Chapter 32, A 15q11–q13 Duplication Mouse Model of Autism Spectrum Disorders

It is unknown why the group with type I deletions showed age-related mellowing, but a reasonable explanation involves those genes that are deleted in type I individuals but present in others with PWS. Of these, CYFIP1 is of particular interest, as it has been linked to other 15q11—q13 disorders and to an unusual variant of fragile X syndrome. Using a different cohort, Nowicki et al. These atypical cases had fragile X mutations, along with obesity, hyperphagia, compulsivity, symptoms of ASD, and other sporadic PWS features.

Additional studies are needed on the role that CYFIP1 and other non-imprinted genes play in the expression and trajectory of compulsivity and other behaviors in PWS. Self-injurious behaviors Self-injurious behaviors SIBs are often studied alongside repetitive behaviors and stereotypies. Skin picking may lessen with age, is not related to IQ, and is slightly less common in those with mUPD.

Neither behavioral nor pharmacological treatments have succeeded in consistently reducing skin picking in PWS. Relating repetitive behaviors and SIBs in children with autism to their levels of whole blood serotonin, Kolevzon et al. The specificity of serotonin to SIBs is interesting, as previous studies have not generally found associations between plasma serotonin and behavioral functioning in autism see Veenstra-VanderWeele et al. Focusing on adults, Cohen et al. Given the preponderance of males with autism, females are less likely to be studied, and apparent gender differences in SIBs underscore the need for more research with females on the autism spectrum.

In brief, PWS and ASD involve both similarities and differences in their profiles of characteristic repetitive and self-injurious behaviors. Even against a shared backdrop of insistence on sameness, repetitive questioning, and narrow interests, PWS is distinguished by hoarding and skin picking, and autism by stereotypies and more diverse and severe SIBs. Further research is needed on the underlying neurobiology of these behaviors in both PWS and autism, and on behavioral or pharmacological treatments that address these salient problems. Although many persons with PWS have problems getting along with others, data are scant on social impairment, which is unfortunate given the central role that social dysfunction plays in autism.

They also have the same numbers of friends but they see these friends less often, are less competent with them, and experience more social problems in general Dykens and Kasari ; Rosner et al. Further, socially competent behaviors in PWS do not seem to increase with age and the lack of age-related gains in these competencies contrast with age-related gains in both Williams and Down syndromes Rosner et al. While these data depict social problems, they do not address specific impairments that constitute the hallmark of autism in face processing, social cognition, or communication.

Aberrant face processing has been identified in people with ASD using eye tracking, event-related potentials ERPs , and functional neuroimaging. Studies are now underway using eye tracking in PWS. In ERP work, the N is often used as an electrophysiological marker for the encoding of upright faces and children with autism appear to have a dampening of the N in response when viewing faces Grice et al. A preliminary study in PWS found a similar dampening effect in eight individuals with paternal deletions Halit et al.

The eight participants with mUPD showed a more typical N response to faces, but their eye gaze processing was similar to adults with autism. Data suggest unusual perceptual processing of faces in both genetic subtypes of PWS. At least neuroimaging studies have examined aspects of face or emotional processing in people with autism or those at risk for ASD, including siblings.

The five fMRI studies published to date in PWS have all examined various aspects of food processing, reward circuits, and satiety. Findings show marked delays in satiety and aberrant post-meal activation of circuits involved in hunger see Dimitropoulos and Schultz Beyond face processing, data are also scant on other aspects of social cognition in PWS. Tager-Flusberg and Sullivan found that children with PWS fared as well if not better than children with Williams syndrome or other disabilities in theory of mind tasks tapping false beliefs, social actions, and emotional recognition.

Difficulties in PWS may arise, however, when tasks require an appreciation for more complex or abstract mental states. Using a social attribution task involving ambiguous stimuli moving shapes in a video , Koenig et al. Participants with PWS made simple cognitive attributions about the moving shapes but were less able to make inferences about affective states related to the scenario e.

They thus failed to attend to pertinent details and produce a coherent social story. Additional research is clearly needed on social functioning in PWS, especially work that uses similar neural and behavioral methodologies as the autism literature. The lack of detailed data on social or communicative functioning in PWS limits its usefulness as a genetic model for autism, and, on a practical level, it muddies the intervention waters considerably. Infants with PWS or ASD demonstrate developmental delays, as well as gradual changes over time in temperament, emotional regulation, and difficulties in shifting attention from food or other perseverative interests.

