This disorder is a rare genetic/neuro-developmental disorder, initially described by Angelman (1965), characterised by severe learning difficulty, particular facial appearance, and an awkward gait plus 'jerky' arm movements.

ASF's mission is to advance the awareness and treatment of Angelman Syndrome through education, information exchange and research.

The aim was to explore the comorbidity between Angelman syndrome and autism spectrum disorders (ASDs). Identification of autism in children with Angelman syndrome presents a diagnostic challenge. In the present study, 16 children with Angelman syndrome, all with a 15q11-13 deletion, were examined for ASDs. Thirteen children with Angelman syndrome received an ADOS-G algorithm classification of ASD; the remaining three were outside the autistic spectrum. Ten fulfilled the criteria for autism, and three for PDD-NOS. The 10 children with Angelman syndrome and comorbid autism were compared with eight children with only autism regarding their social and communicative skills. The results indicated that Angelman syndrome is better understood in terms of developmental delay, and autism in terms of developmental deviance. It is concluded that autism might have been overdiagnosed due to the extremely low mental age of the children with Angelman syndrome.

Children with comorbid autism and AS scored lower on measures of language, adaptive behavior, and cognition, and demonstrated a slower rate of improvement over the course of the study. Furthermore, they demonstrated deficits in communication and socialization that mirror those observed in children with idiopathic autism. The study highlights the phenotypic overlap between autism and AS and increases the probability that dysregulation of UBE3A may play a role in the causation of autism.

We describe here a 15q11�q13 genomic inversion in mothers of AS BP2/3-deleted patients and in 9% of subjects of the general population. Since BP2 and BP3 segmental duplications are usually in a tail-to-tail orientation (10,11), the inverted chromosomes are likely to arise by non-homologous recombination events between the high sequence identity of these segmental duplications.

Maternal duplications of the imprinted 15q11-13 domain result in an estimated 1%ndash2% of autism-spectrum disorders, and linkage to autism has been identified within 15q12-13. UBE3A, the Angelman syndrome gene, has, to date, been the only maternally expressed, imprinted gene identified within this region, but mutations have not been found in autistic patients. Here we describe the characterization of ATP10C, a new human imprinted gene, which encodes a putative protein homologous to the mouse aminophospholipid-transporting ATPase Atp10c. ATP10C maps within 200 kb distal to UBE3A and, like UBE3A, also demonstrates imprinted, preferential maternal expression in human brain. The location and imprinted expression of ATP10C thus make it a candidate for chromosome 15ndashassociated autism and suggest that it may contribute to the Angelman syndrome phenotype.

The most common etiology for Prader-Willi syndrome and Angelman syndrome is de novo interstitial deletion of chromosome 15q11-q13. Deletions and other recurrent rearrangements of this region involve four common `hotspots' for breakage, termed breakpoints 1-4 (BP1-BP4). Construction of an ~4 Mb YAC contig of this region identified multiple sequence tagged sites (STSs) present at both BP2 and BP3, suggestive of a genomic duplication event. Interphase FISH studies demonstrated three to five copies on 15q11-q13, one copy on 16p11.1-p11.2 and one copy on 15q24 in normal controls, while analysis on two Class I deletion patients showed loss of approximately three signals at 15q11-q13 on one homolog. Multiple FISH signals were also observed at regions orthologous to both human chromosomes 15 and 16 in non-human primates, including Old World monkeys, suggesting that duplication of this region may have occurred ~20 million years ago. A BAC/PAC contig for the duplicated genomic segment (duplicon) demonstrated a size of ~400 kb. Surprisingly, the duplicon was found to contain at least seven different expressed sequence tags representing multiple genes/pseudogenes. Sequence comparison of STSs amplified from YAC clones uniquely mapped to BP2 or BP3 showed two different copies of the duplicon within BP3, while BP2 comprised a single copy. The orientation of BP2 and BP3 are inverted relative to each other, whereas the two copies within BP3 are in tandem. The presence of large duplicated segments on chromosome 15q11-q13 provides a mechanism for homologous unequal recombination events that may mediate the frequent rearrangements observed for this chromosome.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, encoding methyl-CpG-binding protein 2 (MeCP2). Brain samples from several related neurodevelopmental disorders, including autism, pervasive developmental disorder, Prader-Willi and Angelman syndromes showed significant differences in MeCP2 expression from age-matched controls by apparently different transcriptional and post-transcriptional mechanisms. These results suggest that multiple pathways regulate the complex developmental expression of MeCP2 and are defective in autism-spectrum disorders in addition to RTT.

The syndrome was first recognized in 1965, when English physician Harry Angelman described peculiar behavioral abnormalities in three patients and hypothesized that the cases were linked to a single but as-yet unnamed disease. The children with their flapping arms and laughter reminded Angelman of an oil painting by Gian Francesco Caroto, "Boy With a Puppet."

Angelman syndrome (AS) is characterized by mental retardation, absence of speech, seizures and motor dysfunction. AS is caused by maternal deletions for chromosome 15q11-q13, paternal uniparental disomy (UPD), imprinting defects or loss-of-function mutations in the UBE3A locus which encodes E6-AP ubiquitin-protein ligase. The UBE3A gene is imprinted with paternal silencing in human brain and similar silencing of the Ube3a locus in Purkinje cells and hippocampal neurons in the mouse. We have sequenced the major coding exons for UBE3A in 56 index patients with a clinical diagnosis of AS and a normal DNA methylation pattern. The analysis identified disease-causing mutations in 17 of 56 patients (30%) including 13 truncating mutations, two missense mutations, one single amino acid deletion and one stop codon mutation predicting an elongated protein. Mutations were identified in six of eight families (75%) with more than one affected case, and in 11 of 47 isolated cases (23%); no mutation was found in one family with two siblings, one with a typical and one with an atypical phenotype. Mutations were de novo in nine of the 11 isolated cases. An amino acid polymorphism of threonine substituted for alanine at codon 178 was identified, and a 3 bp length polymorphism was found in the intron upstream of exon 8. In all informative cases, phenotypic expression was consistent with imprinting with a normal phenotype when a mutation was on the paternal chromosome and an AS phenotype when a mutation was on the maternal chromosome. Laboratory diagnosis and genetic counseling for AS are complex, and mutation analysis is valuable in clinically typical AS patients with a normal methylation analysis.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two distinct neurological disorders that map to human chromosome 15q11-q13 and involve perturbations of imprinted gene expression. PWS is caused by a deficiency of paternal gene expression and AS is caused by a deficiency of maternal gene expression. Experiments in the last year have focused on molecular analysis of the human chromosomal region as well as the homologous region on central mouse chromosome 7. New transcripts and exons have been identified and the epigenetic status of the PWS/AS region in mice and humans has been examined. The imprinting center that is hypothesized to control the switch between the maternal and paternal epigenotypes has also been characterized in greater detail and a mouse model that deletes the homologous element demonstrates a conservation in imprinting center function between mice and humans. In addition, analysis of non-deletion AS patients has revealed that UBE3A intragenic mutations are found in a significant number of cases. However, both human patients and mouse model systems indicate that other genes may also contribute to the AS phenotype. Thus, although much has been learned in the last year, considerable information is still required before these complex syndromes are fully understood.