detection of a translocation or other anomaly involving proximal 15q. If no deletion or other chromosomal abnormality is detected, UPD studies (requiring blood from both parents) are conducted. If UPD is not detected, referral to a specialized laboratory for sequence analysis of the imprinting center for a microdeletion can be accomplished. Individuals with an imprinting center defect are the only ones at significant risk of recurrence. Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing abnormality (deletion, UPD, or imprinting mutation) in the family. Prenatal Testing High risk. Prenatal detection of all the molecular genetic alterations in the PWS/AS region that give rise to PWS is possible through analysis of DNA extracted from cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15-18 weeks' gestation. Prenatal testing should only be undertaken after molecular confirmation of PWS has been established in the individual and the couple has been counseled regarding the risk to the unborn child. • Parents who have had one child with PWS caused either by deletion or UPD are not routinely offered prenatal testing in subsequent pregnancies, but could be offered such testing for reassurance. • Parents who have had one child with PWS caused by a defect in the imprinting control element should be offered prenatal testing because of the high recurrence risk; methylation analysis can also be used in these cases.

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• Prenatal testing for an inherited translocation involving chromosome 15 and resulting in a deletion is relevant because of the theoretical 25% risk for PWS in the offspring. Note: (1) Although methylation analysis has been validated in both CVS and amniocentesis samples [Kubota et al 1996], it should be noted that most laboratories offer methylation studies on cells obtained from amniocentesis only. Laboratories offering prenatal testing typically perform FISH deletion studies or uniparental disomy studies on cells from either CVS or amniocentesis. (2) Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Low risk. For low-risk pregnancies in which no family history of PWS exists, PWS may be a possibility: • If a 15q deletion is suspected on cytogenetic studies from CVS or amniocentesis. FISH is indicated. In this instance, parent-of-origin studies should be performed after confirmation of a deletion to determine if the deletion is maternally derived (fetus has AS) or paternally derived (fetus has PWS).

If trisomy 15 or mosaic trisomy 15 is detected on CVS and if subsequent amniocentesis reveals 46 chromosomes, the possibility of trisomy rescue leading to AS (paternal UPD) through loss of a maternal chromosome 15 or PWS (maternal UPD) through loss of a parental chromosome 15 can be considered. In this instance, parent-of-origin (UPD) studies or methylation analysis on amniocytes should be considered [EUCROMIC 1999, Shaffer et al 2001]. If an inherited or de novo translocation involving chromosome 15 is present or if a supernumerary chromosome derived from chromosome 15 is detected, FISH (to rule out a deletion) and parent-of-origin studies (to rule out UPD) are indicated.

Preimplantation genetic diagnosis (PGD) may be available for families in which a mutation in the imprinting control element has been identified. For laboratories offering PGD. PGD can also be used in cases of familial translocation to rule out UPD.

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General Facts about PWS
Frequency United States Most cases of PWS are sporadic. Burd et al reported a prevalence rate of 1 per 16,062 population. Butler reported a prevalence rate of 1 per 25,000 population. International PWS has been reported worldwide. Reported prevalence rates for PWS range from 1 per 8000 population in rural Sweden to 1 per 16,000 population in western Japan.Despite findings that suggest a prevalence rate of 1 per 52,000 population in the United Kingdom, Whittington et al estimate that the actual prevalence rate is higher and propose a true prevalence rate of 1 per 45,000 population. Mortality/Morbidity Complications due to obesity (eg, slipped capital femoral epiphyses, sleep apnea, cor pulmonale, diabetes mellitus type II) and behavioral problems are major contributors to morbidity and mortality in individuals with PWS Lamb et al reported premature development of atherosclerosis with severe coronary artery disease in an patient aged 26 years with PWS, morbid obesity, and non–insulin-dependent diabetes mellitus. Wharton et al described a series of 6 patients with PWS with dramatic acute gastric distention preceded by symptoms of gastroenteritis. One half of the cases rapidly progressed to massive gastric dilatation and gastric necrosis. One patient died of overwhelming sepsis and disseminated intravascular coagulation. Gastric dilatation spontaneously resolved in 2 children. Gastrectomy was performed in 2 patients; in one patient, gastrectomy was subtotal and distal, whereas in the other patient,
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gastrectomy was combined with partial duodenectomy and pancreatectomy. In a series of 152 patients with PWS, choking episodes were reported as the cause of death in 7.9%. Race Differences in prevalence rates between racial groups have not been consistently reported. However, in a study of 10 African Americans with PWS, Hudgins et al (1998) suggested that clinical features in African American patients differ from those of white patients. In African American patients, growth is less affected, hand lengths are usually normal, and the facies are less typical. Sex PWS is caused by the loss of the paternal copy in the proximal arm of chromosome 15 in the region of 15p11-13. Differences in prevalence rates between sexes have not been reported. Age PWS is a genetic disorder with lifelong implications. Genotype-Phenotype Correlations Some clinical differences exist between individuals with PWS who have deletion 15q and those who have maternal uniparental disomy (UPD). Individuals with UPD are less likely to have the typical facial appearance, hypopigmentation, or skill with jigsaw puzzles [Dykens 2002]; they also have a somewhat higher IQ and milder behavior problems [Dykens et al 1999, Roof et al 2000, Hartley et al 2005]. Individuals with UPD are more likely to have psychosis [Holland et al 2003] and autism spectrum disorders [Veltman et al 2004, Whittington et al 2004b , Veltman et al 2005, Descheemaeker et al 2006]. Recent studies suggest that as many as 62% of those with UPD develop atypical psychosis compared with 16% of those with deletion 15q [Soni et al 2007]. Individuals with 15q deletion showed a higher frequency of need for special feeding techniques, sleep disturbance,
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hypopigmentation, and speech articulation defects in a recent study of 91 children [Torrado et al 2007]. In one study individuals with deletions with breakpoint 1 (breaking more proximally) were reported to have more behavior problems than those with deletions with breakpoint 2. The behavior problems included poorer adaptive behavior skills and specific obsessive-compulsive behaviors [Butler, Bittel, Kibiryeva et al 2004] and physical depression [Hartley et al 2005]. They also had poorer reading and math skills [Butler, Bittel, Kibiryeva et al 2004]; however, other studies failed to show these differences between the two groups [Milner et al 2005, Hartley et al 2005, Milner et al 2005]. The study by Hartley et al (2005) showed greater physical depression in those with breakpoint 1 than in those with breakpoint 2.

