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At least 19 recordsLinked to original sources
PubMed1998

Methylation PCR analysis of Prader-Willi syndrome, Angelman syndrome, and control subjects.

We report on a relatively large survey of Prader-Willi syndrome, Angelman syndrome, and control subjects with the newly described methylation polymerase chain reaction (PCR) method to determine its usefulness for molecular diagnosis. Sixty-one Prader-Willi syndrome (PWS) individuals (26 men and 35 women), 9 Angelman syndrome (AS) patients (5 men and 4 women), and 58 other individuals were studied with methylation PCR following sodium bisulfite treatment of genomic DNA. In addition, multiple tissues, including fetal tissue, were studied from several individuals to determine the effects of various tissues on methylation PCR results. The expected methylation PCR result was observed in each case. This PCR-based assay evaluates the methylation status of the CpG island of the SNRPN gene and allows for rapid molecular diagnosis of PWS or AS with less labor than Southern hybridization for methylation analysis. The PCR results were identical to those achieved by Southern hybridization in those individuals studied.

Angelman Syndrome↗
PubMed2002

Communication profiles of individuals with Down's syndrome, Angelman syndrome and pervasive developmental disorder.

The communication profiles of individuals with Down's syndrome (DS), Angelman syndrome (AS) and pervasive developmental disorder (PDD) were investigated and contrasted. Seventy-seven individuals participated in the study. A within-group analysis revealed that those with DS performed better on tacting or labelling and echoing than on manding or requesting. No other effects were found, apart from an absence of echoing in those with AS, a result that is hardly surprising. A between-groups analysis revealed no differences between the aetiological groups in terms of their use of mands or requests and tacts. Individuals with DS and PDD did not differ in their scores on echoic functioning. The implications of these findings for the study of behavioural phenotypes and for communication intervention are discussed.

Adolescent↗
PubMed1992

The mouse pink-eyed dilution locus: a model for aspects of Prader-Willi syndrome, Angelman syndrome, and a form of hypomelanosis of Ito.

The region of mouse Chromosome (Chr) 7 containing the mouse pink-eyed dilution locus, p, is syntenic with human chromosome 15q11-q13, a region associated with three human syndromes, Prader-Willi syndrome (PWS), Angelman syndrome (AS), and a form of hypomelanosis of Ito (HI). Because some mutant alleles of p also share a subset of phenotypes with PWS, AS, and HI, the same gene or genes disrupted by p locus mutations are potentially involved in the phenotypes of PWS, AS, and HI.

Animals↗
PubMed2004

A familial balanced inverted insertion ins(15)(q15q13q11.2) producing Prader-Willi syndrome, Angelman syndrome and duplication of 15q11.2-q13 in a single family: Importance of differentiation from a paracentric inversion.

We reascertained a family in which first cousins were affected by Angelman syndrome and Prader-Willi syndrome. A paracentric inversion of 15q11-q15 had previously been reported in this family but we show, using fluorescence in situ hybridization (FISH), that the rearrangement segregating in this family is not a paracentric inversion but an inverted intrachromosomal insertion, inv ins(15)(q15q13q11.2). We also describe a further recombinant resulting in a maternal duplication of the Prader-Willi/Angelman critical region. This family illustrates the importance of distinguishing paracentric inversions from intrachromosomal insertions.

Adolescent↗
PubMed1999

Parental imprinting and Angelman syndrome.

