Sleep problems in individuals with Angelman syndrome

Prevalence of severe sleep problems and its association with other variables were investigated with 109 individuals who have Angelman syndrome. Severe settling problems, frequent night waking, and early waking were found in 2%, 37%, and 10% of the individuals, respectively. Sleep problems were persistent in this sample. No statistically significant associations were found between presence of a severe sleep problem and other variables (e.g., epilepsy, age, living environment, cause of genetic disorder, parents' and caregivers' coping strategies). Most parents reported adverse effects of their child's sleep problems on their own well-being. Implications for analysis and treatment of sleep problems in individuals with Angelman syndrome are discussed.     

Sleep disturbances in Angelman syndrome: a questionnaire study

Only few studies are available on sleep disorders in Angelman syndrome (AS), a neurodevelopmental disorder with several behavior disturbances. The aim of this study was to determine the prevalence of sleep disorders in a relatively large group of AS subjects, compared to that of age-matched controls. Forty-nine consecutive parents of patients with AS (26 males and 23 females aged 2.3-26.2 years) were interviewed and filled out a comprehensive sleep questionnaire. Based on their genetic etiology, four groups were defined: deletion of chromosome 15q11-13 (25 subjects); methylation imprinting mutation (six subjects), UBE3A mutations (seven subjects) and paternal uniparental disomy (five subjects). In the remaining cases genetic testings were negative. A significantly high frequency of disorders of initiating and maintaining sleep, prolonged sleep latency, prolonged wakefulness after sleep onset, high number of night awakenings and reduced total sleep time were found in our AS patients, as compared to age-matched controls. We also found other types of sleep disorders, never reported before, such as enuresis, bruxism, sleep terrors, somnambulism, nocturnal hyperkinesia, and snoring. No differences were found between the four genetic aetiology groups. Moreover, we did not find important improvement of sleep disturbances from pre-pubertal to post-pubertal ages. Our data confirm the significant presence of sleep/wake rhythms fragmentation, peculiar of AS, and also demonstrate the presence of several other types of sleep disturbances in this syndrome.     

Sleep polygraphy in schizophrenia: methodological issues

The findings of sleep studies in schizophrenia have remained inconsistent in the literature as exemplified by the recent controversy regarding reduced rapid eye movements (REM) latency in these patients. These inconsistencies can partly be explained by major methodological shortcomings in studies evaluating sleep in schizophrenia. Lack of standardized scoring and diagnostic methods in the earlier studies and more recently, the effect of neuroleptic treatment or its withdrawal, have confounded the sleep results. Data are presented to illustrate the effect of the presence of tardive dyskinesia or active psychotic symptoms that further skew the sleep polygraphic measurements in these patients. Studies in drug-naive patients can circumvent some of these confounds but then these studies are weakened by sampling bias. Available data suggest that previous duration of neuroleptic treatment, duration of neuroleptic withdrawal, presence of tardive dyskinesia, and severity of psychotic symptoms should be considered when interpreting REM sleep measures in schizophrenic patients.     

Epilepsy in Angelman syndrome.

Angelman syndrome is a neurogenetic disorder caused by lack of UBE3A gene expression from the maternally inherited chromosome 15 due to various 15q11-q13 abnormalities. In addition to severe developmental delay, virtual absence of speech, motor impairment, a behavioural phenotype that includes happy demeanor, and distinctive rhythmic electroencephalographic features, over 90% of patients have epilepsy. Many different seizure types may occur, atypical absences and myoclonic seizures being particularly prevalent. Non-convulsive status epilepticus is common, sometimes in the context of the epileptic syndrome referred to as myoclonic status in non-progressive encephalopathies. Epilepsy predominates in childhood, but may persist or reappear in adulthood. Management is difficult in a proportion of patients. It might be improved by better understanding of pathophysiology. Current hypotheses involve abnormal inhibitory transmission due to impaired regulation of GABAA receptors related to functional absence of UBE3A and abnormal hippocampal CaMKII activity.     