Nomenclature The term HHHO (hypogonadism, hypotonia, hypomentia, obesity) is no longer used. The condition is sometimes called Willi-Prader syndrome or PraderLabhart-Willi syndrome. Prevalence The estimated prevalence of PWS is 1:10,000 to 1:30,000 in a number of populations.

Treatment attempts

Partial Treatment of Manifestations A team approach to management is recommended [Eiholzer & Whitman 2004, Cassidy 2005]. Special feeding techniques, including special nipples or gavage feeding, may be necessary for the first weeks to months of life to assure adequate nutrition and avoid failure to thrive.
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Early intervention in children before age three years, particularly physical therapy, may improve muscle strength and encourage achievement of developmental milestones. In older individuals, daily muscle training increases physical activity and lean body mass [Schlumpf et al 2006]. Cryptorchidism may resolve spontaneously, even up to adolescence, but usually requires hormonal and surgical approaches; however, preservation of fertility is not an issue. Standard treatment is appropriate. Management of strabismus is as for any infant. When hyperphagia begins or weight centiles are increasing (often age two to four years), a program of a well-balanced, low-calorie diet, regular exercise, and close supervision to minimize food stealing should be instituted to prevent obesity and its consequences. The same program is appropriate if obesity is present at any time. Consultation with a dietician and close followup are usually necessary, and locking of the kitchen, refrigerator, and/or cupboards is often required. The energy requirement of people with PWS, which rarely exceeds 1000 to 1200 Kcal/day, should be considered in planning daily food intake. Assessment of adequacy of vitamin and mineral intake by a dietician and prescription of appropriate supplementation are indicated, especially for calcium and vitamin D. Growth hormone treatment normalizes height, increases lean body mass, decreases fat mass, and increases mobility, which are beneficial to weight management. Dose recommendations in children are generally similar to those for individuals with isolated growth hormone deficiency, i.e., about 1 mg/m2. Treatment can be started in infancy or at the time of diagnosis. The adult dose of growth hormone is 20%-25% of the dose recommended in children. Controlled trials of growth hormone therapies have demonstrated significant benefit from infancy through adulthood [Lindgren et al 1997, Carrel et al 1999, Ritzen et al 1999, Eiholzer et al 2000, Mogul et al 2000, Carrel et al 2002, Carrel et al 2004, Eiholzer & Whitman 2004, Hoybye 2004, Whitman et al 2004. Hoybye et al 2005, Hoybye 2007, Myers et al 2007]:
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An increase in language and cognitive skills in treated infants [Myers et al 2007] and an improvement in mental speed and flexibility as well as motor performance in adults [Hoybye et al 2005] have been reported based on controlled trials. • A review of the results of one to two years of growth hormone treatment among 328 children documented in the database of one pharmaceutical company indicated improved height velocity, particularly in prepubertal children, but no change in BMI [Craig et al 2006]. • Significantly greater adult height was demonstrated in 21 individuals treated long term versus 39 untreated individuals without an increase in adverse side effects [Angulo et al 2007]. • Although there was initial concern that growth hormone treatment contributed to scoliosis in PWS, recent studies show no difference in frequency or severity in those treated compared to those who were not treated [Nagai et al 2006, Angulo et al 2007]. Appropriate educational programming should be initiated in children: • Begin speech therapy for language delay and articulation abnormalities in infancy and childhood. • Special education, either in an inclusion setting or in a selfcontained classroom setting, is usually necessary during school age. An individual aide is helpful in assuring attendance to task. Social skills training groups have been beneficial. Behavioral disturbance should be addressed with behavioral management programs, including firm limit setting. While no medication is beneficial in managing behavior in all individuals with PWS, serotonin reuptake inhibitors have helped the largest proportion of affected individuals, particularly those with obsessive-compulsive symptoms [Brice 2000, Dykens & Shah 2003]. Psychosis is reported to respond well to selective serotonin reuptake inhibitors but not to mood stabilizers [Soni et al 2007].
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Replacement of sex hormones produces adequate secondary sexual characteristics but is somewhat controversial because of the possible role of testosterone replacement in behavior problems in males and the role of estrogen replacement in the risk of stroke as well as hygiene concerns related to menstruation in females. Daily use of the testosterone patch or gel, or use of slow-release testosterone injection every three months, may avert exacerbation of behavior problems by providing a more even blood level. The risk of osteoporosis should be considered in deciding about hormone replacement. Management of scoliosis, hip dysplasia, and complications of obesity is as in the general population. Decreased saliva production can be addressed with products developed for the treatment of dry mouth, including special toothpastes, gels, mouthwash, and chewing gum. Disturbed sleep in children and adults should prompt a sleep study, as treatment may be available. Treatment depends on the cause and may include tonsillectomy and adenoidectomy and/or CPAP, as in the general population. For adults with PWS, one successful living situation for behavior and weight management is a group home specially designated for individuals with PWS. Affected individuals generally require a sheltered employment environment. Issues of guardianship, wills, trusts, and advocacy should be investigated, no later than adolescence. Recent reports of fertility in two women with PWS raise the issue of the need for birth control [Akefeldt et al 1999, Schulze et al 2001]. Prevention of Primary Manifestations Obesity may be prevented if the diet, exercise, and supervision program described in Treatment of Manifestations is instituted. If started at a young age, growth hormone therapy may prevent obesity and high proportion of fat mass. It may also prevent development of the typical facial appearance. Prevention of Secondary Complications Diabetes mellitus rarely occurs in the absence of obesity.
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Calcium supplementation may be beneficial, as low-calorie diets are often low in dairy products and osteoporosis has been documented in most older children and adults with PWS. Although no formal study exists, individuals with PWS tend to be very sensitive to medications of all kinds. Starting with lower doses is recommended. Surveillance To assure appropriateness of exercise program and diet, including adequacy of vitamin and mineral intake, monitor height, weight, and BMI (weight in kg/height in m2) as follows: • Monthly in infancy • Every six months in the first decade of life • At least annually thereafter Cryptorchidism can recur after orchidopexy; therefore, testicular position should be monitored. Evaluate for the presence of diabetes mellitus by standard methods (e.g., obtaining glycosylated hemoglobin concentration) in anyone with significant obesity or rapid significant weight gain. Obtain history of any sleep disturbance; if present, perform a sleep study. Monitor for development of scoliosis clinically or, in the presence of obesity, radiographically at least annually. Perform bone densitometry by DEXA to evaluate for possible osteoporosis every three to five years in adulthood. Obtain history for behavioral and psychiatric disturbance at least annually.

