Correlates of compulsivity Correlates of repetitive, compulsive behaviors in PWS have also been identified. Gender differences, for example, are not generally found in these behaviors, although increased severity of compulsive symptoms have occasionally been reported in males Clarke et al. Level of IQ is negatively correlated with repetitive behaviors in PWS, such that those with lower IQs show more pronounced compulsivity, a finding also seen in those with intellectual disabilities in general Dykens et al.
Data are contradictory regarding the role that PWS genetic subtypes play in repetitive, compulsive-like behaviors. Aside from somewhat lower skin picking in mUPD cases Symons et al. Some groups find more cleaning and redoing compulsions and lower adaptive and academic skills in people with type I deletions Butler et al.
Inconsistent findings may be due to small sample sizes e. In the largest cohort studied to date, with 55 deletion and 33 mUPD cases, Dykens and Roof found behavioral differences across genetic subtypes only in relation to age. Age-related increases were seen in obsessional thinking and hoarding in those with mUPD, which is consistent with their vulnerabilities to psychiatric illnesses in young adulthood. In those with type II deletions, no relations were found between age and compulsive or other behaviors.
In contrast to both of these genetic subtypes, those with type I deletions showed consistent, negative associations between age and compulsivity, externalizing problems, adaptive behavior skills, and hyperphagia. In essence, although their problem behaviors appear to mellow over time, they may also show less engagement and activities in general. 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.
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. Individuals with PWS have mild to moderate intellectual disability 14 , 15 and poor academic achievement is typical and may be exacerbated by behavioral difficulties in addition to developmental and intellectual disability Features similar to obsessive compulsive disorder and skin picking are common. Some of the behaviors are consistent with autism, and indeed some individuals with PWS meet diagnostic criteria for autism.
This may be more common in individuals with maternal uniparental disomy Facial features associated with PWS include almond shaped eyes; narrow, but prominent nasal bridge; high, narrow forehead; thin upper lip; and downturned mouth. Prader-Willi syndrome is caused by the loss of paternally-inherited chromosome 15q The loss of expression from this chromosomal region typically occurs by one of three mechanisms: Notably, there are no instances of a point mutation in any gene causing PWS, suggesting that PWS is a true contiguous gene syndrome, resulting from the loss of more than one gene.
The promoter, exon 1 and intron 1 of SNRPN are unmethylated on the paternal allele and thus expressed, and methylated on the maternal, non-expressed allele. A normal individual will have both a methylated and unmethylated SNRPN allele, whereas individuals with PWS will have only the maternally methylated allele 5. Methylation analysis allows for identification of patients with PWS, but provides no information about the molecular class of the disease.
Differentiation of the molecular class of PWS allows the physician to provide more accurate prognostic information and is crucial for accurate recurrence risk counseling. Testing should proceed in the order outlined below, from most to least common cause. MPLA testing has the ability to assess methylation at 5 sites in the PWS region, as opposed to one site in the standard methylation assay. It also will detect a deletion, if present, but cannot distinguish between UPD and imprinting defects.
Failure to thrive in infancy results from poor suck in the setting of hypotonia. Special nipples or gavage feeding are often required. Close monitoring of growth parameters is required in the first year of life 2. If failure to thrive is noted, despite adequate caloric intake, testing for hypothyroidism is indicated, as this is not uncommon in infancy As weight gain begins to increase from the age of 2 onwards, careful supervision of caloric intake is necessary.
Weight gain often begins after the age of 2, though appetite increase is not typical until after age 4. It is important to monitor food intake, before the onset of obesity. Nutritional supervision to assess appropriate intake and supplementation of vitamin D, calcium and other nutrients is recommended. Locking of cupboards and refrigerator is often necessary as appetite increases. Evidence suggests that early dietary intervention with a controlled prescribed diet as early as 14 months of age may result in a normal BMI Continued monitoring of diet and weight is central to long-term health including avoidance of diabetes mellitus and other obesity related complications.
Early treatment appears beneficial with normalization of height, increase in muscle mass and decrease in fat mass. Treatment should begin between 4 months and two years of age as benefits in head circumference, gross motor and language development and cognition have been demonstrated with early treatment 32 , Due to concern about the possibility of an increase in the rate of sudden death from upper airway obstruction in the first months of treatment, a sleep study is recommended prior to initiating treatment, 6 to 12 weeks after initiation of treatment and on an annual basis thereafter Children with PWS are at increased risk of obstructive and central apnea and this risk may rise with GH treatment, possibly due to lymphoid hyperplasia.