Sleep disturbances in Ube3a maternal-deficient mice modeling Angelman syndrome

BACKGROUND: Angelman syndrome (AS) is a severe neurodevelopmental disorder with electroencephalographic (EEG) abnormalities and sleep disturbances. It results from lack of the functional maternal allele of UBE3A, which encodes a ubiquitin-protein ligase. Different mechanisms of UBE3A inactivation correlate with clinical phenotypes of varying severity; the majority of cases of AS are due to a de novo maternal deletion of the 15q11-q13 region. METHODS: Ube3a maternal-deficient mice (Ube3a m-/p+) were generated in a C57Bl/6J background. This study compares cortical EEG and architecture of the sleep-waking cycle in adult Ube3a m-/p+ mice compared with those of age-matched WT (m+/p+) mice, under baseline conditions or after 4-h sleep deprivation (SD). RESULTS: Ube3a m-/p+ mice exhibited: reduced slow-wave sleep (SWS) amount with increase waking (W) at the dark/light transitions; increased SWS and W episode numbers; and deterioration of paradoxical sleep (PS) over 24 h [amount: -44%; episode duration: -46%; episode number: -40%; theta peak frequency (TPF) acceleration: 7.6 Hz vs. 7.0 Hz in WT mice]. Characteristic paroxysmal EEG discharges are observed during W and SWS associated with synchronous muscle bursting activity during hypoactive W. During the recovery period following SD, Ube3a m-/p+ mice exhibited no rebound either in slow-wave activity (+89% in WT) or in delta-power spectra but a slight rebound in PS amount (+20%). CONCLUSIONS: These data validate the mouse model produced by null mutation of the maternal Ube3a gene and provide useful results to investigate and better understand the molecular basis of sleep disturbances in AS patients.     

Sleep in individuals with Angelman syndrome: parent perceptions of patterns and problems

The diagnostic criteria for Angelman syndrome includes sleep disturbance as an associated characteristic. There are, however, few researchers who have examined sleep problems in this population. Our goal in this study was to better characterize the sleep patterns and problems in individuals with Angelman syndrome. Parents of 339 individuals between the ages of 3 and 22 completed a previously validated sleep questionnaire. Results confirmed that a variety of sleep problems exist in a significant portion of individuals with Angelman syndrome, most prominently in the areas of sleep initiation, sleep duration, reliance on sleep facilitators, being awakened by loud noises, and being disoriented when aroused. Developmental trends, syndrome specificity of findings, clinical implications, and directions for future research are discussed.     

Sleep in children and adolescents with Angelman syndrome: association with parent sleep and stress

Background Sleep concerns are common in children with Angelman syndrome, with 20–80% of individuals having a decreased sleep need and/or abnormal sleep–wake cycles. The impact of these sleep behaviours on parental sleep and stress is not known. Method Through the use of standardised questionnaires, wrist actigraphy and polysomnography, we defined the sleep behaviours of 15 children/adolescents with Angelman syndrome and the association of the child/adolescents sleep behaviours on parental sleep behaviours and parental stress. Results Both children/adolescents and their parents exhibited over 1 h of wake time after sleep onset and fragmented sleep. Prolonged sleep latency in the child was associated with parent insomnia and daytime sleepiness. Additionally, variability in child total sleep time was associated with parental stress. Conclusions Poor sleep in children/adolescents with Angelman syndrome was associated with poor parental sleep and higher parental stress. Further work is warranted to identify the underlying causes of the poor sleep, and to relate these findings to daytime functioning, behaviour and the family unit.     

Behaviour problems in Angelman syndrome

Angelman syndrome (AS) is a genetic disorder that is associated with a deletion on chromosome 15, and is characterized by abnormalities or impairments in neurological, motor and intellectual functioning. While behaviour problems have been reported iri clients with AS, relatively little is known about their developmental course and outcome. In this study, data on the nature and prevalence of behaviour problems among clients with AS were gathered from two sources: (i) a review of published case reports; and (2) parent responses to a survey of behaviour problems in a small (n= 11) sample of children with AS. Data from both sources showed that behaviour problems were present in males and females of all ages, and included language deficits, excessive laughter, hyperactivity, short attention span, problems with eating and sleeping, aggression, noncompliance, mouthing of objects, tantrums, and repetitive and stereotyped behaviour. Identification and treatment of severe behaviour problems in clients with AS may improve their adaptive functioning.     

