Angelman syndrome in adolescence and adulthood: A retrospective chart review of 53 cases

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1 Received: 5 June 2017 Revised: 25 February 2018 Accepted: 5 March 2018 DOI: /ajmg.a ORIGINAL ARTICLE Angelman syndrome in adolescence and adulthood: A retrospective chart review of 53 cases Ankita Prasad Olivia Grocott Kimberly Parkin Anna Larson Ronald L. Thibert Angelman Syndrome Clinic, Massachusetts General Hospital, Boston, Massachusetts Correspondence Ronald L. Thibert, Angelman Syndrome Clinic, Massachusetts General Hospital, 175 Cambridge Street, Suite 340, Boston, MA rthibert@mgh.harvard.edu Angelman syndrome is a neurogenetic disorder with varying clinical presentations and symptoms as the individual ages. The goal of this study was to characterize changes over time in the natural history of this syndrome in a large population. We reviewed the medical records of the 53 patients who were born prior to 2000 and seen at the Angelman Syndrome Clinic at Massachusetts General Hospital to assess neurological, sleep, behavioral, gastrointestinal, orthopedic, and ophthalmologic functioning. The average age of this cohort was 24 years. Active seizures were present in 35%, nonepileptic myoclonus in 42%, and clinically significant tremors in 55%. Anxiety was present in 57%, increasing to 71% in those ages years. In terms of sleep, 56% reported 8 hr of sleep or more, although 43% reported frequent nocturnal awakenings. Gastrointestinal issues remain problematic with 81% having constipation and 53% gastroesophageal reflux. The majority lived in a parent s home and remained independently mobile, though scoliosis was reportedly present in 30%, and 20% had reported low bone density/osteoporosis. The results of this study suggest that the prevalence of active seizures may decrease in adulthood but that the prevalence of movement disorders such as tremor and nonepileptic myoclonus may increase. Anxiety increases significantly as individuals age while defiant behaviors appear to decrease. Sleep dysfunction typically improves as compared to childhood but remains a significant issue for many adults. Other areas that require monitoring into adulthood include gastrointestinal dysfunction, and orthopedic/mobility issues, such as reported scoliosis and bone density, and ophthalmologic disorders. KEYWORDS adolescents, adults, Angelman syndrome, anxiety, myoclonus, seizures 1 INTRODUCTION Angelman syndrome (AS) is a neurogenetic disorder with distinctive features due to loss of expression of maternal UBE3A protein, which is encoded on chromosome 15q (Albrecht et al.,1997; Kishino et al., 1997; Knoll et al., 1989). Primary phenotypic features in adulthood include epilepsy, cognitive impairment with limited expressive speech, movement disorder, sleep impairment, anxiety, challenging behaviors, and gastrointestinal and ophthalmologic issues (Williams et al., 2006). Across age groups, sleep dysfunction may include reduced total sleep duration, increased sleep latency, and frequent night awakenings (Pelc, Cheron, Boyd, & Dan, 2008). The loss of expression of UBE3A can occur by four main molecular mechanisms: microdeletion of the 15q region (68%), mutation of UBE3A (12%), paternal uniparental disomy (7%), or imprinting error (3%) (Dagli, Buiting, & Williams, 2011; Dagli & Williams, 1993; Thibert et al., 2013). Microdeletions of the 15q region have been shown to confer the most severe phenotype with the highest rates of epilepsy (Clayton-Smith & Laan, 2003; Thibert et al., 2009). Distinguishing the molecular mechanism of AS is clinically beneficial for predicting the severity of clinical outcome and helping guide the course of treatment. The incidence of AS is approximately 1/12,000 1/20,000 individuals (Buckley, Dnno, & Weber, 1998; Kyllerman, 1995; Petersen et al., 1995). Life expectancy has yet to be evaluated by epidemiologic measures, but case reports show mixed findings with Williams, Driscoll, and Dagli (2010), suggesting that it may be reduced by years and Clayton-Smith and Laan (2003) suggesting that it may not diverge from that of the general population. There are few reports of individuals with AS living beyond 70 years (Bjerre et al., 1984; Williams et al., 2010). Am J Med Genet. 2018;176A: wileyonlinelibrary.com/journal/ajmga VC 2018 Wiley Periodicals, Inc. 1327