A rich literature exists on young children suspected of having autism or who are at high risk for ASD given their sibling and familial status. This body of research has identified the sensitivity and specificity of several autism screening tools for young children, standards for best practices in making autism diagnoses in young children, the nuances of social, cognitive, and motor developments and the efficacy of different models of early intervention see Zwaigenbaum for a review. In contrast, infants with PWS have not been studied through the same careful developmental lens, and major gaps in knowledge exist on early social and communicative functioning and indices of autism in these children.

Infants with PWS are hypotonic, lethargic, have difficulty sucking, and often need to be awakened for feedings; one feeding can literally take hours. Children and adults with PWS also have well-documented growth hormone deficiency and growth hormone treatment is now an Food and Drug Administration-approved best practice in the management of infants and children see Miller et al. The benefits of growth hormone therapy GHT are well-established and include reduced body fat and increased lean muscle mass, linear growth, agility, muscle strength, coordination, and exercise tolerance; a softening of the classic PWS facial features and in toddlers, earlier ages of walking independently Carrel et al.

Anecdotally, parents report that their children on GHT are more alert, energetic, attentive, and cooperative Carrel et al. It is unclear if such gains in infants or toddlers are sustained over the course of development. In brief, recent studies on infants with PWS have primarily evaluated the effects of GHT, and in years past, described their failure to thrive, metabolic rates, body fat, and delayed motor and language milestones.

Unlike infants with ASDs, studies have not identified trajectories of social or communicative development in infants with PWS. Clinical lore suggests that infants with PWS are pleasant, cooperative, and friendly Cassidy et al. After this period of apparent social responsiveness, they develop notable behavior problems, including temper tantrums, stubbornness, skin picking, and eventually food seeking Dimitropoulos et al.

No data have been published that specify early social and communicative deficits in children with PWS in eye gaze, shared positive affect, and social gestures such as pointing, joint attention and orientation to name. Prospective studies are needed that examine these key indices of social—communicative functioning, including factors that discriminate infants with PWS from those who are later diagnosed with ASD. Salient associated features in autism or PWS include co-occurring psychiatric disorders, concerns with food and obesity, difficulties with sleep, and apparent strengths in visual—spatial functioning.

Although not exhaustive, these features are relatively well-studied within each disorder and suggest several intriguing avenues for future research that directly compares groups with PWS versus ASD. Psychiatric studies in PWS have relied solely on diagnostic labels, leaving specific psychiatric symptoms unclear or poorly described. Examining PWS cases that screened positive for psychopathology, Soni et al. Further, they note that more severe psychiatric presentations, including bipolar illness and psychosis with or without depression, were only seen in those with mUPD.

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In contrast, Descheemaeker et al. Unlike those with deletions, our mUPD sample also manifested significant, age-related increases in thought problems, noncompliant behavior, obsessions, and hoarding. These findings are consistent with previous reports of age-related increases in psychopathologies in this genetic subtype.

Explanations for high rates of psychosis in mUPD generally implicate increased expression of maternally imprinted genes, especially UBE3A. While other DMRs in the 15q11—q13 region showed complete maternal or paternal methylation, this GABRG3 region was only partially methylated, suggesting that imprinting at this site is weakly regulated Sharp et al.

Relatively weaker parent of origin expression may help explain previous conflicting reports about methylation at the GABRG3 site. If the majority of people with mUPD develop psychosis or severe affective illness by late adolescence or early adulthood Boer et al. However, the specific symptoms associated with psychosis in PWS have yet to be well-described, leaving it unknown if these episodes are characterized by visual or auditory hallucinations, cognitive distortions, magical thinking, paranoia, severe or unusual obsessions, or by withdrawal, irritability, oppositionality, and changes in sleep, appetite, or activity levels.

Using a retrospective record review of adults with mUPD and psychosis, Vogels et al. This finding is puzzling, as data on secondary psychiatric conditions in people with ASD consistently find increased rates of depression and anxiety disorders, but substantially less overlap with psychosis or schizophrenia Joshi et al. Based on a psychopharmacology clinic sample of children and adolescents, Joshi et al. If psychosis is indeed rare in autism, then comorbidities of both autism and psychosis in PWS is quite discrepant with the general ASD population. It is not clear how to best reconcile research indicating high rates of both autism and psychosis in PWS.

