Bone health in children with Angelman syndrome at the ENCORE Expertise Center.

Angelman syndrome (AS) is a rare genetic disorder due to lack of UBE3A function on chromosome 15q11.2q13 caused by a deletion, uniparental paternal disomy (UPD), imprinting center disorder (ICD), or pathological variant of the UBE3A gene. AS is characterized by developmental delay, epilepsy, and lack of speech. Although fractures are observed frequently in our clinical practice, there are few studies on bone health in AS. The aim of this study is to investigate bone health in children with AS. In this prospective cohort study, we describe bone health in 91 children with AS visiting the ENCORE Expertise Center for AS between April 2010 and December 2021. Bone health was assessed with the bone health index (BHI) in standard deviation score (SDS) measured by digital radiogrammetry of the left hand using BoneXpert software. Risk factors analyzed were age, sex, genetic subtype, epilepsy, anti-seizure medication use, mobility, body mass index (BMI), and onset of puberty. Children with AS had a mean BHI of -1.77 SDS (SD 1.4). A significantly lower BHI was found in children with a deletion (-2.24 SDS) versus non-deletion (-1.02 SDS). Other factors associated with reduced BHI-SDS were inability to walk and late onset of puberty. Children with a history of one or more fractures (22%) had a significantly lower BHI than children without fractures (-2.60 vs -1.56 SDS). Longitudinal analysis showed a significant decrease in BHI-SDS with age in all genetic subtypes.  Conclusions: Children with AS have a reduced bone health. Risk factors are deletion genotype, no independent walking, and late onset of puberty. Bone health decreased significantly with age. What is Known: • Children with neurological disorders often have a low bone health and higher risk of fractures. • Little is known about bone health in children with Angelman syndrome (AS). What is New: • Children with AS showed a reduced bone health and this was significantly associated with having a deletion, not being able to walk independently, and late onset of puberty. • Longitudinal analysis showed a significant decrease in bone health as children got older.

Child characteristics associated with child quality of life and parenting stress in Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterised by severe intellectual disability, movement disorder, epilepsy, sleeping problems, and behavioural issues. Little is known on child health-related quality of life (HRQoL) in AS. AS family studies have reported elevated parenting stress and a high impact of the child's syndrome on the parent. It is unclear which factors influence child HRQoL and parenting stress/impact in AS. METHODS: We collected data prospectively through standardised clinical assessments of children with AS at the ENCORE Expertise centre for Angelman Syndrome at the Erasmus MC Sophia Children's Hospital. A linear regression analysis was conducted for the following outcome variables: (1) child HRQoL (Infant and Toddler Quality of Life Questionnaire); (2) the impact of the child's syndrome on the parent (Infant and Toddler Quality of Life Questionnaire); and (3) parenting stress (Parenting Stress Index). Predictor variables were child genotype, epilepsy, sleeping problems (Sleep Disturbance Scale for Children), cognitive developmental level (Bayley Cognition Scale), autistic features (Autism Diagnostic Observation Schedule) and emotional/behavioural problems (Child Behaviour Checklist). Covariates were sex, age and socio-economic status. RESULTS: The study sample consisted of 73 children with AS, mean age = 9.1 years, range = 2-18 years. Emotional/behavioural problems were the strongest significant predictor of lowered child HRQoL. Internalising problems were driving this effect. In addition, having the deletion genotype and higher age was related to lower child HRQoL. Sleeping problems were related to a higher impact of the child's syndrome on the parent. Finally, emotional/behavioural problems were associated with higher parenting stress. Cognitive developmental level, autistic features and epilepsy were not a significant predictor of child HRQoL and parenting stress/impact. CONCLUSIONS: These results suggest that interventions aimed at increasing child HRQoL and decreasing parenting stress/impact in AS should focus on child emotional/behavioural problems and sleeping problems, using a family-centred approach.

Feasibility of wearable technology for 'real-world' gait analysis in children with Prader-Willi and Angelman syndromes.