2 1328 PRASAD ET AL. Our current understanding of the natural history of AS through adulthood is largely in its infancy. The diagnosis of AS became more definitive with genetic testing in the late 1980s. As the first generations of individuals diagnosed with AS in childhood are now aging into adulthood, we are continuing to learn how to optimize their care. To date, there have been multiple case reports characterizing AS in adulthood (Buntinx et al., 1995; Clayton-Smith, 2001; Giroud et al., 2015; Laan et al., 1996; Larson et al., 2015; Sandanam et al., 1997). We completed a large interview series with caregivers in 2015 to help characterize the impact of age and genotype on clinical outcomes for adolescents and adults with AS (Larson et al., 2015). Giroud et al. (2015) and Clayton- Smith (2001) performed retrospective case series of adult patients in which they assessed neurological parameters such as epilepsy and tremor. Clayton-Smith analyzed neurological parameters as well as general health, behavioral issues, communication, and self-help skills. Across age groups, up to 10% of individuals are nonambulatory (Bird, 2014). Movement disorders associated with AS include tremor and nonepileptic myoclonus (NEM). NEM is episodes of sustained myoclonic (jerky, twitchy) movements, but generally low, amplitude without impaired awareness varying in duration from seconds to hours and is increasingly understood as a primary feature of adulthood (Goto et al., 2015; Larson et al., 2015). Sandanam et al. (1997) analyzed and performed genetic testing on institutionalized, previously undiagnosed adults to determine whether they had deletion-positive AS and recorded the prevalence of clinical manifestations present in the group identified to have deletions. Laan et al. (1996) analyzed a group of adult patients with AS and compared rates of comorbidities in their cohort to known rates found in childhood. Buntinx et al. (1995) reviewed 47 patients varying in age to assay how the phenotype of AS changes with age. These prior studies helped guide our work. The goal of this study was to further characterize clinical and social factors impacting care for adolescents and adults with AS. 2 MATERIALS AND METHODS In this institutional review board-approved study, data were collected by a retrospective review of the medical records of 170 individuals, seen by Ronald Laurent Thibert (RLT) in the Angelman Syndrome Clinic at the Massachusetts General Hospital from January 2002 to June Individuals who were born during or before the year 2000, and had a genetically confirmed diagnosis of AS, were included in this study. Demographic data, including age, sex, and genotype, were collected. Epilepsy severity indices included seizure frequency, age of onset, and seizure semiologies. Clinical seizure data were available for 48 individuals. Seizure frequency was grouped into three categories: daily, monthly, or yearly/episodic seizures, which were defined as seizures that occurred one to two times per year or clustered around certain events such as seasonal changes, illness, or allergies. Seizure freedom was defined as no events for two or more years at the time of data collection. Age of seizure freedom was reported from date of last reported seizure. Current antiepileptic drug (AED) trials and dietary therapies were reported. Data were collected on the following clinical outcomes: rates of NEM, tremor, sleep quantity/quality, mood/behavior, gastrointestinal/dietary, mobility/orthopedics, ophthalmic pathology, and social/living arrangements. Sleep quantity was defined as number of hours slept per night per parental report and sleep quality was determined based on parental report of night awakenings, which were the frequency that parents reported hearing their child awaken from sleep. The number of individuals with sleep dysfunction was calculated based on the number taking medications for sleep daily as well as individuals whose parents reported poor overall sleep, frequent or early waking, or few hours of sleep. 3 RESULTS 3.1 Demographics Demographic and genotypic data for this cohort are presented in Table 1 (n 5 53). The average age of this cohort was 25 years, ranging from 16 to 43 years. In the age grouping of there were 32 individuals, and in the remainder aged 26 years or older there were 21 individuals. Fifty-three individuals met inclusion criteria. Age of seizure onset was available for 47/48 individuals with a history of seizures, and age of seizure freedom was available for 26/31 individuals who were currently seizure free. Data on gastrointestinal issues were reported by 47/53, mobility was reported by 50/53, orthopedic issues by 50/53, sleep quantity by 27/53 and sleep quality by 47/53, and dietary restrictions by 34/53 individuals in our cohort. Chi-square tests between the age groupings of years of age and over 26 years of age were calculated to determine if there was a statistical difference between the prevalence of each clinical outcome between these age groups. There was a nearly equal distribution of males (47%) and females (53%). The distribution of molecular subtypes was maternal deletions 72%, UBE3A mutations 11%, paternal uniparental disomy 11%, mosaic/nondeletions 4%, and imprinting center defect 2%. 3.2 Neurological sequelae Ninety-one percent (48/53) of patients in this cohort had a history of one or more seizures. Seizure characteristics and other neurologic TABLE 1 Adult patient demographics Demographic Total cohort (n 5 53), n (%) Age at time of study (years) (60) (40) Sex Female 28 (53) Male 25 (47) Genotype Maternal deletion 38 (72) UBE3A mutation 6 (11) UPD 6 (11) Mosaic/nondeletion 2 (4) Imprinting center defect 1 (2) UBE3A 5 UBE3A mutation; UPD 5 uniparental disomy.