In this view, autism diagnoses are an unsuccessful or superficial effort to capture premorbid personality or social dysfunction or what is essentially a prodromal state on the road to psychosis. Still others hypothesize that autism and psychosis are diametric disorders in their clinical phenotypes, and genetic and neural underpinnings Crespi and Badcock Crespi used disruptions in maternal imprinting and proneness to autism in AS versus disrupted paternal imprinting and proneness to psychosis in PWS to support the conflict theory of imprinting in evolutionary biology.

However, none of these possible explanations can be properly evaluated without detailed data on aberrant social, cognitive, or emotional processes in PWS. Categorical diagnoses of autism or psychosis are inadequate, and more fine-tuned and nuanced phenotypic descriptions in PWS are needed in order to address these hypotheses. An unclear symptom picture in PWS also severely limits treatment.

If the majority of persons with mUPD develop psychosis, then treatment can also move to a prevention mode, perhaps minimizing disease course via pharmacotherapy, behavioral, or other interventions. Preventative measures, however, first require identification of the symptoms being targeted and when they emerge or worsen. Although hyperphagia in PWS stands out, the drive for food in affected individuals is actually quite nuanced.

Full-blown hyperphagia varies in length and also waxes and wanes in severity Dykens et al. People with PWS rarely vomit or report gastrointestinal GI distress, yet these relatively benign complaints in most people can signal a life-threatening emergency in PWS related to acute gastric dilation, perforation, necrosis, and death Stevenson et al. Higher risks of gastric dilation and rupture are seen in individuals with rapid weight loss or who are generally slim but have a binge-eating episode. Relative to the general population, children and adolescents with ASD are more likely to be obese or overweight.

Risk factors for obesity in ASD are similar to those seen in other disability groups, including a sedentary lifestyle, lack of regular activities or exercise, not being able to readily access gyms or recreational sports, limited knowledge about nutrition or healthy food choices, and appetite-altering side effects of psychotropic medications. Although obesity is increasingly identified in ASD, few evidence-based, weight-reduction programs exist that take into account the unique aspects of ASD. Complications of obesity are the leading causes of premature death in adults with PWS e.

In the general population, being overweight or obese is often associated with low self-esteem, and losing weight and being fit and trim with improved esteem e. People with PWS, however, seem to show the opposite pattern. Specifically, adolescents and adults with lower body mass indices have increased compulsive behaviors, hoarding, and withdrawal, and are also more nervous, tense, tearful, distressed, upset, agitated, and cognitively disorganized Dykens ; Hartley et al. Although reasons for these counterintuitive finding are unknown, they may be associated with the effort, and physiological and psychological stress, of maintaining a lower weight.

Due to their hypotonia and low-resting metabolic rate, persons with PWS typically require fewer calories than others to lose or maintain weight. Future studies using biomarkers of stress could shed some light on these hypotheses and inform decisions about balancing dietary restrictions with quality of life in persons with PWS and their families.

Sleep disturbances occur in the majority of children with autism, especially sleep-onset insomnia, nocturnal awakening, and shorter overall nighttime sleep duration Goldman et al. Examining sleep in a large cohort of children with ASD, Goldman et al. Further, actigraphic measures of wakefulness after sleep onset and sleep fragmentation were correlated with hyperactivity and restrictive and repetitive behaviors.

Aberrant sleep in PWS is well-described, including high rates of central and obstructive sleep apnea, abnormal arousal, abnormal circadian rhythm in rapid eye movement REM sleep, night awakenings, and excessive daytime sleepiness Maas et al. Obesity may worsen some of these sleep parameters, yet does not completely explain abnormal REM or excessive daytime sleepiness, which are likely related to hypothalamic dysfunction Bruni et al. Indeed, excessive daytime sleepiness can be quite impairing for individuals, regardless of their weight.

Although disrupted sleep is associated with behavior problems in people with autism and intellectual disabilities in general see Richdale and Schreck for a review , such relations are not readily apparent in PWS e. Beyond behavior problems, compelling evidence from both clinical and typical populations link sleep duration and quality to specific aspects of memory and cognition see Durmer and Dinges for a review.

Even so, researchers have yet to examine relations between sleep and cognition in PWS, autism, or other disability groups. Persons with PWS are prone to obstructive sleep apnea e. Relative to their verbal skills, persons with autism appear to have strengths in visual—spatial processing.

Earlier work found that people with ASD performed relatively well on standardized tasks assessing visual—spatial and pattern recognition, including block design, object assembly, or the imbedded figures test. More recent studies have fine-tuned these observations, pointing, for example, to intact or enhanced performance on static visual features or patterns, and inferior performance on more complex and dynamic spatial memory tasks Bertone et al.