BACKGROUND: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurodevelopmental disorders in need of innovative 'real-world' outcome measures to evaluate treatment effects. Instrumented gait analysis (IGA) using wearable technology offers a potentially feasible solution to measure "real-world' neurological and motor dysfunction in these groups. METHODS: Children (50% female; 6-16 years) diagnosed with PWS (n = 9) and AS (n = 5) completed 'real-world' IGA assessments using the Physilog®5 wearable. PWS participants completed a laboratory assessment and a 'real-world' long walk. The AS group completed 'real-world' caregiver-assisted assessments. Mean and variability results for stride time, cadence, stance percentage (%) and stride length were extracted and compared across three different data reduction protocols. RESULTS: The wearables approach was found to be feasible, with all participants able to complete at least one assessment. This study also demonstrated significant agreement, using Lin's concordance correlation coefficient (CCC), between laboratory and 'real-world' assessments in the PWS group for mean stride length, mean stance % and stance % CV (n = 7, CCC: 0.782-0.847, P = 0.011-0.009). CONCLUSION: 'Real-world' gait analysis using the Physilog®5 wearable was feasible to efficiently assess neurological and motor dysfunction in children affected with PWS and AS.

Association between early and current gastro-intestinal symptoms and co-morbidities in children and adolescents with Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a neurogenetic disorder that causes severe intellectual disability, expressive language deficits, motor impairment, ataxia, sleep problems, epileptic seizures and a happy disposition. People with AS frequently experience gastrointestinal (GI) symptoms. METHOD: This study used data from the Global Angelman Syndrome Registry to explore the relationship between early and current GI symptoms and co-morbidity in children and adolescents with AS (n = 173). Two groups that experienced a high (n = 91) and a low (n = 82) frequency of GI symptoms were examined in relation to feeding and GI history in infancy, sleep and toileting problems, levels of language and communication and challenging behaviours. Predictors of GI symptoms were then investigated using a series of logistic regressions. RESULTS: This analysis found that constipation and gastroesophageal reflux affected 84% and 64%, of the sample, respectively. The high frequency of GI symptoms were significantly associated with: 'refusal to nurse', 'vomiting', 'arching', 'difficulty gaining weight', gastroesophageal reflux, 'solid food transition', frequency of night-time urinary continence and sleep hyperhidrosis during infancy. GI symptoms were not significantly associated with sleep, toileting, language or challenging behaviours. Significant predictors of high frequency GI symptoms were gastroesophageal reflux and sleep hyperhidrosis. CONCLUSIONS: Future research needs to investigate the association between AS and GI co-morbidity in adults with AS.

Clinical aspects of a large group of adults with Angelman syndrome.

Descriptions of the clinical features of Angelman syndrome (AS) have mainly been focused on children. Here, we describe the evolution of the clinical phenotypes of AS in adulthood, using clinical data from 95 individuals (mean age 31.6 years, median 29.0 years, range 18-83 years), with genetically confirmed AS. Data was collected through physical examination and inspection of medical records, combined with questionnaires and interviews. Adults with AS experience substantial debilitating health problems. Constipation, reflux, visual problems, scoliosis, behavioral and sleeping problems occurred frequently and require appropriate attention. Epilepsy was reported in 57% of adults, negatively affecting the level of functioning. Non-convulsive status epilepticus was not observed in the adults, however some individuals developed prolonged episodes of rhythmic shaking while awake. A decline in mobility was noted in the majority of adults. A minority of adults with AS showed microcephaly. Taken together, this first phenotypic study of adults with AS to include in person interviews with care-givers and physical examination of patients, including the eldest adult reported to date, provides important insight in the development of the syndrome into adulthood. This knowledge is required to improve care for adult individuals with AS and to evaluate future therapies for this group.

Towards a therapy for Angelman syndrome by targeting a long non-coding RNA.

Angelman syndrome is a single-gene disorder characterized by intellectual disability, developmental delay, behavioural uniqueness, speech impairment, seizures and ataxia. It is caused by maternal deficiency of the imprinted gene UBE3A, encoding an E3 ubiquitin ligase. All patients carry at least one copy of paternal UBE3A, which is intact but silenced by a nuclear-localized long non-coding RNA, UBE3A antisense transcript (UBE3A-ATS). Murine Ube3a-ATS reduction by either transcription termination or topoisomerase I inhibition has been shown to increase paternal Ube3a expression. Despite a clear understanding of the disease-causing event in Angelman syndrome and the potential to harness the intact paternal allele to correct the disease, no gene-specific treatment exists for patients. Here we developed a potential therapeutic intervention for Angelman syndrome by reducing Ube3a-ATS with antisense oligonucleotides (ASOs). ASO treatment achieved specific reduction of Ube3a-ATS and sustained unsilencing of paternal Ube3a in neurons in vitro and in vivo. Partial restoration of UBE3A protein in an Angelman syndrome mouse model ameliorated some cognitive deficits associated with the disease. Although additional studies of phenotypic correction are needed, we have developed a sequence-specific and clinically feasible method to activate expression of the paternal Ube3a allele.