Summary
Disease characteristics. Prader-Willi (PWS) syndrome is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity (unless eating is externally controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. A distinctive behavioral phenotype (with
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temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common; characteristic facial features, strabismus, and scoliosis are often present, and non-insulindependent diabetes mellitus often occurs in obese individuals. Diagnosis/testing. Consensus clinical diagnostic criteria are accurate, but the mainstay of diagnosis is DNA-based methylation testing to detect abnormal parent-specific imprinting within the Prader-Willi critical region (PWCR) on chromosome 15; this testing determines whether the region is maternally inherited only (i.e., the paternally contributed region is absent) and detects more than 99% of affected individuals. Methylation-specific testing is important to confirm the diagnosis of PWS in all individuals, but especially those who have atypical findings or are too young to manifest sufficient features to make the diagnosis on clinical grounds. Management. Treatment of manifestations: in infancy, special nipples or gavage feeding to assure adequate nutrition; physical therapy to improve muscle strength; consideration of hormonal and surgical treatments for cryptorchidism. In childhood, strict supervision of daily food intake based on height, weight, and body mass index (BMI) to provide energy requirements while limiting weight gain (keeping BMI <30); growth hormone replacement therapy to normalize height, increase lean body mass and mobility, and decrease fat mass. Evaluation and treatment of sleep disturbance per the general population. Educational planning; speech therapy as needed. Firm limit-setting to treat behavior problems; serotonin reuptake inhibitors are helpful for most individuals. Replacement of sex hormones at puberty produces adequate secondary sexual characteristics. In adulthood, a group home for individuals with PWS that regulates behavior and weight management may prevent morbid obesity; growth hormone may help to maintain muscle bulk. Prevention of secondary complications: weight control to prevent development of diabetes
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mellitus; calcium supplementation to prevent osteoporosis. Surveillance: screening of infants for strabismus; routine monitoring of height, weight, and BMI to assure appropriateness of exercise program and diet. Other: No medications are known to aid in controlling hyperphagia. Genetic counseling. PWS is caused by absence of the paternally derived PWS/AS (Angelman syndrome) region of chromosome 15 by one of several genetic mechanisms. The risk to the sibs of an affected child of having PWS depends upon the genetic mechanism that resulted in the absence of the paternally contributed PWS/AS region. The risk to sibs is less than 1% if the affected child has a deletion or uniparental disomy (UPD), up to 50% if the affected child has a mutation of the imprinting control center, and up to 25% if a parental chromosomal translocation is present. Prenatal testing is possible for pregnancies at increased risk if the underlying genetic mechanism is known

ANGELMAN SYNDROME
History
Dr. Harry Angelman, a pediatrician working in Warrington (then in Lancashire) first reported three children with this condition in 1965.[1] He titled the paper "Puppet Children" and later explained that this was because of an oil paiting he had seen: "I happened to see an oil painting...called... "Boy with a Puppet". The boy's laughing face and the fact that my patients exhibited jerky movements gave me the idea of writing an article about the three children with a title of Puppet Children."[1] The condition was initially incorrectly presumed to be rare. In 1987, it was first noted that around half of the children with Angelman syndrome have a small piece of chromosome 15 missing (chromosome 15q partial deletion).
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Summary
Disease characteristics. Angelman syndrome (AS) is characterized by severe developmental delay or mental retardation, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an inappropriate happy demeanor that includes frequent laughing, smiling, and excitability. In addition, microcephaly and seizures are common. Developmental delays are first noted at around six months of age; however, the unique clinical features of AS do not become manifest until after one year of age, and it can take several years before the correct clinical diagnosis is obvious.

Diagnosis/testing
The diagnosis of Angelman syndrome rests upon a combination of clinical features and molecular genetic testing and/or cytogenetic analysis. Consensus clinical diagnostic criteria for AS have been developed. Analysis of parent-specific DNA methylation imprints in the 15q11.2-q13 chromosome region detects approximately 78% of individuals with AS, including those with a deletion, uniparental disomy, or an imprinting defect; fewer than 1% of individuals have a cytogenetically visible chromosome rearrangeme nt (i.e., translocation or inversion). UBE3A sequence analysis detects mutations in an additional ~11% of individuals. Accordingly, molecular genetic testing (methylation analysis and UBE3A sequence analysis) identifies alterations in about 90% of individuals. The remaining 10% of individuals with classic

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phenotypic features of AS have a presently unidentified genetic mechanism and thus are not amenable to diagnostic testing.

Management
Feeding difficulties in newborns with AS may require special nipples; gastroesophageal reflux associated with poor weight gain and emesis is treated with upright positioning and motility drugs; fundoplication is sometimes required. Anticonvulsant medications such as valproic acid, clonazepam, topiramate, lamotrigine, and ethosuximid, are used to treat seizures; vigabatrin and tigabine should be avoided. Unstable or non-ambulatory children may benefit from physical therapy. Occupational therapy may help improve fine motor and oral-motor control. Adaptive chairs or positioners may be required for extremely ataxic children. Speech therapy should focus on nonverbal methods of communication; augmentative communication aids such as picture cards or communication boards are used at the earliest appropriate time and signing should be taught as soon as the child is sufficiently attentive. Children with AS with excessive hypermotoric behaviors need an accommodating classroom space; some children may benefit from the use of stimulant medications such as methylphenidate. Individualization and flexibility in the school are important educational strategies. Sedatives such as chloral hydrate or diphenylhydramines may accommodate nighttime wakefulness. Strabismus may require surgical correction. Laxatives such as high fiber or lubricating agents are used to treat constipation. Orthopedic problems can be corrected by orthotic bracing or surgery. Thoraco-lumbar jackets may be needed for scoliosis; individuals with severe spinal curvature may benefit from surgical rod stabilization. Genetic counseling Angelman syndrome is caused by the loss of the maternally imprinted contribution in the 15q11.2-q13 (AS/PWS) region that can occur by one of at least five different known genetic mechanisms. The risk to sibs of an affected child of having AS depends upon the genetic mechanism of the loss of the maternally contributed AS/PWS region. The risk to sibs of an
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affected child who has a deletion or uniparental disomy is typically less than 1%. The risk is as high as 50% to the sibs of a child with an imprinting defect or a mutation of the UBE3A gene. Members of the mother's extended family are also at increased risk when an imprinting defect or a UBE3A mutation is present. Cytogenetically visible chromosome rearrangements may be inherited or de novo. Prenatal testing is possible when the underlying genetic mechanism is a deletion, uniparental disomy, an imprinting defect, a UBE3A mutation, or a chromosome rearrangement.