Persons with PWS have a similar profile. Early studies indicated relative strengths in visual—spatial functioning on standardized IQ tasks e. Compared to others with intellectual disabilities, those with PWS spend more time engaged with puzzles Dykens and Rosner , and they also far outperform both IQ- and age-matched controls on jigsaw puzzles Dykens Interestingly, they have only modest relative strengths in standardized visual spatial tasks. Although the PWS group performed relatively poorly on the spatial tasks, they performed very well on interlocking jigsaw puzzles, including achromatic puzzles.

The typical control group used a visual approach to puzzle solving, while those with PWS had a pronounced, shape-based approach.

PWS and autism: genetic links and prevalence

Persons with autism are also rumored to excel at jigsaw puzzles, and a competency with puzzles is one of several specialized interests tapped in the ADI-R. Even so, researchers have yet to formally assess puzzle skills in this population and how they relate to broader visual—spatial functioning. Although far from exhaustive, this review highlights phenotypic similarities and differences across PWS and ASD, as well as salient knowledge gaps that need to be addressed in future research.

Future comparative studies are needed that take several methodological considerations into account. Consistent with best practices, then, researchers need to carefully review ADOS scores along with other behavioral, developmental, and medical data in making autism diagnoses in PWS and other genetic disorders. A second issue pertains to comparison groups. Depending on the questions under study, various combinations of groups could be compared including individuals with PWS who do versus do not have autism diagnoses and who are appropriately matched to individuals with autism spectrum disorders or other intellectual disabilities.

While these groups help distinguish features seen in PWS versus autism, a more nuanced approach uses comparison groups that selectively target the constructs under study. Social—cognitive deficits could be compared across individuals with PWS, autism, schizophrenia, and atypical psychosis including the neurobiological underpinnings of these impairments see Sasson et al.

Finally, gaps in knowledge need to be filled in with an eye toward clinical relevance. These behavioral and neural discoveries are needed to make more informed and immediate decisions about intervention. For example, should pharmacotherapy or other treatments begin as soon as adolescents with PWS show even a slight worsening or subtle onset of problems in thinking or mood? What other risk or protective factors derived from the autism, schizophrenia, or intellectual disabilities literature could inform treatment in PWS? Conversely, how does PWS inform genetic and other risks for autism or psychosis in the general population?

Although PWS has not been as rigorously studied as other genetic conditions associated with autism or psychosis, it holds considerable promise for shedding new light on mechanisms and treatments for these otherwise debilitating disorders. The authors are grateful to the families and individuals with Prader—Willi syndrome who have participated in our work. National Center for Biotechnology Information , U. Journal List J Neurodev Disord v. Published online Aug Dykens , Evon Lee , and Elizabeth Roof. Author information Article notes Copyright and License information Disclaimer.

Received Mar 7; Accepted Jul This article has been cited by other articles in PMC. Prader—Willi syndrome, Chromosome 15q11—q13, Autism, Psychosis. BN, a 7-year-old boy with PWS associated with mUPD, lives at home with his parents, three siblings, and attends a regular elementary school.

His body mass index is in the average range. During his research visit, BN was extremely active and asked incessant questions about staff and the assessment procedures. BN sniffed several test items and tended to ask the same question again and again, or to repeat odd phrases, e. BN had to be redirected to complete many tasks and seemed to be easily distracted and overstimulated.

He was somewhat concrete but oriented to place, person, and time. Based on his ASD diagnosis, BN was assigned a classroom aide and, with this support, is now doing considerably better at school. Open in a separate window. Do infants with PWS show the same warning signs of autism that are reliably established in young children with idiopathic autism? What are the specific social, communicative, and behavioral impairments in PWS that lead to suspicions of autism in the first place?

How do autism findings relate to the high rates of psychosis, mood disorders, and severe psychiatric illness in those with mUPD? Features of autism in PWS Studies on psychopathology in PWS primarily report psychiatric diagnoses, yet these diagnoses are often problematic. Repetitive and restrictive behaviors Types of compulsive behaviors Repetitive and restrictive behaviors include highly frequent, inappropriate, and invariant behaviors that are often seen in people with a variety of intellectual and developmental disabilities.

Table 2 Frequency of repetitive, compulsive-like behaviors in individuals with Prader—Will syndrome. Social and communicative impairment Although many persons with PWS have problems getting along with others, data are scant on social impairment, which is unfortunate given the central role that social dysfunction plays in autism. Infants and young children with PWS Infants with PWS or ASD demonstrate developmental delays, as well as gradual changes over time in temperament, emotional regulation, and difficulties in shifting attention from food or other perseverative interests.