3 PRASAD ET AL TABLE 2 Neurological parameters in a population of AS adults Total cohort (n 5 48) years (n 5 29) years (n 5 19) Chi-square p value Currently having seizures 17 (35%) 12 (38%) 5 (26%).2859 Daily NA Monthly NA Yearly/episodic NA No seizures for 2 years 31 (65%) 17 (58%) 14 (74%) Other neurological symptoms (n 5 38) Nonepileptic myoclonus 22 (42%) 13 (41%) 9 (43%).862 Intention tremors 29 (55%) 20 (63%) 9 (43%).135 diagnoses are reported in Table 2. Average age of seizure onset was 2.4 years. In this cohort, 35% (17/48) of individuals had active seizures with 65% (11/17) of those individuals experiencing multiple seizure types. The most common seizure types were atonic (n 5 12) and generalized tonic-clonic (n 5 10) followed by absence (n 5 5), myoclonic (n 5 4), and focal (n 5 2). Sixty-five percent (31/48) of the cohort had been seizure free for over 2 years. The average age of seizure freedom was 16 years. In this cohort, 42% (22/53) had a history of NEM, of which 72% (16/22) also had active seizures, and 55% had a history of tremor. Caregivers reported that 56% of individuals slept greater than 8 hr per night, 21% reported no night awakenings, 36% reported awakenings less than one night per week, and 43% reported awakenings more than one night per week. Thirty-three (59%) individuals reported poor sleep. The average duration of sleep was 8 hr. 3.3 Other clinical outcomes Several other clinical outcomes are described in Table 3. Fifty-seven percent exhibited signs and symptoms of anxiety. The incidence of anxiety was significantly greater in patients over 26 years of age than in patients between ages 16 and 25 years of age (p ). Examples of these behaviors include self-harm behaviors such as headbanging or slapping, pacing, cyclic vomiting, fits, and outbursts associated with separation from parents or encountering unfamiliar environments. Twenty-five percent of the cohort had aggressive and/ or impulsive behaviors and 12% had defiant behaviors. Behavioral examples consisted of hitting, biting, pinching, and kicking. Constipation was reported in 81% and gastroesophageal reflux was reported in 53% of the cohort. Ninety-eight percent of individuals were ambulatory, 64% walking independently, and 34% walking with assistance. The review of orthopedic features/conditions revealed that 30% had a history of reported scoliosis and 20% had reported low bone density/ osteoporosis. Ophthalmic impediments such as strabismus, exotropia, and esotropia were reported by 36% of individuals in the cohort. Ninety-one percent of individuals live with family members and the other 9% live in residential facilities or group homes. 3.4 Medications Ninety-four percent of the cohort was taking one or more medications for seizure, movement disorder, sleep, or behavioral disturbances (42%) (Table 4). The assessment of prescription alleviation revealed that most adult participants were taking at least one medication for seizures and/ or NEM (32%) and one medication for behavioral/sleep disturbances (38%) (Table 4). The most commonly used medications for various neurological and mood/behavioral disturbances are listed in Table 5. The most common AED in this cohort was lamotrigine (28%) followed by levetiracetam (25%), valproic acid (23%), clobazam (17%), and clonazepam (8%). A small percentage of the cohort was being treated with the ketogenic diet (5%) or the low-glycemic index treatment (18%) for seizure or NEM control. For NEM, levetiracetam (21%), clonazepam (13%), and clobazam (6%) were the most commonly prescribed. Of those taking levetiracetam for NEM, three also took this for seizures; of those taking clobazam, two were also taking this for anxiety; and of those taking clonazepam, one was also taking it for seizures. Thirteen out of 33 individuals with sleep dysfunction took medication to treat sleep disturbances in this cohort, trazodone (27%) and clonidine (15%) were most commonly prescribed. For anxiety, clobazam (19%) was most commonly used followed by buspirone (13%), clonazepam (13%), and lorazepam (8%). Of those taking clobazam for anxiety, two were also using it for seizure control and of those taking lorazepam for anxiety, one was also taking it for seizures and another for NEM. 4 DISCUSSION This study is one of the largest retrospective reviews of adults