Epilepsy and cataplexy in Angelman syndrome. Genotype-phenotype correlations

BackgroundAngelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, epilepsy, and low threshold for laughter.AimsWe investigated the occurrence and severity of epilepsy and laughter-induced loss of postural muscle tone determined by the different genetic subtypes.MethodsThis study included 39 children with AS. Deletion breakpoints were determined by high resolution CGH microarray (1 × 1 M Agilent). Clinical data were based on a parent interview and medical record review.ResultsAll patients with AS based on a deletion had epilepsy. Epilepsy was present in 3/4 children with UBE3A mutation, and 4/5 with pUPD. Onset of epilepsy occurred earlier in deletion cases compared to pUPD or UBE3A mutations cases. Laughter-induced postural muscle tone loss occurred only among deletion cases. We found no differences in severity of epilepsy between children with a larger Class I or a smaller Class II deletions, or between the total group with a deletion compared to children with pUPD or a UBE3A mutation. The drugs most frequently prescribed were benzodiazepines in monotherapy, or a combination of benzodiazepines and valproic acid.ConclusionEpilepsy is very common in patients with AS, especially in patients with a deletion. Postural muscle tone loss and collapsing during outbursts of laughter were seen in patients with a deletion only.     

Natural history of Angelman syndrome

This is an extract from Chapter 2 by Karine Pelc and Bernard Dan of 'Angelman Syndrome' by Bernard Dan. The figures, tables, and references have been removed. The book has recently been published by Mac Keith Press as part of the Clinics in Developmental Medicine Series.     

Sleep polygraphy: diagnostic value in depressive pseudo-dementia. Attempt to improve visual scoring by digital periodic analysis

ARGUMENT: Pseudo depressive dementia is a common pathology for elderly patients. Classically, it is said that depression is taking the mask of dementia, but very often deterioration and depression are present at the same time. Sleep EEG can help the clinician to differentiate dementia and depression in pseudo depressive dementia. Slow Wave Sleep (SWS) is a good indicator of deterioration process. We tried to improve the sleep recording and analysis and our ability to differentiate SWS in this indication. We use a portable digital recording material (Hypnotrace). The signal is analysed by the association of a visual standard method to Digital Periodic Analysis (DPA) which is very sensitive to SWS. The visual analysis gives informations about the macroarchitecture of the night. The Digital Periodic Analysis gives at any moment the value of the wave frequency and thus informations about the microarchitecture. Our hypothesis is that this association helps to better recognise SWS and thus improves sleep EEG as a diagnostic tool in this indication. METHODS: 23 inpatients meeting both the criteria for major depression and dementia (DSM IV) have been recorded during two nights after 15 days of wash out and before antidepressant treatment. The recordings are analysed with the visual standard method and with the help of DPA. The patients are evaluated every 15 days during two months in order to define three groups based on the clinical evolution. RESULTS: The scoring with DPA is more sensitive to Slow Wave Sleep, particularly for the patients with good clinical evolution (with the strongest depressive component). Thus, this method could be a good diagnostic tool to differentiate dementia and depression in pseudo depressive dementia.     

Notched delta, phenotype, and Angelman syndrome.

The notched delta pattern is one of the characteristic EEG features found in Angelman syndrome patients. The purpose of this study was to evaluate the possibility of using the notched delta pattern as a detection tool for Angelman syndrome patients by analyzing its frequency in a tertiary care pediatric center, its specificity for Angelman syndrome, and the age at which it was observed. The authors performed a retrospective review of the video-EEG recordings of all the patients who had either the notched delta pattern or a phenotype consistent with Angelman syndrome. The notched delta was observed in 1.1% of all the EEGs performed. Its specificity for Angelman syndrome was evaluated at 38%. The youngest age at which it was noted was 14 months. The results indicate that the notched delta pattern is relatively rare, but more frequent than expected, and is easily recognizable. The pattern was observed not only in Angelman syndrome patients, but also in children with a spectrum of conditions wider than reported. It is a powerful detection tool for Angelman syndrome when correlated to a suggestive phenotype, and the association of these features should raise suspicion for Angelman syndrome in both infants and adults.     