Table 3 Characteristics of infants and young children with PWS or autism spectrum disorders. Associated features of autism or PWS Salient associated features in autism or PWS include co-occurring psychiatric disorders, concerns with food and obesity, difficulties with sleep, and apparent strengths in visual—spatial functioning. Psychiatric disorders Psychiatric studies in PWS have relied solely on diagnostic labels, leaving specific psychiatric symptoms unclear or poorly described.

His parents were diligent with his diet and locking food. At age 14 JJ experienced auditory and visual hallucinations, including an episode when his parents found him sitting naked on a couch outside their bedroom door, seeing and talking to make believe cartoon characters. He was subsequently placed on anti-psychotic medications but continued to have looseness of thoughts and magical thinking. His parents were quite concerned that his escalating and bizarre behavior would not allow him to continue in the vocational day program and they feared that they would need to quit working in order to take care of him.

The research team referred JJ to a PWS residential program for evaluation and possible placement as his escalating behaviors and thought disturbances required a more intensive treatment approach. Food and obesity Although hyperphagia in PWS stands out, the drive for food in affected individuals is actually quite nuanced. Sleep Sleep disturbances occur in the majority of children with autism, especially sleep-onset insomnia, nocturnal awakening, and shorter overall nighttime sleep duration Goldman et al. Visual—spatial strengths Relative to their verbal skills, persons with autism appear to have strengths in visual—spatial processing.

Next steps for research Although far from exhaustive, this review highlights phenotypic similarities and differences across PWS and ASD, as well as salient knowledge gaps that need to be addressed in future research. Acknowledgments The authors are grateful to the families and individuals with Prader—Willi syndrome who have participated in our work. Food selectivity in children with autism spectrum disorders and typically developing children.

Enhanced and diminished visuo-spatial information processing in autism depends on stimulus complexity. Etiological heterogeneity in autism spectrum disorders: Duplications in the 15q11q13 region, which is prone to genomic rearrangement due to the presence of repeated DNA elements, are most often detected through array CGH 77 , which has become a standard screening tool when evaluating children with hypotonia, autism or developmental delay.

Prior to the widespread use of this technology, standard high resolution karyotype along with FISH analysis identified cases of inverted duplication 15 idic 15 syndrome, visible as a marker chromosome Cases of idic 15 may still be identified in this manner, though interstitial duplications, would typically not be detectable by chromosomal analysis. Array CGH also allows for the precise delineation of break points and size of the duplicated material.

Identification of an interstitial duplication or idic 15 should be followed by a test to clarify parent of origin, which impacts phenotype This could be done either by methylation analysis of the proband sample, or targeted array of parental samples. Several studies have confirmed that phenotype is more severe for those children with idic 15 than interstitial duplications 78 , In addition, maternally inherited interstitial duplications appear to be more consistently expressed than paternally inherited ones, and are associated with significantly higher risk of autism spectrum disorder The impact of paternally inherited duplications remains unclear, though some pathogenicity is clear.

Hypotonia, particularly impacting oro-facial musculature can lead to feeding difficulties in infancy, more often in idic 15 children, and may require special attention to feeding and growth. Delay in acquisition of motor milestones is also most pronounced in those with idic 15 than interstitial duplications, and early intervention with physical therapy may be beneficial. Given the high risk of autism with idic 15 and maternally inherited duplication, evaluation by a Developmental Pediatrician is recommended. This should be considered for paternally inherited duplications as well, particularly if concerns about behavior and social relatedness exist.

Children with Dup15q syndrome will also benefit from early intervention with speech and educational therapies. Risk for infantile spasms is high in idic 15 and parents should be advised to watch for early signs of this seizure type, as early treatment is beneficial. Screening EEG may be warranted. Seizures often evolve into Lennox Gastaut and appear to respond to medications typically beneficial for those with generalized epilepsy including valproic acid, rufinamide, lamotrigine and zonisamide, though formal studies remain limited.

Prader-Willi, Angelman, and 15qq13 duplication syndromes

Carbamazepine was also reported to be effective in many, suggesting epilepsy may be multifocal as opposed to primary generalized. Children with idic 15 do not respond well to benzodiazepines and seizure exacerbation was also reported in almost half of those treated with Leviteracetam There is little information available regarding the efficacy of the ketogenic diet or vagal nerve stimulator in this population.