Angelman syndrome is an inherited disorder that includes severe mental retardation and epilepsy. Patients have no speech, puppet-like gait with jerky movements, hyperactivity, disturbed sleep, bouts of inappropriate laughter, a pronounced jaw, and widely spaced teeth. The syndrome results from deletion or mutation within maternal chromosome 15q11-q13. Considerable evidence suggests that the gene or genes responsible for Angelman syndrome are expressed only from the maternal chromosome 15, a situation known as parental imprinting. This epigenetic marking of certain regions of the parental genomes is characterized by parent-of-origin-specific allelic DNA methylation, allele-specific DNA replication timing, and physical pairing of the two chromosome 15 homologues. Imprinting is important for normal development, and its disregulation causes several human disorders. The epilepsy of Angelman syndrome has been studied and indicates a rather typical electroencephalographic abnormality with slowing and notched wave and spikes. Various types of seizures occur, usually including myoclonus and atypical absence. Variable severity among patients suggests potential molecular diversity in the genetic mechanism, possibly the involvement of more than one gene. Angelman syndrome can arise from the following molecular genetic defects: a deletion in 15q11-q13 that covers the Angelman gene or genes, mutations that alter imprinting, and paternal uni-parental disomy for the region. Another 20% or so of patients with clinical symptoms of Angelman syndrome have none of these three defects but are believed to have mutations in one or more genes in the region, and this may be familial. The UBE3A gene, which codes for the enzyme ubiquitin protein ligase involved in protein degradation and processing, has been found to be mutated in many but not all of patients with Angelman syndrome and can be considered a major Angelman candidate gene. Other potential candidate genes in the region include a cluster of three GABAA receptor subunits, which are involved in inhibitory synaptic transmission in the brain. The GABRB3 gene, which codes for the beta 3 subunit, is deleted in most persons with Angelman syndrome. The absence of this gene in mice causes craniofacial abnormalities and neurologic impairment with seizures. The exact role of UBE3A and GABRB3 in the syndrome and their imprinting status are under investigation.

Alleles↗
PubMed2005

Analysis of the characteristics of epilepsy in 37 patients with the molecular diagnosis of Angelman syndrome.

Angelman syndrome is a genetic disorder caused by defects in the maternally inherited imprinted domain located on chromosome 15q11-q13. Most patients with Angelman syndrome present with severe mental retardation, characteristic physical appearance, behavioral traits, and severe, early-onset epilepsy. We retrospectively reviewed the medical histories of 37 patients, all with the molecular diagnosis of Angelman syndrome and at least three years of follow-up in our neurology department, for further information about their epilepsy: age of onset, type of seizures initially and during follow-up, EEG recordings, treatments and response. The molecular studies showed 87% deletions de novo, 8% uniparental, paternal disomy, and 5% imprinting defects. The median age at diagnosis was 6.5 years, with 20% having begun to manifest febrile seizures at an average age of 1.9 years. Nearly all (95%) presented with epilepsy, the majority under the age of three (76%). The most frequent seizure types were myoclonic, atonic, generalized tonic-clonic and atypical absences. At onset, two patients exhibited West syndrome. EEG recordings typical of Angelman syndrome were found in 68%. Normalization of EEG appeared in 12 patients after nine years. Control of epileptic seizures improved after the age of 8.5 years. The most effective treatments were valproic acid and clonazepam. We conclude that epilepsy was present in nearly all of our cases with Angelman syndrome, and that the EEG can be a useful diagnostic tool. On comparing the severity of epilepsy with the type of genetic alteration, we did not find any statistically significant correlations.

Adolescent↗
PubMed1999

Distinctive pattern of behavioral functioning in Angelman syndrome.

Angelman syndrome is a neurogenetic disorder that is characterized by impairments in neurological, motor, and intellectual functioning. This study compared 27 participants with Angelman syndrome to clinical and community participants with developmental disabilities of mixed etiology to determine whether Angelman syndrome is associated with a distinctive pattern of behavioral functioning. The groups with and without Angelman syndrome were matched on chronological age, gender, and level of intellectual functioning. The dependent measure was parent ratings of maladaptive behavior using the Aberrant Behavior Checklist. The Angelman syndrome group had significantly lower scores on measures of irritability and lethargy. Results contribute to the delineation of a behavior phenotype for the syndrome.

Adolescent↗
PubMed2002

Drowning as a cause of death in Angelman syndrome.