While receiving GH treatment, close monitoring for scoliosis, hypothyroidism, diabetes and elevation of IGF-1 is suggested Treatment with GH may need to continue into adulthood, as recent studies suggest that BMI may increase significantly following cessation of GH therapy Cryptorchidism should be identified with referral to urology and treatment if noted in infancy. Treatment of hypogonadism should be considered, with human chorionic gonadotrophin hCG or testosterone, to assist with testicular descent, as well as scrotal and phallic development and growth 2. Testosterone or hCG increases endogenous testosterone production in the setting of hypogonadism in boys beginning at 12 to 13 years Monitoring of free thyroxine in addition to TSH should be done annually in childhood Central adrenal insufficiency has been observed in PWS, though frequency is unclear.
Consideration of measuring ACTH and Cortisol levels with illness is appropriate and some have advocated stress dose steroids with illness or before surgery Monitoring for Type 2 Diabetes Mellitus is essential in adults. Physical therapy beginning in infancy assists with motor skills development with speech therapy often warranted by 2 years of age.
Requirement for educational support should be anticipated including personal classroom aides and behavior management given the frequency of challenging behaviors such as tantrums, compulsive and stubborn behaviors. Serotonin reuptake inhibitors can be helpful for severe behavioral issues, including psychosis, which may emerge in adolescence Adolescents and adults often are successful residing in a group home where attention to daily exercise and diet can be emphasized.
Annual assessment for scoliosis should begin in early childhood.
UBE3A function & expression
Opthalmological evaluation for strabismus and impaired acuity should be done in the first year of life and continue thereafter. Given the increased risk for osteoporosis, bone density studies DEXA studies are recommended beginning in adolescence and continuing to adulthood Several medication trials are ongoing, aimed at addressing the hyperphagia and associated symptoms of PWS.
Oxytocin nasal spray is being studied, as there is a reduction in oxytocin producing neurons in the hypothalamic periventricular nucleus in individuals with PWS. A recent publication, however, did not demonstrate benefit in 30 individuals in an week double-blind, placebo-controlled crossover trial Other trials are ongoing.
A trial of a candidate obesity drug called Beloranib is also underway. Belonarib is an inhibitor of methionine aminopeptidase-2 and works to reduce fatty acid synthesis, insulin levels, and food consumption. It also increases mobilization of fats and energy expenditure Family counseling is recommended. Most deletions, UPD, and epimutations are associated with a low recurrence risk. Angelman syndrome AS is characterized by developmental delay, intellectual disability, absent speech, seizures, ataxic gait, easily excitable happy demeanor, and characteristic facies Table 2.
Most infants with AS do not show any signs of the disorder at birth. However, delayed attainment of gross and fine motor skills, language, and social skills are usually evident within the first year of life Motor skill delays can be severe, and many individuals with AS are not able to walk. Tremors can further complicate fine motor skill development.
Toilet training is typically severely delayed, but is achieved in many with adults with AS. Functionally, individuals with AS only reach a developmental level of approximately 24 to 30 months Cognitive ability is severely impaired, however, cognition is difficult to ascertain due to the profound lack of speech, hyperactivity, and inability to pay attention in individuals with AS. Adults with AS are not capable of independent living, although many can perform tasks with supervision, can dress themselves, and can use feeding utensils 43 , Language development in individuals with AS is severely impaired.
Most individuals with AS are entirely non-verbal, some will speak a few words, and a rare few have some phrase speech. Augmentative communication devices and sign language can be successfully used to communicate with individuals with AS. Their receptive communication exceeds expressive communication Angelman Syndrome is typically associated with generalized epilepsy, though focal seizures occur in up to one third, often in combination with other seizure types 44 , 46 , Epilepsy tends to be more severe in early childhood, often easing as children reach puberty, though epilepsy risk appears to persist in to adulthood Epilepsy tends to be more severe in those with a maternal deletion, as does disease severity in general 47 , EEG often shows a characteristic pattern, most classically with posterior predominant spike and sharp waves mixed with high amplitude sharply contoured 3 to4 Hz activity.
Individuals with AS have a slow, stiff legged gait.
Typical posture includes raised arms, flexed at the elbows and wrists. Hand flapping is common when walking or excited. Movements are generally jerky and abrupt. The specific brain region responsible for the movement disorder is not known. Individuals with AS have a characteristic happy demeanor and are easily excitable. They have frequent, sometimes inappropriate laughter. Hyperactivity and hypermotoric activity often accompany the happy disposition. Individuals with AS are typically highly social, with social interest beginning in infancy.
Most children with AS are eager to communicate, despite difficulty in doing so Social disinhibition is common and there is little fear of strangers. Other behavioral features associated with AS include stereotypic movements such as hand flapping , difficulty sleeping, and anxiety. Individuals with AS are frequently fascinated with water. Facial features associated with AS include lightly pigmented skin, hair, and eyes; strabismus; tongue protrusion; prognathia; and widely spaced teeth. This arises due to one of four mechanisms: In contrast to PWS, the presence of individuals with AS due to point mutations in the maternal copy of the UBE3A gene demonstrate that AS is a single gene disorder, although other genes in the deletion region can contribute to the severity of AS.