Hyperactive behaviour in Angelman syndrome: the association with sleep problems and age of epilepsy onset.

BACKGROUND: Sleep problems are common in many neurodevelopmental disorders, but little is known about how sleep is related to behavioural symptoms in Angelman syndrome (AS) or other genetic disorders. Hyperactive behaviour, sleep problems and epilepsy seem to be more common in AS than in other genetic conditions associated with severe intellectual disability. We hypothesised that both more sleep problems and earlier onset of epileptic seizures would predict more symptoms of hyperactivity. Hence, the aim of the project was to explore the association between hyperactive behaviour, sleep problems and age of epilepsy onset in individuals with AS. METHOD: All known parents/guardians (n = 115) of individuals with AS in Norway were invited to participate in this descriptive correlational study. Fifty-six individuals (49%) responded, and 42 people (25 male and 17 female; mean age 18.5 years, range 2-57 years) with genetically verified AS were included. Scores for 'hyperactivity' and 'sleep problems' were derived from questionnaire data. Information on epilepsy was obtained from medical records. RESULTS: 'Hyperactivity' was positively correlated with 'total sleep problems' (r = 0.46, P = 0.002) and negatively correlated with 'age of epilepsy onset' (r = -0.47, P = 0.01). 'Age of epilepsy onset' was not correlated with 'total sleep problems'. An overall multiple regression model with 'hyperactivity' as the dependent variable and 'age of epilepsy onset' and 'total sleep problems' as covariates was significant (R2  = 0.39, F = 8.16, P = 0.002). Hence, hyperactivity in AS could be predicted from both age of epilepsy onset and current sleep problems. CONCLUSIONS: Sleep problems may increase hyperactivity symptoms in individuals with AS. The association between hyperactivity and sleep problems in AS indicates that both should be investigated together as part of routine clinical assessment and intervention for either area of difficulty. Younger age of epilepsy onset was associated with more hyperactivity in AS, which may be related to encephalopathic effects of seizures and epilepsy.

Characterization of sleep habits and medication outcomes for sleep disturbance in children and adults with Angelman syndrome.

The objectives of this study were to characterize the sleep habits of 50 clinically referred individuals with Angelman syndrome (AS) and to retrospectively compare the effectiveness/tolerability of the three most commonly prescribed sleep medications in the sample. An experienced physician assigned a Clinical Global Impressions-Severity scale (CGI-S) score for each subject's AS-specific symptoms. Caregivers completed the Child Sleep Habits Questionnaire (CSHQ; screen for sleep problems in school-aged [4-10 years] children), a screening assessment for sleep problems. Caregivers provided information about medication trials targeting disturbed sleep, with the physician assigning a CGI-Improvement scale (CGI-I) score for each trial. Linear regression showed significant negative association between age and CSHQ score. In their lifetime, 72% of participants had taken a medication for sleep, most commonly melatonin, clonidine and trazodone. The majority continued these for 6 months or longer. With these medications, many demonstrated significant improvement in sleep disturbances, with no difference in odds of improvement between medications. Disturbed sleep was common in this cohort and significantly worse in younger-aged participants. The majority received at least one medication trial for disturbed sleep and each of the most commonly prescribed medication was effective for a substantial percentage of participants. Most participants remained on medication for at least 6 months, suggesting favorable tolerability.

Profiles of atypical sensory processing in Angelman, Cornelia de Lange and Fragile X syndromes.

BACKGROUND: There is growing evidence to suggest that children with neurodevelopmental disorders may evidence differences in their sensory processing. The aim of this study was to compare sensory processing patterns in three genetic syndromes associated with sensory difference. METHODS: Sensory processing in Angelman syndrome (n = 91), Cornelia de Lange syndrome (n = 28) and Fragile X syndrome (n = 40) was examined using the informant report measure the Sensory Experiences Questionnaire (SEQ). RESULTS: All three groups were associated with a heightened prevalence of unusual sensory processing in comparison with normative data, evidenced in over 80% of all participants. Cross-syndrome comparisons highlighted syndrome-specific sensory processing profiles, with heightened hypo responsivity in Cornelia de Lange syndrome and sensory seeking in Angelman syndrome. CONCLUSIONS: The results have important implications for the understanding of sensory processing in genetic syndromes and the development of tailored behavioural interventions.