Diagnosis Clinical Diagnosis
Consensus criteria for the clinical diagnosis of Angelman syndrome (AS) have been developed in conjunction with the Scientific Advisory Committee of the US Angelman Syndrome Foundation [Williams, Angelman et al 1995]. Newborns typically have a normal phenotype. Developmental delays are first noted at around six months of age. However, the unique clinical features of AS do not become manifest until after one year of age, and it can take several years before the correct clinical diagnosis is obvious. All affected individuals typically have: • Normal prenatal and birth history, normal head circumference at birth, no major birth defects • Normal metabolic, hematologic, and chemical laboratory profiles • Structurally normal brain by MRI or CT, although mild cortical atrophy or dysmyelination may be observed • Delayed attainment of developmental milestones without loss of skills • Evidence of developmental delay by six to 12 months of age, eventually classified as severe

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• Speech impairment, with minimal to no use of words; receptive language skills and nonverbal communication skills are higher than expressive language skills • Movement or balance disorder, usually ataxia of gait and/or tremulous movement of the limbs • Behavioral uniqueness, including any combination of frequent laughter/smiling; apparent happy demeanor; excitability, often with hand-flapping movements; hypermotoric behavior; short attention span More than 80% of affected individuals have: • Delayed or disproportionately slow growth in head circumference, usually resulting in absolute or relative microcephaly by age two years • Seizures, usually starting before three years of age • Abnormal EEG, with a characteristic pattern of large amplitude slow-spike waves Fewer than 80% of affected individuals have: • Flat back of the head (brachycephaly) • Strabismus • Hypopigmentation of the skin and eyes • Tongue thrusting, sucking and swallowing disorders, frequent drooling, excessive chewing and mouthing behaviors • Feeding problems during infancy • Wide mouth, wide-spaced teeth, prominent mandible • Hyperactive tendon reflexes • Uplifted, flexed arms during walking • Increased sensitivity to heat • Sleep disturbance • Attraction to/fascination with water

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Testing
Fluorescent in situ hybridization (FISH). Approximately 70% of individuals with AS have a 4to 6-Mb deletion of 15q11.2-q13. Note: Fluorescent in situ hybridization (FISH) analysis with the D15S10 and/or the SNRPN probe is the preferred method of identifying the deletion since it is typically not detected by routine chromosome study. Alternatively, comparative genomic hybridization (CGH) can be used to detect the deletion. Cytogenetic analysis. Fewer than 1% of individuals with AS have a cytogenetically visible chromosome rearrangement (i.e., translocation or inversion) of one number 15 chromosome involving 15q11.2-q13 that can usually be detected using chromosome and FISH studies. Gene. The cardinal features of AS are caused by deficient expression or function of the maternally inherited UBE3A allele in certain brain regions [Jiang et al 1999 , Lossie et al 2001 , Nicholls & Knepper 2001 , Clayton-Smith & Laan 2003]. Clinical uses • Diagnostic testing • Prenatal diagnosis Clinical testing • DNA methylation analysis ○ Unaffected individuals have a methylated and an unmethylated SNRPN allele in both the Southern blot analysis [Glenn et al 1996] and methylation-specific PCR (MSP) assay [Kubota et al 1997 , Zeschnighk et al 1997]. ○ Individuals with AS caused by a 4- to 6-Mb deletion of 15q11.2-q13, uniparental disomy (UPD), or an imprinting defect (ID) have only an unmethylated (i.e., "paternal") contribution (i.e., an abnormal parent-specific DNA
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methylation imprint).

Note: Because an abnormal parent-specific DNA methylation imprint cannot distinguish between AS resulting from a deletion, from UPD, or from ID, further testing of individuals with an abnormal parent-specific DNA methylation imprint using the following methods is required to identify the underlying molecular mechanism: ○ Fluorescent in situ hybridization (FISH). In 68% of individuals, 4- to 6-Mb deletions are detected by cytogenetic analysis using FISH. ○ Uniparental disomy (UPD) study. In approximately 7% of individuals, uniparental disomy (UPD) is detected using DNA polymorphism testing. • Sequence analysis. UBE3A sequence analysis is available for individuals with a normal parent-specific DNA methylation imprint who are suspected of having AS. It is estimated that approximately 11% of probands with AS have identifiable UBE3A mutations [Malzac et al 1998 , Fang et al 1999 , Lossie et al 2001]. Research testing • Targeted mutation analysis. Individuals with an imprinting defect (ID) account for about 3% of affected individuals. They have abnormal (paternal-only pattern) DNA methylation imprint, but inheritance of 15q11.2-q13 DNA polymorphisms from both parents. Data suggest that about 10%-20% of the imprinting defects are microdeletions (6-200 kb) that include the AS imprinting center (IC). The nature of the other 80%90% is thought to be an epigenetic mutation occurring during maternal oogenesis or in early embryogenesis [Buiting et al 2001 , Buiting et al 2003]. Characterization of the imprinting defect as either an imprinting center deletion or epigenetic defect is available in only a few research laboratories. Table 1 summarizes molecular genetic testing for this disorder.
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Table 1. Molecular Genetic Testing Used ParentSpecific Abnorma DNA Test Method lity Methylati Detected on Imprint 4- to 6-Mb deletion FISH 15q11.2q13 Abnormal Uniparental disomy ( UPD UPD) study

in AS Prevalen Test ce of Availabil Abnorma ity lity 1

~68%

Clinical Testing

~7% Research only Clinical Testing

Targeted mutation an Imprinting ~3% alysis 2 defect (ID) Normal Sequence analysis UBE3A sequence ~11% variant