with genetically confirmed AS. Strengths of this study include that the rates of genetic subtypes and history of epilepsy within our study cohort mirror prior reports of the AS population (Galvan-Manso et al., 2005; Laan et al., 1997; Ruggieri & McShane, 1998; Thibert et al., 2009; Williams et al., 2006). Another strength of this study is that all subjects saw the same provider (RLT) and the data were collected only from clinic notes written by that provider. Limitations of this study include possible reporting bias favoring a more severe clinical phenotype among the patients seen in our tertiary referral center. Additionally, the majority of our data were reliant on clinical and physical history as opposed to primary diagnostic data such as a sleep study to provide a number of hours of sleep per night or a DEXA scan to provide an osteoporosis diagnosis. Finally, the majority of individuals in this study live with family. As such, the medical issues for individuals living in alternative environment such as residential facilities are not well represented. One of the hallmarks of AS has been the occurrence of epilepsy in early childhood, with the diagnosis of AS often following seizure onset,

4 1330 PRASAD ET AL. TABLE 3 Various clinical outcomes for a population of AS adults Total cohort (n 5 53) years (n 5 32) years (n 5 21) Chi-square p value Opthalmic pathology a (n 5 53) 19 (36%) 10 (31%) 9 (43%).389 Gastrointenstinal (n 5 47) n 5 28 n 5 19 Reflux 25 (53%) 12 (43%) 13 (68%).084 Vomiting 5 (11%) 1 (4%) 4 (21%) NA Constipation 38 (81%) 24 (86%) 14 (74%) NA Mood/behavior (n 5 53) n 5 32 n 5 21 Anxiety symptoms 30 (57%) 15 (47%) 15 (71%).00004* Aggressive/impulsive behavior 13 (25%) 7 (22%) 6 (29%).580 Defiant behavior 6 (12%) 5 (16%) 1 (5%) NA Walking (n 5 50) n 5 29 n 5 21 Independently 32 (64%) 20 (69%) 12 (57%).390 With assistance 17 (34%) 8 (28%) 9 (43%).261 Nonambulatory 1 (2%) 1 (3%) 0 (0%) NA Orthopedics (n 5 50) n 5 29 n 5 21 Scoliosis 15 (30%) 10 (34%) 5 (24%).416 Low bone density/osteoporosis 10 (20%) 4 (14%) 6 (29%).197 Sleep n 5 16 n 5 11 Average number of hours per night (n 5 27) <5 hr/night 4 (15%) 1 (6%) 3 (27%) NA 5 8 hr/night 8 (30%) 5 (31%) 3 (27%) NA >8 hr/night 15 (56%) 10 (63%) 5 (45%).381 Night awakenings (n 5 47) n 5 29 n 5 20 None 10 (21%) 5 (17%) 5 (25%).508 Rarely (<1 night per week) 17 (36%) 12 (41%) 5 (25%).236 Regularly (>1 night per week) 20 (43%) 10 (34%) 10 (50%).277 Living conditions (n 5 53) n 5 32 n 5 21 Parent s home 48 (91%) 31 (97%) 17 (81%) NA Residential facility/group home 5 (9%) 1 (3%) 4 (19%) NA NA 5 Unable to calculate p value due to greater than 20% of values equaling less than 5. a Includes strabismus, esotropia, or exotropia. *Significant difference between age groups. especially before genetic testing became more readily available (Valente et al., 2013). The onset of seizures most often occurs between 1 and 3 years, although there have been some reports of seizures occurring earlier or later (Dagli et al., 2011; Valente et al., 2013). This cohort further supports this range, as the mean age of seizure onset was 2.4 years old. As individuals with AS progress through childhood and into adulthood, the frequency has been known to decrease in severity, with the most severe seizures occurring before age 11 (Clayton-Smith & Laan, 2003; Larson et al., 2015; Thibert et al., 2009; Valente et al., 2013). In previous reports, individuals with AS have had a burst of seizure activity in childhood followed by a remission in puberty (Dan & Pelc, 2008; Ruggieri & McShane, 1998; Valente et al., 2006), and then a possible recurrence of activity for a subset of the population in adulthood (Laan et al., 1997; Larson et al., 2015; Pelc, Boyd, Cheron, & Dan, 2008; Thibert et al., 2009). Seizure frequency patterns seen among the adults and adolescents in this study align with these prior results with 35% of the cohort experiencing active seizures at the time of evaluation, down from 91% who had a history of seizures in childhood. Of those with active seizures in adulthood, a large proportion (47%) reported monthly events of which a few individuals (12%) had catamenial seizure activity. Many adults with AS also exhibit symptoms of NEM and 42% of our patient cohort had a history of NEM. This is an area of ongoing investigation in the field