Unfortunately, epilepsy risk appears persistent in idic 15 with seizures continuing into adulthood in two thirds Behavioral difficulties with defiant and aggressive behaviors, particularly in idic 15 patients, can be challenging and may require medical management In addition, sleep difficulties may be noted, possibly secondary to epileptic discharges, thus overnight EEG and sleep study may be helpful in directing management. Current work toward future therapies may focus on reducing UBE3A expression levels or activity in Dup15q patients 81 , although no specific therapies have been reported.

Idic 15 is associated with a low recurrence risk. The chromosome 15q region contains several genes that are regulated by genomic imprinting and impact neurodevelopment. Despite being caused by variation of the same genetic region, Prader-Willi, Angelman, and Dup15q syndromes are distinct disorders with different phenotypic manifestations and diagnostic strategies. Since imprinted genes are involved in these disorders, potential therapies may involve modulating expression of the implicated genes and provide optimism for improved outcomes in the future.

The authors have nothing to disclose. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. National Center for Biotechnology Information , U. Pediatr Clin North Am.

Author manuscript; available in PMC Jun 1. Louisa Kalsner and Stormy J. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at Pediatr Clin North Am. See other articles in PMC that cite the published article. Abstract Three distinct neurodevelopmental disorders arise primarily from deletions or duplications that occur at the 15qq13 locus: Introduction Chromosome 15qq13 is a region that harbors several genes regulated by genomic imprinting, a phenomenon in which genes are expressed preferentially from one parental allele.

Open in a separate window. Map of 15qq13 region Individual genes are depicted as boxes with their respective names above them. Table 1 Features of Prader-Willi syndrome. Hypotonia Hypotonia becomes evident during pregnancy as decreased fetal movement and atypical presentation at delivery.

Hypogonadism Hypogonadism is often evident at birth as gonadal hypoplasia in both males and females. Growth deficits Growth deficits associated with PWS likely begin in utero. Hyperphagia and obesity Individuals with PWS pass through a series of seven nutritional phases relating to appetite and weight gain Other features Facial features associated with PWS include almond shaped eyes; narrow, but prominent nasal bridge; high, narrow forehead; thin upper lip; and downturned mouth. Recent advances in genetics and pathomechanism of diseases Prader-Willi syndrome is caused by the loss of paternally-inherited chromosome 15q Diagnostic strategy for Prader-Willi syndrome Blue boxes indicate the diagnostic test, pink boxes indicate the diagnosic decision.

Search for a deletion. If done with simultaneous chromosomal analysis, rare cases caused by translocation or inversion will be identified. Increasingly, CMA chromosomal microarray analysis is sent instead of FISH, and allows for accurate measurement of deletion size in addition to providing information about other genomic changes, if present. The extent of the deletion is expected to become increasingly important as our understanding of genotype-phenotype correlations in PWS grows. CMA is more expensive than FISH, but is increasingly available, and typically is the first test done when a patient with a suspected genetic condition is evaluated, particularly if PWS was not initially considered.

In this case, methylation testing is important as a confirmatory test, as identification of a deletion does not distinguish between Prader-Willi and Angelman Syndromes, which may have considerable clinical overlap in the young child. Additionally, CMA may identify rare patients that have deletions that do not include the imprinting center. Sequencing of the imprinting center can be done in specialized laboratories. Current Management Diet and Nutrition Failure to thrive in infancy results from poor suck in the setting of hypotonia.

Behavioral and Educational Physical therapy beginning in infancy assists with motor skills development with speech therapy often warranted by 2 years of age. Other Annual assessment for scoliosis should begin in early childhood. Future Potential Therapies Several medication trials are ongoing, aimed at addressing the hyperphagia and associated symptoms of PWS. Recommendation for family counseling Family counseling is recommended. Clinical background of the disease Angelman syndrome AS is characterized by developmental delay, intellectual disability, absent speech, seizures, ataxic gait, easily excitable happy demeanor, and characteristic facies Table 2.

Table 2 Features of Angelman syndrome. Speech Language development in individuals with AS is severely impaired. Happy demeanor Individuals with AS have a characteristic happy demeanor and are easily excitable. Other features Other behavioral features associated with AS include stereotypic movements such as hand flapping , difficulty sleeping, and anxiety. Recent advances in genetics and pathomechanism of diseases AS is caused by the lack of function of maternal UBE3A 51 , If methylation testing is consistent with AS, testing should proceed as follows: Diagnostic strategy for Angelman syndrome Blue boxes indicate the diagnostic test, pink boxes indicate the diagnosic decision.