Mouse models of AS have suggested some underlying neuronal pathologies associated with the disorder. Deficits in long-term potentiation 59 , 60 , inhibitory CAMKII phosphorylation 60 , presynaptic release probability in inhibitory neurons 61 , and golgi acidification and protein surface sialylation 62 have been reported. Absence of a maternal methylation pattern is indicative of AS, but typically will not distinguish between deletion, UPD or imprinting defect as the cause.
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If methylation testing is consistent with AS, testing should proceed as follows:. Seizures are often difficult to control. Patients may require polypharmacy and status epilepticus is not uncommon 47 , Seizures typically respond best to medications traditionally effective for generalized epilepsy including valproic acid, leviteractem, lamotrigine, clonazepam and clobazam.
Seizures also may respond well to the ketogenic diet.
Prader-Willi, Angelman, and 15qq13 duplication syndromes
Medications most likely to exacerbate seizures include vigabatrin, tiagabine, oxcarbazepine and carbamazepine Children with AS frequently have disrupted sleep with difficulty both in falling asleep and maintaining sleep and possibly a reduced requirement for sleep 65 , Sleep disturbance can be a tremendous strain on caregivers and families. Treatment with melatonin one hour before bedtime has been shown to decrease sleep latency and nighttime awakening Doses as low as 0.
Additional medical management may be needed as well as providing a safe and restricted environment for children when they do wake at night. Hypotonia is frequent in young children though spasticity of limbs often develops over time. Gait is typically ataxic Children should receive physical and occupational therapy services. Orthotics and other adaptive devices are often helpful and orthopedic consultation may be warranted for issues including scoliosis.
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. Children with AS should have regular opthalmolgic assessment for management of strabismus, and hyperopia 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.
Recent studies are focusing on methods of unsilencing the paternal UBE3A allele.
Prader-Willi, Angelman, and 15q11-q13 duplication syndromes
A recent report of restoration of paternal Ube3a expression in the AS mouse model by genetically terminating transcription of the antisense RNA also provides hope for improving disease treatment in the future Dup15q syndrome is characterized by central hypotonia, developmental delay, intellectual disability, seizures, and autism Table 3.
There is remarkable diversity in the severity of these symptoms, even in individuals with exactly the same genotype. Muscle hypotonia is observed in almost all individuals with Dup15q syndrome, and can be severe, prompting testing for PWS Feeding difficulties are common. Joint hyperextensibility and drooling accompanies the hypotonia in most individuals.
Major motor milestones such as rolling over, sitting and walking are delayed. Weak cry is often reported. While hypotonia can persist in some adults, it also can subside or progress to hypertonia in the limbs Gross and fine motor skill delays are common in individuals with Dup15q syndrome. Hypotonia contributes to these delays.
Sitting is reportedly achieved between 10 and 20 months, with walking typical between 2 and 3 years. Although some children with Dup15q syndrome do not walk, the vast majority do walk independently.
Fine motor delays include non-functional use of objects and immature exploration of objects. Comprehension is very limited. Seizures are a major medical issue for Dup15q syndrome. Seizures often first present as infantile spasms and later progress to a Lennox-Gastaut type syndrome. Seizures are more common in children with isodicentric chromosome 15 idic 15 than in those with interstitial duplications.
Most affected children reportedly have multiple seizure types, including infantile spasms, tonic, atonic, tonic-clonic, myoclonic, complex partial, and atypical absence Seizures can be intractable. Many individuals without overt seizures, have abnormal electroencephalogram EEG activity A majority of individuals with Dup15q syndrome meet the diagnostic criteria for autism Speech and language delays occur in most individuals.
While some individuals are completely non-verbal, a few are highly verbal. Expressive language is typically severely impacted, and may even be absent. Language is often echolalic with pronoun reversal Intent to communicate is also absent or very poor in many individuals. Inappropriate social interactions are typical in individuals with Dup15q.
Gaze and bodily contact avoidance is common. Symbolic play is almost never acquired, and individuals with Dup15q syndrome usually do not show interest in their peers. Difficult behaviors such as tantrums, shouting, and aggressiveness often occur, as do stereotypies. Hand flapping, clapping, or wringing are frequently seen, as well as finger biting, head turning, and repeated spinning. Subtle facial features that are characteristic for Dup15q syndrome can be seen in most affected individuals.
Increased pigmentation can be observed. Dup15q syndrome usually occurs in one of two forms. Isodicentric chromosome 15q idic 15 and maternal interstitial duplication Idic 15 is the most common presentation. E6-associated protein E6-AP is a dual function coactivator of steroid hormone receptors. The angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily.
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