Perampanel for nonepileptic myoclonus in Angelman syndrome

BackgroundAngelman syndrome (AS) is a neurodegenerative disorder caused by functional loss of the maternal ubiquitin-protein ligase 3A gene. Nonepileptic myoclonus, also described as tremulous movement, often occurs during puberty and increases in adulthood. The involuntary movement in AS has not been defined patho-physiologically and the drugs used such as levetiracetam and piracetam are not always effective. Recently, the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist, perampanel (PER), was used to alleviate myoclonus in progressive myoclonus epilepsy. Herein, we tested the efficacy of PER for nonepileptic myoclonus.Methods and resultsFour patients with AS, aged from 20 to 40 years at the beginning of treatment, were enrolled in our study. All patients reported disruption to their daily lives from the myoclonus movement. They experienced mild to moderate improvement with the starting dose of 2 mg. The dose was increased to 4 mg in one patient to achieve sufficient efficacy, while two had their dose reduced to 1 mg due to dizziness or possible exacerbation of myoclonus. The last patient continued to take the starting dose. Follow-up over 16–20 months revealed a significant reduction in the severity of nonepileptic myoclonus in all patients.ConclusionOur study suggests that PER could be one of the promising drugs for nonepileptic myoclonus in AS.     

Sleep patterns in Kleine-Levin syndrome.

Diurnal and nocturnal sleep records were obtained from a male and a female with Kleine-Levin syndrome, during excessive daytime sleep attacks and while they were asymptomatic. A common pattern of abnormal sleep was seen in both patients even during the asymptomatic period. The female, aflicted with a severe form of periodic hypersomnia, showed nocturnal and diurnal sleep onset REM periods. The different pattern of sleep abnormality in the female could be an expression of the severity of her symptoms or might indicate a variant of sleep abnormality present only in females with Kleine-Levin syndrome.     

Sleep breathing and periodic leg movement pattern in Angelman Syndrome: a polysomnographic study.

OBJECTIVE: The aim of this study was to evaluate the sleep breathing patterns and to detect the eventual presence of periodic leg movements (PLMs) in patients affected by Angelman syndrome (AS). METHODS: Ten children with AS were recruited to participate in the study; the clinical diagnosis was confirmed by the genetic analysis (maternal 15q deletion, uniparental paternal disomy, or mutation of the UBE3A gene). All patients but two had presented epileptic seizures. Two age-matched groups of patients with mental retardation (MR) associated (MRE+) or not (MRE-) to epilepsy were used as control groups. All subjects underwent one polysomnographic recording, after one adaptation night. Sleep stages were scored according to standard criteria slightly modified in order to take into account the specific EEG patterns of AS, also the apnea/hypopnea index (AHI) was quantified; PLMs were identified and the PLM index (PLMI) was computed. The statistical analysis was carried out by means of the one-way ANOVA, followed by the Fisher LSD post-hoc test, when appropriate, and by means of the linear correlation coefficient between AHI and PLMI. RESULTS: Sleep macrostructure showed only few significant differences between children with AS and the other two groups of subjects: AS patients showed higher percentage of wakefulness after sleep onset and sleep onset latency; moreover, the percentage of REM sleep was reduced in AS and in MRE+ subjects. A tendency for AS subjects to present a higher PLMI than the other two groups was also found. AHI >5 was found in 30% of AS subjects, in 30.8% of MRE+, and only in 20% of MRE- patients (chi(2) = 2.359, NS); 70% of AS patients, 38.5% of MRE+, and 46.7% of MRE- subjects had PLMI >5 (chi(2) = 3.088, NS). CONCLUSIONS: These results confirm our previous questionnaire-based findings of a high prevalence of sleep breathing disorder and important PLMs in AS and allow us to hypothesize that epilepsy, rather than mental retardation, might exacerbate these sleep disorders. SIGNIFICANCE: Sleep breathing disorder and PLMs might contribute to the cognitive impairment and to the worsening of life quality of subjects with AS and with MR (mostly those with epilepsy). Therefore, our findings suggest the need to explore these sleep disorders in children affected by MR and to set up a correct treatment.     