Social-emotional processing in nonverbal individuals with Angelman syndrome: evidence from brain responses to known and novel names.

BACKGROUND: The combination of intellectual, communicative and motor deficits limits the use of standardised behavioural assessments in individuals with Angelman syndrome (AS). The current study aimed to objectively evaluate the extent of social-emotional processing in AS using auditory event-related potentials (ERPs) during passive exposure to spoken stimuli. METHODS: Auditory ERP responses were recorded in 13 nonverbal individuals with the deletion subtype of AS, age 4-45 years, during the name recognition paradigm, in which their own names and names of close others (relative or friend) were presented among novel names. No behavioural responses were required. RESULTS: Contrary to findings in typical children and adults, there was no significant evidence of differential neural response to known vs. novel names in participants with AS. Nevertheless, greater amplitude differences between known and unknown names demonstrated the predicted association with better interpersonal relationships and receptive communication abilities. CONCLUSIONS: These findings indicate good tolerability of ERP procedures (85% success rate). The lack of own name differentiation is consistent with increased incidence of the autism-related symptoms in AS. Strong associations between the caregiver reports of adaptive functioning and neural indices of known name recognition support the utility of brain-based measures for objectively evaluating cognitive and affective processes in nonverbal persons with neurodevelopmental disorders.

Anxiety-associated and separation distress-associated behaviours in Angelman syndrome.

BACKGROUND: Anxiety is considered a 'frequent' feature in the clinical criteria for Angelman syndrome; however, the nature and severity of anxiety symptoms have not been well characterised in this population. Anxiety behaviours, especially in response to separation from a preferred caregiver, have been described clinically but have not yet been explored empirically. METHOD: This study used a combination of standardised and clinician-derived survey items to assess the frequency, nature and severity of behaviours associated with anxiety and separation distress in 100 individuals with Angelman syndrome. Family (e.g. income and maternal education) and individual (e.g. age, sex, genetic subtype, sleep difficulties and aggressive behaviours) variables were also gathered to assess possible predictors of higher anxiety levels. Approximately half of the sample was seen in clinic and assessed with standardised measures of development and daily functioning, allowing for an additional exploration of the association between anxiety symptoms and extent of cognitive impairment. RESULTS: Anxiety concerns were reported in 40% of the sample, almost 70% were reported to have a preferred caregiver and over half displayed distress when separated from that caregiver. Individuals with the deletion subtype and individuals who are younger were less likely to have anxiety behaviours. Sleep difficulties and aggressive behaviour consistently significantly predicted total anxiety, the latter suggesting a need for future studies to tease apart differences between anxiety and aggression or anger in this population. CONCLUSIONS: Anxiety concerns, especially separation distress, are common in individuals with Angelman syndrome and represent an area of unmet need for this population.

Lovastatin suppresses hyperexcitability and seizure in Angelman syndrome model.

Epilepsy is prevalent and often medically intractable in Angelman syndrome (AS). AS mouse model (Ube3am-/p+) shows reduced excitatory neurotransmission but lower seizure threshold. The neural mechanism linking the synaptic dysfunction to the seizure remains elusive. We show that the local circuits of Ube3am-/p+in vitro are hyperexcitable and display a unique epileptiform activity, a phenomenon that is reminiscent of the finding in fragile X syndrome (FXS) mouse model. Similar to the FXS model, lovastatin suppressed the epileptiform activity and audiogenic seizures in Ube3am-/p+. The in vitro model of Ube3am-/p+ is valuable for dissection of neural mechanism and epilepsy drug screening in vivo.

Diazepam for outpatient treatment of nonconvulsive status epilepticus in pediatric patients with Angelman syndrome.

Nonconvulsive status epilepticus (NCSE) is present in multiple pediatric neurogenetic syndromes with epileptic encephalopathies. While intravenous (IV) medications are used inpatient for treatment of critical illness-related NCSE, there is no consensus on treatment of ambulatory NCSE. Up to 50% of patients with Angelman syndrome (AS) have NCSE with myoclonic or atypical absence status. Here we report our experience in pediatric patients with AS and NCSE treated outpatient with a tapering course of oral diazepam. We conducted a chart review of 104 patients seen in the Angelman Syndrome Clinic at Massachusetts General Hospital from January 2008 to March 2017, who met the criteria. Response to treatment was defined as cessation of NCSE symptoms with electroencephalogram (EEG) confirmation when possible. Twenty-one patients with NCSE were identified, and 13 patients (9 male) with 25 episodes of NCSE were included. Mean age at NCSE episode was 5years 4months (15months-12years). Six patients had one episode of NCSE, and 7 patients had recurrent episodes (mean: 2.7; range: 2-4). Median diazepam treatment was 6days (4-12days), with a mean dose of 0.32mg/kg/day divided over 2-3 administrations, decreased every 2days. Nine episodes required multiple courses; however, oral diazepam alone was ultimately successful in 80% (20/25) of NCSE episodes. Oral diazepam was well-tolerated with no major side effects. A short course of oral diazepam is well-tolerated and effective in patients with AS who have ambulatory NCSE. It may be considered prior to escalating to inpatient care in AS and possibly other epilepsy syndromes.