1. In 11% of individuals with Angelman syndrome, all testing for Angelman syndrome described in this table is normal. 2. Targeted mutation analysis detects small deletions, which account for 10%-20% of imprinting defects. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here. Possible explanations for the failure to detect mutations in the 11% or more of individuals with clinically diagnosed AS who do not have laboratory proof of AS include: (1) incorrect clinical diagnosis, (2) undetected mutations in the regulatory region(s) of UBE3A, and (3) other unidentified mechanisms or gene(s) involved in UBE3A function that can result in AS when a mutation occurs. Testing Strategy For diagnosis
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DNA methylation analysis identifies approximately 80% of individuals with AS and thus is the single most sensitive diagnostic test for AS. • If DNA methylation analysis is normal, UBE3A sequence analysis is the next appropriate diagnostic test. • Note: For an older child (>5 years old) with classic AS features and hypopigmentation some clinicians may opt to start with FISH analysis rather than DNA methylation. For genetic counseling • If the DNA methylation analysis is positive, the next step is FISH analysis. • If the FISH analysis is normal, studies using DNA polymorphism analysis can be used to distinguish between UPD and ID. • If an ID is present, further DNA studies can determine if an ID deletion is present. • For all affected individuals, it is appropriate to have standard or high-resolution chromosome analysis in addition to the specific diagnostic test because it is possible (though rare; see Table 1) to have a chromosomal rearrangement that alters the recurrence risks. Note: DNA analyses (methylation and uniparental disomy studies) do not detect chromosomal rearrangements. Genetically Related (Allelic) Disorders Prader-Willi syndrome (PWS) is caused by loss of the paternally contributed 15q11.2-q13 region. While PWS and Angelman syndrome are clinically distinct in older children, some clinical overlap exists (e.g., feeding difficulties, hypotonia, developmental delay) [Cassidy et al 2000] in children younger than age two years. Maternally inherited interstitial duplications of 15q11.2-q13 can cause a disorder clinically distinct from either AS or PWS. Individuals with dup15q11.2-1q13 do not have facial dysmorphism but have mild to moderately severe learning deficits and may have behaviors in the autism spectrum [Boyar et al 2001]. Clinical Description Natural History
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Prenatal history, fetal development, birth weight, and head circumference at birth are usually normal. Young infants with AS may have breast or bottle feeding difficulties (as a result of sucking difficulties) and muscular hypotonia. Angelman syndrome may be first suspected in the toddlers because of delayed gross motor milestones, muscular hypotonia, and speech delay [Williams, Angelman et al 1995 ; Williams, Zori et al 1995]. Some infants have a happy affect with excessive chortling or paroxysms of laughter. Fifty percent of children develop microcephaly by 12 months of age. Strabismus may also occur. Tremulous movements may be noted prior to 12 months of age, often with increased deep tendon reflexes. Seizures typically occur between one and three years of age and can be associated with generalized, somewhat specific EEG changes: runs of high-amplitude delta activity with intermittent spike and slow wave discharges; runs of rhythmic theta activity over a wide area; and runs of rhythmic sharp theta activity of 5-6/s over the posterior third of the head, forming complexes with small spikes. These are usually facilitated by or seen only with eye closure [Boyd et al 1997 , Rubin et al 1997]. Seizure types can be quite varied and include both major motor (e.g., grand mal) and minor motor types (e.g., petit mal, atonic) [Galvan-Manso et al 2005]. Infantile spasms are rare. Brain MRI may show mild atrophy and mild dysmyelination, but no structural lesions. The average child with AS walks between two and one-half and six years of age [Lossie et al 2001] and at that time may have a jerky, robot-like, stiff gait, with uplifted, flexed, and pronated forearms, hypermotoric activity, excessive laughter, protruding tongue, drooling, absent speech, and social-seeking behavior [Zori et al 1992]. Ten percent of children are non-ambulatory. Sleep disorders are common, especially frequent night waking and early awakening [Didden et al 2004 , Bruni et al 2004]. Essentially all young children with AS have some component of hyperactivity; males and females appear equally affected. Infants and toddlers may have seemingly ceaseless activity, constantly keeping their hands or toys in their mouth, moving from object to object. Parents
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report that decreased need for sleep and abnormal sleep/wake cycles are characteristic of AS. Sleep disturbances have been reported in infants with AS and abnormal sleep/wake cycles have been studied in one affected child who benefited from a behavioral treatment program. Short attention span is present in most. Language impairment is severe. Appropriate use of even one or two words in a consistent manner is rare. Receptive language skills are always more advanced than expressive language skills. Most older children and adults with AS are able to communicate by pointing and using gestures and by using communication boards. Effective fluent use of sign language does not occur [Clayton-Smith 1993]. Puberty is generally normal in adolescents with AS and procreation appears possible for both males and females [Williams, Zori et al 1995]. Until recently no cases of reproduction in either a male or female with AS had been documented. Lossie and Driscoll (1999) reported transmission of AS by an affected mother who has a 15q11.2-q13 deletion. Therefore, the absence of reproduction previously seen in individuals with AS was most likely social or cognitive rather than physiologic in origin. Young adults appear to have good physical health with the exception of possible seizures. Constipation is common. Scoliosis becomes more common with advancing age. Independent living is not possible for adults with AS, but most can live at home or in home-like placements. Life span data are not available, but life span appears to be nearly normal.