of AS. Previously described in the literature as cortical myoclonus (Goto et al., 2015; Larson et al., 2015), the characteristic features of NEM in adults with AS include clinical events consisting of jerking or twitching that display no electrographic correlate with performed electroencephalogram (EEG), no clear alteration of consciousness during episodes, and duration lasting minutes to hours. The twitching typically begins in the upper extremities, often spreading to the face, lower extremities and at times trunk. NEM has been described across age groups but in our cohort, it clinically presents most often in early adolescence and adulthood. The differential diagnosis for these shaking events includes myoclonic seizures, which are common in AS (though more typically present in childhood) as well as tremor. The clinical history of myoclonus with preserved consciousness and no clear postictal period is key to the early diagnosis and subsequent treatment of NEM. Capturing events on EEG showing no electrographic correlate confirms the diagnosis.

5 PRASAD ET AL TABLE 4 Frequency of medication taken by adults with AS for seizures, myoclonus, behavior, and sleep issues Total frequency of medications a Total cohort (n 5 53), n (%) years (n 5 32), n (%) years (n 5 21), n (%) None 3 (6) 2 (6) 1 (5) 1 6 (11) 4 (13) 2 (10) 2 10 (19) 7 (22) 3 (14) 3 22 (42) 12 (38) 10 (48) 4 7 (13) 3 (9) 4 (19) 5 or more 5 (9) 4 (13) 1 (5) AED/myoclonus medications None 9 (17) 6 (19) 3 (14) 1 17 (32) 10 (31) 7 (33) 2 11 (21) 8 (25) 3 (14) 3 14 (26) 6 (19) 8 (38) 4 2 (4) 2 (6) 0 (0) Behavioral/sleep medications None 15 (28) 9 (28) 6 (29) 1 20 (38) 12 (38) 8 (38) 2 12 (23) 8 (25) 4 (19) 3 3 (6) 1 (3) 2 (10) 4 or more 2 (4) 1 (3) 1 (5) AED 5 antiepileptic drug. a Includes both AED/myoclonus and behavioral/sleep medication frequencies. Another neurological symptom common in adults with AS is an intention tremor. Intention tremor is often present in individuals with AS beginning in infancy and can be an important distinguishing diagnostic feature of AS (Bjerre et al., 1984; Thibert et al., 2013). For 55% of our cohort, tremors persisted through adulthood and were felt to be clinically significant, although only 43% of the older 26- to 43-year-old subset had tremors. Previous studies show older medications, such as valproic acid, may have a more severe side-effect profile in individuals with AS than the newer AED and could contribute to worsening tremor (Shaaya et al., 2016; Thibert et al., 2009). TABLE 5 Most commonly used antiepileptic drugs and mood/ behavioral medications in AS adults N (%) Seizures (n 5 17) Lamotrigine (Lamictal) 15 (28) Levetiracetam (Keppra) 13 (25) Depakote 12 (23) Clobazam (Onfi) 9 (17) Clonazepam (Klonipin) 4 (8) Myoclonus (n 5 22) Levetiracetam (Keppra) 11 (21) Clonazepam (Klonipin) 7 (13) Clobazam (Onfi) 3 (6) Sleep (n 5 33) Trazodone 9 (27) Clonidine 5 (15) Anxiety (n 5 30) Clobazam (Onfi) 10 (19) Busparione (BuSpar) 7 (13) Clonazepam (Klonipin) 7 (13) Lorazepam (Ativan) 4 (8) AS 5 Angelman syndrome. From clinical observations, other factors such as gastrointestinal issues, poor sleep quality, and even anxiety can trigger or exacerbate an existing seizure disorder or other neurological symptoms such as tremors or NEM in adults. Identifying and treating the underlying systemic stressor can often improve neurological symptoms. Gastrointestinal (GI) dysfunction, such as constipation and reflux, can affect sleep quality or quantity, which may then impact seizure activity. Neurological symptoms arise from the underlying pathology of this genetic syndrome but can increase in frequency and severity due to comorbid conditions such as anxiety and GI dysfunction. Anxiety and other behavioral issues can have a significant impact on quality of life for adults with AS. Although, behavioral issues appear to decrease with age, anxiety becomes significantly more prevalent (Giroud et al., 2015; Larson et al., 2015; Thibert et al., 2013). In this cohort, 57% had a history of anxiety symptoms that impact day-to-day function and quality of life. The older 26- to 43-year-old cohort is more significantly affected, with 71% of individuals exhibiting anxiety symptoms. Anxiety presented in a variety of ways in this cohort, including behavioral changes such as increased fits and