Myoclonus in Angelman syndrome.

Angelman syndrome (AS) is a neurogenetic imprinting disorder caused by loss of the maternally inherited Ube3a gene and is characterized by generalized epilepsy, limited expressive speech, sleep dysfunction, and movement disorders. Myoclonic seizures are often the first seizure type to appear, and myoclonic status, associated with developmental regression, may occur in the first few years of life. Additionally, there have been rare reports of prolonged episodes of myoclonus without electrographic correlate in adults with AS. The medical records of 200 individuals seen in the Angelman Syndrome Clinic at the Massachusetts General Hospital and the Lurie Center for Autism were retrospectively reviewed to identify and characterize myoclonic seizures and episodes of nonepileptic myoclonus. Myoclonic seizures were reported in 14% of individuals with age of onset occurring before 8years. These are brief events, unless the individual was experiencing myoclonic status, and electroencephalographs show interictal generalized spike and wave activity. Nonepileptic myoclonus occurred in 40% of individuals over 10years of age, and prevalence appears to increase with age. The episodes of nonepileptic myoclonus arise during puberty or later, with age of onset ranging from 10 to 26years. These events were captured on 5 video electroencephalographs and had no electrographic correlate. They can last from seconds to hours, always occurring in the hands and spreading to the face and all extremities in some individuals. Episodes of nonepileptic myoclonus have a discrete beginning and end, lacks a postictal period, and are not associated with significant alteration of consciousness or developmental regression. These episodes can be difficult to treat and are often refractory to medication; however, levetiracetam, clobazam, and clonazepam appear to be effective for some individuals. Myoclonic seizures are common in AS, typically occurring in young children and associated with epileptiform changes on electroencephalographs. Prolonged episodes are associated with developmental regression. In contrast, nonepileptic myoclonus typically begins in adolescence or early adulthood and has no electroencephalogram (EEG) correlate, alteration in consciousness, or regression but can significantly impact quality of life.

Vagal nerve stimulation for medically refractory epilepsy in Angelman syndrome: a series of three cases.

BACKGROUND: We describe three children with Angelman syndrome and medically refractory epilepsy. METHODS: Case series of three pediatric patients with Angelman syndrome and medically refractory epilepsy. All three patients failed medical treatment and were recommended for vagal nerve stimulator (VNS) implantation. RESULTS: Following VNS implantation, all three patients experienced reduction in seizure frequency greater than that afforded by medication alone. CONCLUSION: We present vagal nerve stimulator implantation as a viable treatment option for medically refractory epilepsy associated with Angelman syndrome.

Main causes of hospitalization in people with Angelman syndrome.

BACKGROUND: The objective was to describe the main causes of hospitalization in people with Angelman syndrome (AS). METHOD: Population-based cross-sectional study in the Community of Madrid (CM), Spain. The information source for AS cases was the information system for rare diseases in the CM. Variables related to hospitalization, for the period 2006-2014, were the following: number of episodes, outcome, main cause, length of stay and type of admission. Main causes of hospitalization were described by age group and sex. RESULTS: The most frequent causes of hospitalization were the following: oral-dental care (28.9%), seizures (19.6%), orthopaedic problems (14.4%) and acute respiratory disorders (12.4%). The percentage of hospitalizations was higher for oral-dental care in women and for orthopaedic problems in men (p-value <.05). Hospitalizations for an acute respiratory disorder were higher in adults (p-value <.05). CONCLUSIONS: Some differences in the causes of hospitalization of people with AS were observed by sex and age.

Rescue of altered HDAC activity recovers behavioural abnormalities in a mouse model of Angelman syndrome.