Angelman syndrome is characterized by mental retardation, seizures, ataxia, inappropriate laughter, lack of speech, a particular facial appearance, and generally a chromosome 15q11-q13 deletion. Recently, a fascination with water and water-related activities has been reported in individuals with the syndrome. We report on a 9.6-year-old male previously diagnosed with Angelman syndrome who died unexpectedly by drowning in a shallow backyard wading pool. This case further illustrates the fascination with water by individuals with Angelman syndrome and highlights that this fascination may lead to death. We wish to alert careproviders that this fascination with water and water-related activities may contribute to death and that these individuals should be closely supervised when in the presence of water.

Angelman Syndrome↗
PubMed2002

Effects of environmental events on smiling and laughing behavior in Angelman syndrome.

Angelman syndrome is a neurogenetic disorder associated with unique behaviors and characteristics, including an unusually happy expression, inability to speak, ataxia, mental retardation, and abnormal EEG. Previous research has suggested that smiling and laughing behaviors in Angelman syndrome are inappropriate, excessive, and dissociated from contextual events. In the present study, the variability of smiling and laughing behaviors of 3 individuals with Angelman syndrome was examined across typical social contexts. Results indicate that laughing and smiling increased during social situations and occurred at low levels during non-social situations. The behaviors, therefore, did not occur totally inappropriately, as has been suggested. The findings illustrate the need to divert attention to the examination of environmental influences on purported phenotypic behavior in genetic syndromes.

Adolescent↗
PubMed2004

From electrophysiology to chromatin: a bottom-up approach to Angelman syndrome.

Angelman syndrome is one of the most studied human diseases related to a gene that is expressed on the maternal chromosome only in at least some brain cells. It is caused by inactivation of the UBE3A gene in the brain due to various abnormalities of the 15q11-q13 chromosome inherited from the mother. It is characterized by severe developmental delay, seizures, virtual absence of speech, motor impairment, and a particular behavioral phenotype. Studies of cortical, electromyographic and cerebellar electrophysiology in patients with Angelman syndrome and a mouse model revealed unique rhythmic neurophysiological activities in the cerebral cortex, cerebellar cortex, and muscles. The oscillatory patterns may be linked to molecular pathophysiology of the syndrome involving dysregulation of synaptic neurotransmission through UBE3A-related modulation of functional GABAA receptor complexes.

Angelman Syndrome↗
PubMed1998

Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome.

Angelman syndrome (AS) is a severe neurodevelopmental disorder resulting from a deletion/mutation in maternal chromosome 15q11-13. The genes in 15q11-13 contributing to the full array of the clinical phenotype are not fully identified. This study examines whether a loss or reduction in the GABAA receptor beta3 subunit (GABRB3) gene, contained within the AS deletion region, may contribute to the overall severity of AS. Disrupting the gabrb3 gene in mice produces electroencephalographic abnormalities, seizures, and behavior that parallel those seen in AS. The seizures that are observed in these mice showed a pharmacological response profile to antiepileptic medications similar to that observed in AS. Additionally, these mice exhibited learning and memory deficits, poor motor skills on a repetitive task, hyperactivity, and a disturbed rest-activity cycle, features all common to AS. The loss of the single gene, gabrb3, in these mice is sufficient to cause phenotypic traits that have marked similarities to the clinical features of AS, indicating that impaired expression of the GABRB3 gene in humans probably contributes to the overall phenotype of Angelman syndrome. At least one other gene, the E6-associated protein ubiquitin-protein ligase (UBE3A) gene, has been implicated in AS, so the relative contribution of the GABRB3 gene alone or in combination with other genes remains to be established.

Age Factors↗
PubMedDate not supplied

EEG--a valuable tool in early diagnosis of Angelman syndrome.

Angelman Syndrome (happy puppet syndrome) is one of the genetic diseases causing developmental delay in children. Late diagnosis used to be the rule because of delayed appearance of disease markers such as craniofacial dysmorphism, ataxia, unprovoked laughter and seizure. However, reports have described characteristic EEG changes such as 2-3 Hz large amplitude slow wave paroxysms which appear early and are quite specific to the syndrome. With EEG aid, we made very early diagnosis in a 9 month-old young infant. And we would like to advocate the use of EEG study in cryptogenic psychomotor retardation in children.