INHERITANCE
Angelman syndrome results from a lack of maternal contribution from chromosome 15q11-q13, arising from de novo deletion in most cases or from uniparental disomy in rare cases. Most families are therefore associated with a low recurrence risk. Although Angelman syndrome is not typically mendelian, familial occurrence has been reported.
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Pashayan et al. (1982) reported Angelman syndrome in 2 brothers, Hersh et al. (1981) reported affected monozygotic twins, and Kuroki et al. (1980) reported 2 affected sisters. Dijkstra et al. (1986) and Fisher et al. (1987) reported affected brothers and sisters. Baraitser et al. (1987) reported 7 cases of Angelman syndrome from 3 families: 2 brothers in the first family, 3 sisters in the second, and 2 brothers in the third. The EEG changes were striking in all 7 patients. Robb et al. (1989) observed 3 sibships with more than 1 affected sib: 3 affected sisters, 2 affected brothers, and 2 affected sisters. Pashayan et al. (1982) found reports of 27 sporadic cases with a male-to-female ratio of 1:1. Paternal age was not remarkable in the patients of Williams and Frias (1982). Willems et al. (1987) reported what they believed to be the fourth family with affected sibs out of a total of 52 cases in the literature. The findings suggested a low but not negligible recurrence risk. Clayton-Smith et al. (1992) studied 11 AS patients and their parents from 5 families using high resolution chromosome analysis and molecular probes from the region 15q11-q13. No deletions were detected. All sets of sibs inherited the same maternal chromosome 15, whereas in 3 families sibs inherited a different paternal chromosome 15. Polymorphic DNA markers gave the same conclusion. The findings indicated that autosomal recessive inheritance is very unlikely and suggested maternal transmission of a mutation within 15q11-q13.

Genotype-Phenotype Correlations In general, all of the AS genetic mechanisms lead to a somewhat uniform clinical picture of severe-to-profound mental retardation, movement disorder, characteristic behaviors, and severe limitations in speech and language. Despite great variability within each group, some clinical differences correlate with genotype [Bottani et al 1994 , Fridman et al 2000 , Lossie et al 2001 , Smith
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et al 1997 , Varela et al 2004]. These correlations are broadly summarized below: • The 4- to 6-Mb deletion class results in the most severe phenotype with microcephaly, seizures, motor difficulties (e.g., ataxia, muscular hypotonia, feeding difficulties) and language impairment. There is some suggestion that individuals with larger deletions (e.g., BP1-BP3 breakpoints compared to those with BP2-BP3 deletions) may have more impaired ability to speak single words. • Individuals with UPD have better physical growth (e.g., less likelihood of microcephaly), fewer movement abnormalities, less ataxia, and a lower prevalence (but not absence) of seizures [Lossie et al 2001]. • Individuals with ID and UPD have relatively higher developmental and language ability. Individuals who are mosaic for the non-deletion imprinting defect (about 20% of the ID group) have the most advanced speech abilities [Nazlican et al 2004]; they may speak up to 50-60 words and use simple sentences. • Individuals with chromosome deletions encompassing the P gene frequently have hypopigmented irides, skin, and hair. The P gene encodes a protein important in tyrosine metabolism that is associated with the development of pigment in the skin, hair, and irides. Penetrance Inherited UBE3A and ID deletions follow an imprinting (or inheritance) pattern in which the paternally transmitted mutation is asymptomatic. Nomenclature Prior to the 1980s, AS was called the "happy puppet syndrome," based in large part on the original paper published by Dr. Harry Angelman who made note of a puppet-like gait and laughter present in his three patients. Prevalence

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The prevalence of Angelman syndrome is one in 12,000-20,000 population [Clayton-Smith & Pembrey 1992 , Steffenburg et al 1996]. Differential Diagnosis The disorders most commonly considered in the differential diagnosis of Angelman syndrome are cerebral palsy of undetermined etiology, Rett syndrome (in infant girls) and idiopathic static encephalopathy [Williams et al 2001]. • Hypotonia and seizures in the child with AS may raise the possibility of an inborn error of metabolism or a defect in oxidative phosphorylation, such as a mitochondrial encephalomyopathy . • Sometimes infants with AS with feeding difficulties, hypotonia, and developmental delay have been misdiagnosed as having Prader-Willi syndrome (PWS) because of the presence of a 15q11.2-q13 deletion detected by FISH analysis. FISH analysis typically does not determine the origin of the deletion (i.e., maternal in AS and paternal in PWS); however, parent-specific DNA methylation analysis can distinguish between AS and PWS. • Infants with AS commonly present with either nonspecific psychomotor delay and/or seizures; thus, the differential diagnosis is often broad and nonspecific, encompassing such entities as cerebral palsy, static encephalopathy, and idiopathic epilepsy. • Other rare chromosome anomalies can also mimic some of the features of AS, especially the 22q13.3 deletion syndrome [Precht et al 1998]. This condition may present with nondysmorphic facial features, absent or minimal speech, and moderate to severe developmental delay, sometimes with behavioral features in the autism spectrum. • Hypotonia and diminished muscle mass may raise the possibility of a myopathic disorder, but muscle biopsy and EMG are normal in individuals with AS. The tremulousness, jerkiness, and ballistic-like limb movements seen in
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individuals with AS distinguish AS from cerebral palsy with ataxia and abnormal speech. Infant girls with AS having seizures and severe speech impairment can resemble girls with Rett syndrome , but children with AS do not have a neuro-regressive course nor do they lose purposeful use of their hands, as do individuals with Rett syndrome. Furthermore, individuals with Rett syndrome do not have the distinctive happy affect characteristic of AS. However, Rett sydrome in older girls can escape earlier diagnosis and may resemble features of the AS, and occasionally a girl with Rett syndrome is mislabeled as having AS [Watson et al 2001]. Testing for mutations of the MCP2 gene, which causes Rett syndrome, is available. Some individuals with Mowat syndrome can present with features suggestive of AS [Zweier et al 2005]. These include happy affect, diminished speech, microcephaly, and history of constipation.

Management Evaluations Following Initial Diagnosis Evaluations at the time of diagnosis are focused on neurologic assessment and good preventive practice. • Baseline brain MRI and EEG are advised. Typically, management of seizures (or assessment of risk for seizures) is not significantly helped by repetitive EEG or MRI testing. • Musculoskeletal examination should assess the possibility of scoliosis and gait impairment (e.g., extent of foot pronation or ankle subluxation; tight Achilles tendons) and the extent of muscular hypotonia. Orthopedic referral should be made if needed. • Ophthalmology examination should evaluate for strabismus, determine the extent of ocular albinism (in deletion-positive AS), and assess visual acuity.

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• Developmental evaluation should focus on: (1) nonverbal language ability and related educational and teaching strategies and (2) physical therapy needs to enable optimal ambulation. • Infants and young children should be assessed for gastroesophageal reflux; diet should be evaluated to assure optimal nutritional status.