Behavior and neuropsychiatric manifestations in Angelman syndrome

Angelman syndrome has been suggested as a disease model of neurogenetic developmental condition with a specific behavioral phenotype. It is due to lack of expression of the UBE3A gene, an imprinted gene located on chromosome 15q. Here we review the main features of this phenotype, characterized by happy demeanor with prominent smiling, poorly specific laughing and general exuberance, associated with hypermotor behavior, stereotypies, and reduced behavioral adaptive skills despite proactive social contact. All these phenotypic characteristics are currently difficult to quantify and have been subject to some differences in interpretation. For example, prevalence of autistic disorder is still debated. Many of these features may occur in other syndromic or nonsyndromic forms of severe intellectual disability, but their combination, with particularly prominent laughter and smiling may be specific of Angelman syndrome. Management of problematic behaviors is primarily based on behavioral approaches, though psychoactive medication (eg, neuroleptics or antidepressants) may be required.     

Neurological aspects of the Angelman syndrome

Angelman syndrome (AS) has emerged as an important neurogenetic syndrome due to its relatively high prevalence and easier confirmation of the diagnosis by improved genetic testing. In infancy, nonspecific clinical features of AS pose diagnostic challenges to the neurologist and these include any combination of microcephaly, seizure disorder, global developmental delay or an ataxic/hypotonic cerebral palsy-like picture. In later childhood, however, absent speech, excessively happy behavior, ataxia and jerky movements usually present as a recognizable clinical syndrome. Brain MRI shows nonspecific or normal findings but occasionally the characteristic EEG patterns alone can lead to the correct diagnosis. The physical, clinical and behavioral aspects appear to be attributable to localized CNS dysfunction of the ubiquitin ligase gene, UBE3A, located at 15q11.2. In certain brain regions, UBE3A normally has mono-allelic expression from the maternally derived chromosome 15. Several distinct genetic mechanisms can inactivate or disrupt the maternally derived UBE3A: chromosome microdeletions, paternal uniparental disomy, imprinting defects and intragenic UBE3A mutations. Those with the deletion type of AS are the most prevalent (about 70% of cases) and appear to have a more severe clinical phenotype. The unique epileptic patterns and distinct behavioral features may be related to multiple actions of UBE3A, possibly occurring during, as well as after, the time of neuronal development.     

Alterations in white matter pathways in Angelman syndrome

Aim Angelman syndrome is a neurogenetic disorder characterized by severe intellectual disability, absent speech, seizures, and outbursts of laughter. The aim of this study was to utilize diffusion tensor imaging (DTI) to examine alterations in white matter pathways in Angelman syndrome, with an emphasis on correlations with clinical severity. Method DTI was used to examine the arcuate fasciculus (AF), uncinate fasciculus (UF), inferior longitudinal fasciculus (ILF), inferior fronto‐occipital fasciculus (IFOF), and the corpus callosum (CC). We enrolled 14 children aged 8 to 17 years (mean age 10y 8mo; SD 2y 7mo) with Angelman syndrome (seven male; seven female) and 13 typically developing children, aged 8 to 17 years, for comparison (five male; eight female; mean age 12y; SD 2y 9mo). Individuals with Angelman syndrome were assessed using standardized measures of development, language, and behaviour. Results The children with Angelman syndrome exhibited lower fractional anisotropy and increased radial diffusivity values than the comparison group for the AF, UF, ILF, and CC (p<0.006 corrected for multiple comparisons). They also had lower fractional anisotropy values for the IFOF and higher radial diffusivity values for the left IFOF (p<0.006). Additionally, children with Angelman syndrome had significantly higher apparent diffusion coefficient values in the AF, CC, ILF, and the left IFOF (p<0.006). Significant correlations were noted between DTI parameters and some of the clinical assessment outcomes (e.g. language, socialization, cognition) for three of the temporal pathways (AF, UF, ILF; p<0.05). Interpretation Changes in DTI parameters in individuals with Angelman syndrome suggest decreased/delayed myelination, decreased axonal density or diameter, or aberrant axonal organization. Our findings suggest a generalized white matter alteration throughout the brain in those with Angelman syndrome; however, only the alterations in temporal white matter pathways were associated with language and cognitive and social functioning.