self-harm, cyclic vomiting, tics, or tremors. Some of the common triggers of anxiety symptoms are changes in routine or being placed in situations with which the individual is unfamiliar (Clayton-Smith & Laan, 2003; Larson et al., 2015). Other studies have found that anxiety may be connected to specific phobias such as fear of crowds or fear of noise (Pelc, Cheron, & Dan, 2008). These triggers were also observed as a source of anxiety in our cohort. If correctly identified and treated, adults who struggle with anxiety could have an improved quality of life and suffer fewer additional comorbidities. Other behavioral symptoms that adults struggle with include aggressive/impulsive behavior and/or defiant behaviors. Previous studies have shown that aggression in cohorts with AS can range from lower rates of 6 10% to rates as high as 72% (Adams et al., 2011; Larson et al., 2015; Summers et al., 1995). In this study, 25% of adults had a history of aggressive behavior and 12% had a history of defiant behaviors. The variations among studies could be attributed to varying definitions of aggression or defiance, or underreporting of these behaviors in the medical record. Defiant behavior in our cohort coincided with young adulthood and decreased from 16% in individuals aged to 5% in the older adult population of individuals aged years. It is possible that these defiant behaviors were anxiety based, which would make the prevalence of anxiety in those closer to those Treatment for individuals with AS has evolved over the years, with newer medications providing a wider range of treatment options. In prior studies, the most common older medications prescribed for seizures were valproic acid and clonazepam, whereas the most common newer AED were topiramate, lamotrigine, levetiracetam, and clobazam (Shaaya et al., 2016; Thibert et al., 2009). Similar to previous reports, lamotrigine, levetiracetam, and valproic acid remained the most commonly prescribed AED in this cohort. Newer AEDs typically have an improved side-effect profile and may provide clinical efficacy for other neurologic symptoms beyond seizures in some cases. Some of the AED in our cohort were used for

6 1332 PRASAD ET AL. multiple indications. For example, levetiracetam was used for both seizures and NEM and clonazepam and clobazam were both used for seizures, NEM, and anxiety. As individuals with AS age, different treatment options may be considered to treat evolving symptoms of NEM and anxiety. Although, we cannot make any conclusions about what medications are most effective for AS individuals, there were trends in our clinic toward newer AED and the use of these medications for multiple indications. More in-depth studies on seizures, NEM, and anxiety in AS adults are needed to determine the effectiveness of these treatments. Sleep dysfunction is a common issue reported in individuals with AS. The proposed mechanism of sleep dysfunction is the decreased expression of the GABA receptor genes on 15q11-13 (DeLorey et al., 1996; Lossie et al., 2001; Minassian et al., 1998), as well as abnormal melatonin secretion and circadian rhythm dysfunction (Takaesu et al., 2012). Previous studies have shown that individuals with AS may have increased sleep onset latency (Bruni et al., 2004; Connant et al., 2009; Miano et al., 2004; Waltz et al., 2005) and some have hypothesized that melatonin treatment can be beneficial in reducing time to sleep onset (Bird, 2014; Clayton-Smith & Laan, 2003). Many studies on AS in adulthood have described improvement in sleep habits with age (Clayton-Smith, 2001; Larson et al., 2015; Miano et al., 2004; Pelc, Cheron, Boyd, & Dan, 2008; Sandanam et al., 1997; Smith et al., 1996). With 56% of caregivers in our cohort reporting 8 hr of sleep or more, this is an improvement from previously reported sleep dysfunction in children with AS (Clayton-Smith & Laan, 2003; Pelc et al., 2008). A study by Bruni et al. (2004), however, found in their cohort that sleep issues such as sleep latency, decreased time of sleep, and overall sleep quality, worsened with age, but our cohort did not support this trend. The improvement with age noted in our cohort may be due the natural history of the disorder, improved treatment of insomnia or other comorbid conditions improving such as gastrointestinal dysfunction or