Partial Treatment of Manifestations
• Feeding problems in newborns may require special nipples and other strategies to deal with weak or uncoordinated sucking. • Gastroesophageal reflux can be associated with poor weight gain and emesis; the customary medical treatment (i.e., upright positioning, motility drugs) is usually effective; sometimes surgical tightening of the esophageal sphincter is required. • Many anticonvulsant medications have been used to treat seizures in individuals with AS; no one drug has proven superior. Medications used for minor motor seizures (e.g., valproic acid, clonazepam, topiramate, lamotrigine, ethosuximide) are more commonly prescribed than are ones for major motor seizures (e.g., diphenylhydantion, phenobarbital) [Nolt et al 2003]. Single medication use is preferred, but seizure breakthrough is common. A few individuals with AS have infrequent seizures and are not on anticonvulsant drugs. Some with uncontrollable seizures have benefited from a ketogenic diet. Children with AS are at risk for medication over-treatment because their movement abnormalities can be mistaken for seizures and because EEG abnormalities can persist even when seizures are controlled. • Hypermotoric behaviors are typically resistant to behavioral therapies; accommodation by the family and provision of a safe environment are important.
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• Most children with AS do not receive drug therapy for hyperactivity, although some may benefit from the use of stimulant medications such as methylphenidate (Ritalin). Use of sedating agents such as phenothiazines is not advised because they cause negative side effects. • Behavioral modification is effective in treating undesirable behaviors that are socially disruptive or self-injurious. • A full range of educational training and enrichment programs should be available. Unstable or non-ambulatory children may benefit from physical therapy. Occupational therapy may help improve fine motor and oral-motor control. Special adaptive chairs or positioners may be required, especially for extremely ataxic children. Speech therapy is essential and should focus on nonverbal methods of communication. Augmentative communication aids such as picture cards or communication boards should be used at the earliest appropriate time. Attempts to teach signing should begin as soon as the child is sufficiently attentive. Special physical provisions in the classroom, along with teacher aides or assistants, may be needed for effective class integration. Children with AS with excessive hypermotoric behaviors need an accommodating classroom space. Individualization and flexibility in the school are important educational strategies. • Many families construct safe but confining bedrooms to accommodate disruptive nighttime wakefulness. Use of sedatives such as chloral hydrate or diphenylhydramines (Benadryl) may be helpful. Administration of 0.3 mg melatonin one hour before sleep may be helpful in some, but should not be given in the middle of the night if the child awakens. • Strabismus may require surgical correction. • Constipation often requires regular use of laxatives such as high fiber or lubricating agents.

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• Orthopedic problems, particularly subluxed or pronated ankles or tight Achilles tendons, can be corrected by orthotic bracing or surgery. • Thoraco-lumbar jackets may be needed for scoliosis, and individuals with severe curvature may benefit from surgical rod stabilization. • Most individuals with AS significantly benefit from speech, physical and occupational therapy, in combination with educational and behavioral interventions. Prevention of Secondary Complications Older adults tend to become less mobile and less active; attention to activity schedules may be helpful and may help reduce extent of scoliosis and obesity. Surveillance • Vigilant observation for the onset of scoliosis is advised. • Older children should be evaluated for the development of obesity associated with an excessive appetite. Agents/Circumstances to Avoid Vigabatrin and tigabine (anticonvulsants that increase brain GABA levels) should not be used to treat seizures. Therapies Under Investigation Clinical trials involving the use of high-dose, orally administered folate and betaine are ongoing. The therapeutic rationale is to augment DNA methylation pathways and possibly increase UBE3A expression of the paternal allele in the CNS. No published results are available yet. Other Excessive tongue protrusion causes drooling; available surgical or medication treatments (e.g., surgical reimplants of the salivary ducts or use of local scopolamine patches) are generally not effective. Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources.
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Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include diseasespecific and/or umbrella support organizations. Mode of Inheritance AS can be caused by: (1) deletion of the AS/PWS region on the copy of chromosome 15 inherited from the mother; (2) paternal uniparental disomy (UPD) in which the father contributes two copies of chromosome 15; (3) an imprinting defect (ID); (4) a mutation in the UBE3A gene; or (5) unidentified mechanism(s). Risk to Family Members Parents of a proband • The parents of a proband are unaffected. • Recommendations for genetic testing of the parents depends upon the cause of AS in the proband. Sibs of a proband. The risk to the sibs of an individual with AS depends on the genetic mechanism of AS in the proband and is summarized in Table 2 . Table 2. Risks to Sibs of a Proband with AS by Genetic Mechanism Molecu Famili lar Genetic Mechanism Risk to Sibs 1 es Class 65%Ia 4- to 6-Mb deletion <1% 75% Unbalanced chromosome Ib <1% translocation or Possibly as high as 50% inherited small interstitial deletion IIa 3-7% Paternal UPD <1% Approaching 100% if Paternal UPD with father has a 15;15 IIb <1% Robertsonian translocati Robertsonian translocati on on
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IIIa

0.5%

Imprinting defect with deletion of imprinting center Imprinting defect without deletion of imprinting center UBE3A mutation "Other" — no identifiable molecular abnormality

As high as 50% if mother also has imprinting center deletion Probably <1% As high as 50% if mother also has a mutation Most cases are not familial, but risk could be as high as 50%