Angelman Syndrome↗
PubMed2002

Familial interstitial 570 kbp deletion of the UBE3A gene region causing Angelman syndrome but not Prader-Willi syndrome.

Angelman syndrome (AS) is a disorder of psychomotor development caused by loss of function of the imprinted UBE3A gene. Since the paternal UBE3A copy is regularly silent, only mutations inactivating the maternal copy cause AS. Among 1,272 patients suspected of AS, we found one with an isolated deletion of the UBE3A gene on the maternally inherited chromosome. Initial DNA methylation testing at the SNURF-SNRPN locus in the patient revealed a normal pattern. The deletion was only detected through allelic loss at microsatellite loci D15S1506, D15S122, and D15S210, and confirmed with fluorescence in situ hybridization (FISH) using bacterial artificial chromosome (BAC) probes derived from the loci. It extends approximately 570 kilobase pairs (kbp), encompassing the UBE3A locus, and is flanked by loci PAR/SN and D15S986. The deletion is familial, and haplotype studies suggest that a great grandfather of the index patient already carried this deletion, and that it causes AS when inherited through the female germline but not Prader-Willi syndrome (PWS) when paternally inherited. Our findings support the hypothesis that the functional loss of maternal UBE3A gene activity is sufficient to cause AS and that the deleted region does not contain genes or other structures that are involved in PWS. Finally, this case highlights that methylation tests can fail to detect some familial AS cases with a recurrence risk of 50%.

Angelman Syndrome↗
PubMed2005

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.

Adolescent↗
PubMed1995

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 in 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: (1) 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.

Adolescent↗
PubMed2000

Novel mutations of ubiquitin protein ligase 3A gene in Italian patients with Angelman syndrome.

Angelman syndrome is a neurobehavioral disorder caused by defects of imprinted gene(s) on chromosome 15q11-13. AS-specific DNA methylation is found in patients carrying 3-4 Mb deletions ( approximately 70%), paternal uniparental disomy (3-5%) or imprinting center mutations (2-9%), while normal methylation pattern with biparental inheritance characterizes the remaining approximately 20-25% AS patients (Stalker et al.,1998; Tsai et al.,1998). Mutations in the Ubiquitin protein ligase 3A gene (UBE3A) have been found in the latter group, but only preliminary figures are available on their frequencies. We selected a sample of 25 AS patients with a clinical diagnosis of AS and a normal methylation pattern in order to search for mutations of the UBE3A gene. Automated sequencing of exons 8, 9, 10, 11 and 12 performed on our 25 patients allowed us to identify three novel mutations: an 897insA in two unrelated familial cases, a 2544insA and an E167X in two sporadic cases. Mutation R482X previously reported in a sporadic patient was identified in a third familial case. Hum Mutat 15:387, 2000.

Adolescent↗
PubMed2004

Cognitive and adaptive behavior profiles of children with Angelman syndrome.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by maternal deficiency of the UBE3A gene that encodes E6-AP ubiquitin-protein ligase. Expression of the UBE3A gene from the maternal chromosome is essential to prevent AS. AS is characterized by severe mental retardation, ataxia, and a defined behavioral pattern characterized mainly by happy/sociable disposition. This study used the Bayley Scales of Infant Development and the Vineland Adaptive Behavior Scales to examine the cognitive abilities and adaptive behavior of children (n = 20) with the four known molecular classes of AS, including patterns of strengths and weaknesses across adaptive behavior domains, and the relationship between adaptive behavior and overall cognitive abilities. Cognitive skills fell within the severe to profound range of mental deficiency. Differences in cognitive skills according to genetic subtype only partially supported previous research and suggest that there is overlap in abilities across genetic subtypes of AS. Adaptive behavior skills were also significantly delayed, with participants demonstrating a significant strength in socialization, and a weakness in motor skills. Strong, positive correlations emerge between cognitive ability scores and adaptive behaviors scores. These results provide further delineation of a cognitive/behavioral phenotype in AS.

Age Factors↗