seizure activity. Previous studies have shown that night awakenings, although still present, decrease with age (Clayton-Smith, 2001; Pelc et al., 2008). Although sleep dysfunction may have decreased in frequency among this cohort, significant number of adults (59%) still reported poor sleep and many (39%) of those were taking a daily sleep medication. Some of the individuals taking medications have been on these medications for years and may have outgrown sleep dysfunction but we still reported them as having sleep dysfunction. This may mean that this number is slightly higher than the prevalence of sleep dysfunction in the actual AS population. Gastrointestinal distress remains a critical issue requiring clinical care for many individuals across age groups in AS. Previous studies have shown constipation as a nearly universal issue across all ages, whereas in this study, constipation improved in the older cohort, most likely due to appropriate medical management (Clayton-Smith, 2001; Larson et al., 2015). Although medical management improved symptoms, reflux remained an ongoing issue in 53% of AS adults. Scoliosis affected 30% of this cohort and did not vary significantly among the two age groups in our cohort. A study by Clayton-Smith and Laan (2003) reported that 10% of children with AS have scoliosis. Another study by Clayton-Smith (2001) of AS in adulthood found that 10/28 (36%) patients in her adult cohort developed scoliosis during their adolescent growth spurt. Similarly, in line with previous reports, we found an increased prevalence of scoliosis in adults with AS (Buntinx et al., 1995; Laan et al., 1996; Larson et al., 2015; Williams, Driscoll, & Dagli, 2010). Scoliosis may limit the mobility of individuals with AS and requires early and consistent monitoring. In our cohort, 20% of individuals were diagnosed with low bone density or osteoporosis. This prevalence may be due to in part to increased monitoring in this population (Larson et al., 2015). Risk factors for fractures and decreased bone density may include decreased mobility and AED treatment (Coppola et al., 2007; Larson et al., 2015). Mobility may be complicated by challenges including ataxia, myoclonus, scoliosis, epilepsy, and behavioral issues among others (Clayton-Smith, 2001; Clayton-Smith & Laan, 2003; Larson et al., 2015; Van Buggenhout & Fryns, 2009). Despite these difficulties, prior reports describe that 68 75%, of adults are independently mobile (Clayton-Smith, 2001; Larson et al., 2015). Similarly, we found 64% of this cohort was independently mobile. 5 CONCLUSION AS is a complex disorder with significant changes that occur as the individual enters adulthood. Seizures decrease in frequency and severity in a majority of individuals. For those who continue to have clinical seizure activity, newer medications with more favorable side-effect profiles may be advantageous. Movement disorders, including NEM and tremors, increasingly affect this population, but appropriate clinical diagnosis and treatment may improve these symptoms. Anxiety is a primary clinical concern for adults with AS. It can be difficult to diagnose due to unusual and diverse presentations, and may contribute to the exacerbation of other neurological conditions. Sleep and gastrointestinal dysfunction, although improved from childhood, still occur and require monitoring and treatment when present. Orthopedic issues, mobility and challenging behaviors are additional elements critical to clinical care. There is a great need for ongoing study in this field. Further characterization and understanding of the natural history of NEM, as well as prospective treatment trials, are needed to guide improved clinical care. Adults with AS are best served by a collaborative and multidisciplinary team that may include neurologists, psychiatrists, gastroenterologists, orthopedists, ophthalmologists, dietitians, and physical, occupational, and speech therapists, working together with the patient and his or her caregivers, striving to optimize health, wellness, and quality of life. ACKNOWLEDGMENTS We would like to acknowledge all of the families who have visited the Angelman Syndrome Clinic at Massachusetts General Hospital and the Lurie Center for Autism. CONFLICT OF INTEREST None.

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