IIIb

2.5%

IV

11% 10%15%

V

1. Based on terminology by Jiang et al 1999 Ia. Mothers of individuals with deletions should have chromosomal and FISH analyses to determine if the mother has a balanced subtle chromosomal rearrangement [Burke et al 1996]. In addition, in spite of the reduced fertility in the Prader-Willi syndrome, a woman with PWS (caused by a paternally derived 15q11.2-q13 deletion) gave birth to an infant with classic AS. This occurrence illustrates the imprinted aspect of the chromosome 15q11.2-q13 region [Schulze et al 2001]. • For probands with a de novo large deletion, the risk to sibs is less than 1% [Connerton-Moyer et al 1997]. Germline mosaicism for these large deletions has been reported on one occasion [Kokkonen & Leisti 2000]. Ib. If a chromosome rearrangement has been identified in a proband, the risks to sibs and other family members depends on whether the rearrangement is inherited or de novo [Horsthemke et al 1996 , Stalker & Williams 1998]. Smaller interstitial deletions that cause AS when inherited maternally and result in a normal phenotype when inherited paternally are rare, but significantly change the recurrence risk for sibs [Saitoh et al 1992].
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IIa. In families in which AS is the result of paternal UPD and in which no Robertsonian chromosomal translocation is identified in the proband, the risk to sibs of having AS is less than 1%. This risk figure is based upon the lack of recurrence among all known cases of UPD in AS with normal chromosomes, the experience with UPD in other disorders, and theoretical consideration regarding the mechanism of UPD. The recurrence risk is not zero, however, as recurrent meiotic nondisjunction of maternal chromosome 15 has been observed [Harpey et al 1998]. In addition, if an individual has AS as a result of paternal UPD and has a normal karyotype, a chromosomal analysis of the mother should be offered in order to exclude the rare possibility that a Robertsonian translocation or marker chromosome was a predisposing factor (e.g., via generation of maternal gamete that was nullisomic for chromosome 15, with subsequent post-zygotic "correction" to paternal disomy). IIb. Individuals with UPD should have chromosomal analysis to ensure that they do not have a paternally inherited Robertsonian translocation that would increase the family's recurrence risk. IIIa. Individuals with an IC deletion can have a phenotypically normal mother who also has an IC deletion. In these situations, the mother has either acquired her defect by a spontaneous mutation on her paternally derived chromosome 15 or inherited the IC deletion from her father, consistent with the imprinting mechanisms governing the 15q11.2-q13 region [Buiting et al 2001]. Additionally, some of these mothers may have germline mosaicism for the IC deletion [Saitoh et al 1996]; this complicates genetic counseling when the mother of a proband with an IC deletion has normal peripheral blood IC genetic studies. If a proband's mother has a known IC deletion, the risk to the sibs is 50%. IIIb. All imprinting defects without an IC deletion have been in individuals with no known family history of AS and thus probably represent a de novo defect in the imprinting process in 15q11.2Page 48

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q13 during the mother's oogenesis [Buiting et al 1998]. Therefore, the risk to the sibs of a proband in such families is less than 1%. IV. UBE3A mutations can be inherited or de novo [Kishino et al 1997 , Matsuura et al 1997 , Lossie et al 2001 , Burger et al 2002]. In addition, several cases of mosaicism for a UBE3A mutation have been noted [Malzac et al 1998]. If a proband's mother has a UBE3A mutation, the risk to the sibs is 50%. V. The majority of cases in this molecular class have not been familial, but some families with more than one affected sibling have been reported. Offspring of a proband. To date, only one individual with AS has been reported to have reproduced [Lossie & Driscoll 1999]. The risk to offspring should be determined in the context of formal genetic counseling. Other family members. If a UBE3A mutation, IC deletion, or structural chromosomal rearrangement has been identified in the mother (or father in the case of UPD and Robertsonian translocations) of a proband, the sibs of the carrier parent should be offered genetic counseling and the option of genetic testing. • IC deletions or UBE3 mutations. If a proband's mother carries a known IC deletion or UBE3A mutation, the mother's sisters are also at risk of carrying the IC deletion or the mutation. Each child of the unaffected sisters who are carriers is at a 50% risk of having AS. Unaffected maternal uncles of the proband who are carriers are not at risk of having affected children, but are at risk of having affected grandchildren through their unaffected daughters who have inherited the IC deletion or UBE3A mutation from them. Related Genetic Counseling Issues Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future,
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consideration should be given to banking DNA particularly for probands in whom the underlying mechanism is unidentified. Prenatal Testing High risk. Prenatal detection of all the known molecular genetic alterations (i.e., molecular classes Ia, Ib, IIa, IIb, IIIa, IIIb, IV) in the 15q11.2-q13 region that give rise to AS is possible through DNA and/or chromosomal/FISH analysis of fetal cells obtained by chorionic villus sampling (CVS) at about 10-12 weeks' gestation or amniocentesis usually performed at about 15-18 weeks' gestation [Kubota et al 1996 , Glenn et al 2000]. Prenatal testing should be undertaken only after the genetic mechanism in the index case has been established and the couple has been counseled regarding the risk to their unborn child, as the risks and the type of molecular genetic testing used vary according to the type of molecular defect in the proband. Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. • Parents with normal chromosomes who have had one child with AS caused by either deletion or uniparental disomy have a low recurrence risk but may be offered prenatal testing for reassurance. • Parents who have had one child with AS caused by a UBE3A mutation should be offered prenatal testing even if the mother has tested negative for the UBE3A mutation because she may still be mosaic for a UBE3A mutation. • Prenatal testing for an inherited translocation involving chromosome 15 is relevant because of the increased recurrence risk. FISH and parent-of-origin (DNA methylation and/or polymorphism) studies should be considered if an inherited translocation involving chromosome 15 is present. Low risk. For low-risk pregnancies in which no family history of AS exists, AS needs to be considered in the following instances: • If a 15q11.2-q13 deletion is suspected on cytogenetic studies from CVS or amniocentesis, FISH is indicated to confirm the deletion. If the deletion is confirmed, parent-ofPage 50

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origin studies [Kubota et al 1996 , Glenn et al 2000] can be performed to determine if the deletion is maternally derived (fetus has AS) or paternally derived (fetus has PWS). • If trisomy 15 or mosaic trisomy 15 is detected on CVS, and if subsequent amniocentesis reveals 46 chromosomes, the possibility of trisomy rescue leading to AS (paternal UPD) or PWS (maternal UPD) through the loss of a parental chromosome 15 must be considered. In this instance, parent-of-origin (DNA) studies on amniocytes can be performed. • If a de novo translocation involving chromosome 15 or a dicentric chromosome 15 marker is detected, FISH and parent-of-origin studies should be considered to evaluate for a possible deletion or UPD. Preimplantation genetic diagnosis (PGD). Preimplantation genetic diagnosis may be available for families in which the underlying mechanism has been identified in the proband.

SUMMARY
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Prader Willi and Angelman syndromes are both untreatable genetic disorders that affect a lot of individuals. Further research and scientific knowledge is required in order to introduce experimental or partial treatments. However, even though the facts that we get from everyday clinical testing about these syndromes are getting continuously discouraging,some research parties devote their time in order to learn more about these syndromes.

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