Paternal UPD is also generally associated with a low recurrence risk. If methylation testing is positive, but microdeletion and UPD testing are negative, an imprinting center defect is suspected. If an imprinting center deletion is not found, an epimutation is presumed and recurrence risk again appears low. Management of Angelman Syndrome Epilepsy Seizures are often difficult to control. Sleep Disturbance Children with AS frequently have disrupted sleep with difficulty both in falling asleep and maintaining sleep and possibly a reduced requirement for sleep 65 , Muscle tone and gait Hypotonia is frequent in young children though spasticity of limbs often develops over time.

Speech Early intervention with speech therapy is important to maximize communication, with emphasis on non-verbal methods of communication such as picture boards and devices recommended. Other Children with AS should have regular opthalmolgic assessment for management of strabismus, and hyperopia Future potential therapies Strategies to augment DNA methylation through administration of supplements such as betaine, folate, or other supplements are being investigated with the goal of increasing expression of the dormant allele, though the results of trials have been disappointing.

Clinical background of the disease Individuals with 15q Table 3 Features of Dup15q syndrome. Hypotonia Muscle hypotonia is observed in almost all individuals with Dup15q syndrome, and can be severe, prompting testing for PWS Epilepsy Seizures are a major medical issue for Dup15q syndrome. Autism A majority of individuals with Dup15q syndrome meet the diagnostic criteria for autism Other Subtle facial features that are characteristic for Dup15q syndrome can be seen in most affected individuals.

Recent advances in genetics and pathomechanism of diseases Dup15q syndrome usually occurs in one of two forms. Diagnosis Duplications in the 15q11q13 region, which is prone to genomic rearrangement due to the presence of repeated DNA elements, are most often detected through array CGH 77 , which has become a standard screening tool when evaluating children with hypotonia, autism or developmental delay. Autism Given the high risk of autism with idic 15 and maternally inherited duplication, evaluation by a Developmental Pediatrician is recommended.

Behavior and sleep Behavioral difficulties with defiant and aggressive behaviors, particularly in idic 15 patients, can be challenging and may require medical management Future potential therapies Current work toward future therapies may focus on reducing UBE3A expression levels or activity in Dup15q patients 81 , although no specific therapies have been reported. Conclusion The chromosome 15q region contains several genes that are regulated by genomic imprinting and impact neurodevelopment. Three distinct neurodevelopmental disorders are caused by copy number variation at human chromosome 15qq Prader-Willi syndrome, Angelman syndrome, and 15qq13 duplication syndrome.

An organized diagnostic strategy is required in order to confirm or full exclude the diagnosis. Prader-Willi syndrome is characterized by infantile hypotonia and failure to thrive followed by obesity, hyperphagia, small stature, and behavioral issues. Early growth hormone treatment improves body habitus and stature.

Angelman syndrome is characterized by severe intellectual disability, absent speech, epilepsy, and characteristic happy affect. It is caused by the loss of function from the maternal UBE3A gene. Duplications that lead to this syndrome are almost always of maternal origin. Footnotes The authors have nothing to disclose. Butler MG, et al. Is gestation in Prader-Willi syndrome affected by the genetic subtype? J Assist Reprod Genet. Clinical report-health supervision for children with Prader-Willi syndrome. Hypogonadism in females with Prader-Willi syndrome from infancy to adulthood: Growth standards of infants with Prader-Willi syndrome.

Endocrine dysfunction in Prader-Willi syndrome: Carrel AL, et al. Growth hormone improves mobility and body composition in infants and toddlers with Prader-Willi syndrome. 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. Whitman B, et al.

Growth hormone improves body composition and motor development in infants with Prader-Willi syndrome after six months. J Pediatr Endocrinol Metab.

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Miller JL, et al. Nutritional phases in Prader-Willi syndrome. American journal of medical genetics. Cummings DE, et al. Elevated plasma ghrelin levels in Prader Willi syndrome. Energy expenditure and physical activity in Prader-Willi syndrome: Am J Med Genet A. Goldstone AP, et al. Visceral adipose tissue and metabolic complications of obesity are reduced in Prader-Willi syndrome female adults: Whittington J, Holland A.