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe intellectual and developmental disabilities. The disease is caused by the loss of function of maternally inherited UBE3A, a gene that exhibits paternal-specific imprinting in neuronal tissues. Ube3a-maternal deficient mice (AS mice) display many classical features of AS, although, the underlying mechanism of these behavioural deficits is poorly understood. Here we report that the absence of Ube3a in AS mice brain caused aberrant increase in HDAC1/2 along with decreased acetylation of histone H3/H4. Partial knockdown of Ube3a in cultured neuronal cells also lead to significant up-regulation of HDAC1/2 and consequent down-regulation of histones H3/H4 acetylation. Treatment of HDAC inhibitor, sodium valproate, to AS mice showed significant improvement in social, cognitive and motor impairment along with restoration of various proteins linked with synaptic function and plasticity. Interestingly, HDAC inhibitor also significantly increased the expression of Ube3a in cultured neuronal cells and in the brain of wild type mice but not in AS mice. These results indicate that anomalous HDAC1/2 activity might be linked with synaptic dysfunction and behavioural deficits in AS mice and suggests that HDAC inhibitors could be potential therapeutic molecule for the treatment of the disease.

Prevalence of gastrointestinal symptoms in Angelman syndrome.

Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, expressive speech impairment, movement disorder, epilepsy, and a happy demeanor. Children with AS are frequently reported to be poor feeders during infancy and as having gastrointestinal issues such as constipation, reflux, and abnormal food related behaviors throughout their lifetime. To assess the prevalence of gastrointestinal disorders in individuals with AS, we retrospectively analyzed medical records of 120 individuals seen at the Angelman Syndrome Clinic at Massachusetts General Hospital and 43 individuals seen at the University of North Carolina Comprehensive Angelman Clinic. The majority of patients' medical records indicated at least one symptom of gastrointestinal dysfunction, with constipation and gastroesophageal reflux disease (GERD) the most common. Other gastrointestinal issues reported were cyclic vomiting episodes, difficulty swallowing, excessive swallowing, and eosinophilic esophagitis. Upper gastrointestinal symptoms such as GERD, swallowing difficulties, cyclic vomiting, and eosinophilic esophagitis were more common in those with deletions and uniparental disomy, likely related to the involvement of multiple genes and subsequent hypotonia. The frequency of constipation is consistent among all genetic subtypes while early feeding issues appear to mainly affect those with deletions. Caregivers and healthcare providers should be aware of the high prevalence of these issues, as proper treatment may improve not only gastrointestinal dysfunction but also sleep and behavioral issues.

Epilepsy and sleep disorders improve in adolescents and adults with Angelman syndrome: A multicenter study on 46 patients.

OBJECTIVE: Actual knowledge on evolution of Angelman syndrome (AS) relies on questionnaire-based cohort studies, phone interviews, or small retrospective cohort studies focused on specific clinical-genetic features. These reports provide conflicting results. The aim of this study was to assess the long-term outcome of epilepsy, sleep disorders, and EEG in a vast series of AS subjects. METHODS: We collected patients with genetically confirmed AS, aged ≥14years, followed in three tertiary epilepsy Centers or attending the meetings of the Italian Organization for AS (OrSA). Retrospective clinical and EEG data were retrieved from hospital archives or family documents. At index evaluation (IE) (last visit at tertiary Centers or single visit during OrSA meetings), caregivers were interviewed about anamnestic data and filled questionnaires on sleep disorders and daily-living skills. Patients underwent general and neurologic evaluation, and video-EEG recordings. All available EEGs were analyzed to compare evolution of spike-wave index (SWI) over the years. RESULTS: Forty-six subjects aged 14-45years were included: 24 from tertiary Centers, 22 from OrSA meetings. During childhood, 42/46 (91.3%) had seizures, which improved over the years in all subjects. Among patients with epilepsy, 27(64%) became seizure-free at a median age of 10years and 4 remained seizure-free even after antiepileptic withdrawal. During childhood, 39/46 (84.8%) had sleep disorders, which improved in 27/39 (69%) over the years. At IE, daily-living skills corresponded to age≤1.6years in 29/46 (63%). Electroencephalogram showed typical AS patterns in 35/46 (76.1%). In EEGs recorded from 10 patients, SWI was not significantly different between infancy/childhood and adolescence/adulthood. CONCLUSION: Improvement of epilepsy or sleep disorders should not disregard the clinical suspicion of AS in adolescent or adult patients with suggestive features. Drug withdrawal might be considered in the management of epilepsy despite the persistence of epileptiform abnormalities.