Neurobehavioral phenotype in Prader-Willi syndrome. Whittington J, et al. Cognitive abilities and genotype in a population-based sample of people with Prader-Willi syndrome. J Intellect Disabil Res. Maladaptive behavior differences in Prader-Willi syndrome due to paternal deletion versus maternal uniparental disomy. Am J Ment Retard. Butler JV, et al. Prevalence of, and risk factors for, physical ill-health in people with Prader-Willi syndrome: Dev Med Child Neurol. Boer H, et al. Psychotic illness in people with Prader Willi syndrome due to chromosome 15 maternal uniparental disomy.

Festen DA, et al. Sleep-related breathing disorders in prepubertal children with Prader-Willi syndrome and effects of growth hormone treatment. Sahoo T, et al.

Prader–Willi syndrome and autism spectrum disorders: an evolving story

Duker AL, et al. Paternally inherited microdeletion at 15q European journal of human genetics: Bieth E, et al. Eur J Hum Genet. Cavaille J, et al. Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization. Bazeley PS, et al. Kishore S, et al. Shen M, et al. Epub Aug Shaffer LG, et al. American College of Medical Genetics statement of diagnostic testing for uniparental disomy. Pituitary abnormalities in Prader-Willi syndrome and early onset morbid obesity.

Successful early dietary intervention avoids obesity in patients with Prader-Willi syndrome: Deal CL, et al. GrowthHormone Research Society workshop summary: Mental and motor development before and during growth hormone treatment in infants and toddlers with Prader-Willi syndrome. Clin Endocrinol Oxf ; Berini J, et al. Growth hormone therapy and respiratory disorders: Oto Y, et al. Exacerbation of BMI after cessation of growth hormone therapy in patients with Prader-Willi syndrome. Endocrine manifestations and management of Prader-Willi syndrome.

Int J Pediatr Endocrinol. Soni S, et al. The course and outcome of psychiatric illness in people with Prader-Willi syndrome: Recommendations for the diagnosis and management of Prader-Willi syndrome.

Prader-Willi, Angelman, and 15q11-q13 duplication syndromes

Einfeld SL, et al. A double-blind randomized controlled trial of oxytocin nasal spray in Prader Willi syndrome. Heymsfield SB, et al. Obesity Silver Spring ; 22 Suppl 1: Autism in Angelman syndrome: Angelman syndrome in adulthood. Am J Med Genet. Gentile JK, et al.



1. O For The Wings Of A Dove;
2. ;
3. UBE3A function & expression.
4. Sensations of Travel: New and Selected Poems 1990-2010!
5. Introduction!

A neurodevelopmental survey of Angelman syndrome with genotype-phenotype correlations. J Dev Behav Pediatr. Analysis of the characteristics of epilepsy in 37 patients with the molecular diagnosis of Angelman syndrome. Thibert RL, et al. Epilepsy in Angelman syndrome: Valente KD, et al. Epilepsy in patients with angelman syndrome caused by deletion of the chromosome 15q Phenotypic variability in Angelman syndrome: Neurological aspects of the Angelman syndrome. Matsuura T, et al. Molecular and Clinical Aspects of Angelman Syndrome.



Wang M, Pickart CM. Different HECT domain ubiquitin ligases employ distinct mechanisms of polyubiquitin chain synthesis. Lee SY, et al. Ube3a, the E3 ubiquitin ligase causing Angelman syndrome and linked to autism, regulates protein homeostasis through the proteasomal shuttle Rpn Cell Mol Life Sci. Margolis SS, et al. Jiang YH, et al. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.

Weeber EJ, et al. Epilepsy in Angelman syndrome. Neurologic manifestations of Angelman syndrome. Bruni O, et al. Sleep disturbances in Angelman syndrome: Sleep problems in individuals with Angelman syndrome. Melatonin for chronic insomnia in Angelman syndrome: Braam W, et al. Exogenous melatonin for sleep problems in individuals with intellectual disability: Ophthalmic findings in Angelman syndrome.

Huang HS, et al. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Meng L, et al. Truncation of Ube3a-ATS unsilences paternal Ube3a and ameliorates behavioral defects in the Angelman syndrome mouse model. Conant KD, et al. A survey of seizures and current treatments in 15q duplication syndrome. Urraca N, et al. The interstitial duplication 15q Smith SE, et al. Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice.

Nakatani J, et al. Abnormal behavior in a chromosome-engineered mouse model for human 15q duplication seen in autism. High-resolution molecular characterization of 15qq13 rearrangements by array comparative genomic hybridization array CGH with detection of gene dosage. Am J Hum Genet. Bolton PF, et al.