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Introduction: Angelman syndrome (AS) is a rare, genetic, neurodevelopmental disorder characterized by severe impairments in speech, cognition, and motor skills accompanied by unique behaviors, distinct facial features, and high prevalence of epilepsy and sleep problems. Despite some reports of short stature among AS patients, this feature is not included in the clinical criteria defined in 2005. We investigated growth patterns among AS patients with respect to mutation type, growth periods, family history, and endocrine abnormalities. Methods: Data were collected from patients' medical files in AS National Clinic. Mutation subtypes were divided to deletion and non-deletion. Four growth periods were defined: preschool, childhood, peak height velocity, and final height. Results: The cohort included 88 individuals (46 males), with 54 (61.4%) carrying deletion subtype. A median of 3 observations per individual produced 280 data points. Final height SDS was significantly lower compared to general population (−1.23 ± 1.26, p < 0.001), and in deletion group versus non-deletion (−1.67 ± 1.3 vs. −0.65 ± 0.96, p = 0.03). Final height SDS was significantly lower compared to height SDS in preschool period (−1.32 vs. −0.47, p = 0.007). Patient's final height SDS was significantly lower than the parents' (∆final-height SDS = 0.94 ± 0.99, p = 0.002). IGF1-SDS was significantly decreased compared to general population (−0.55 ± 1.61, p = 0.04), with lower values among deletion group (−0.70 ± 1.44, p = 0.01). Conclusions: AS patients demonstrate specific growth pattern with deceleration during childhood and adolescence, resulting in significantly decreased final height compared to normal population, and even lower among deletion subgroup, which could be attributed to reduced IGF1 levels. We propose adding short stature to the clinical criteria and developing adjusted growth curves for AS population. [ABSTRACT FROM AUTHOR]

Methyl CpG binding protein-2 (MeCP2) is an essential epigenetic regulator in human brain development. Rett syndrome, the primary disorder caused by mutations in the X-linked MECP2 gene, is characterized by a period of cognitive decline and development of hand stereotypies and seizures following an apparently normal early infancy. In addition, MECP2 mutations and duplications are observed in a spectrum of neurodevelopmental disorders, including severe neonatal encephalopathy, X-linked mental retardation, and autism, implicating MeCP2 as an essential regulator of postnatal brain development. In this review, we compare the mutation types and inheritance patterns of the human disorders associated with MECP2. In addition, we summarize the current understanding of MeCP2 as a central epigenetic regulator of activity-dependent synaptic maturation. As MeCP2 occupies a central role in the pathogenesis of multiple neurodevelopmental disorders, continued investigation into MeCP2 function and regulatory pathways may show promise for developing broad-spectrum therapies.

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation and impaired speech. Because patients with this disorder often exhibit motor tremor and stereotypical behaviors, which are associated with basal ganglia pathology, we hypothesized that AS is accompanied by abnormal functioning of the striatum, the input nucleus of the basal ganglia. Using mutant mice with maternal deficiency of AS E6-AP ubiquitin protein ligase Ube3a ( Ube3am−/p+), we assessed the effects of Ube3a deficiency on instrumental conditioning, a striatum-dependent task. We used whole-cell patch-clamp recording to measure glutamatergic transmission in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). Ube3am−/p+ mice were severely impaired in initial acquisition of lever pressing. Whereas the lever pressing of wild-type controls was reduced by outcome devaluation and instrumental contingency reversal, the performance of Ube3am−/p+ mice were more habitual, impervious to changes in outcome value and action-outcome contingency. In the DMS, but not the DLS, Ube3am−/p+ mice showed reduced amplitude and frequency of miniature excitatory postsynaptic currents. These results show for the first time a selective deficit in instrumental conditioning in the Ube3a deficient mouse model, and suggest a specific impairment in glutmatergic transmission in the associative corticostriatal circuit in AS. [ABSTRACT FROM AUTHOR]

Genomic imprinting is an epigenetic phenomenon affecting a small number of genes, which leads to differential expression from the two parental alleles. Imprinted genes are known to regulate fetal growth and a ‘kinship’ or ‘parental conflict’ model predicts that paternally and maternally expressed imprinted genes promote and inhibit fetal growth, respectively. In this review we examine the role of imprinted genes in postnatal growth and metabolism, with an emphasis on the GNAS/Gnas locus. GNAS is a complex imprinted locus with multiple oppositely imprinted gene products, including the G-protein α-subunit Gsα that is expressed primarily from the maternal allele in some tissues and the Gsα isoform XLαs that is expressed only from the paternal allele. Maternal, but not paternal, Gsα mutations lead to obesity in Albright hereditary osteodystrophy. Mouse studies show that this phenomenon is due to Gsα imprinting in the central nervous system leading to a specific defect in the ability of central melanocortins to stimulate sympathetic nervous system activity and energy expenditure. In contrast mutation of paternally expressed XLαs leads to opposite metabolic effects in mice. Although these findings conform to the ‘kinship’ model, the effects of other imprinted genes on body weight regulation do not conform to this model. [ABSTRACT FROM AUTHOR]

Abstract: The knockout mouse for the beta3 subunit of the GABAA receptor exhibits spontaneous epilepsy and hyperactivity, and has been proposed as a model for the severe developmental disorder, Angelman''s syndrome, which is known to be of genetic origin. We have used this mutant to test an approach of therapeutic intervention prior to seizure onset by daily injection with diazepam during either the first or second postnatal week. Results showed differences between postnatal week 1 and week 2 injections both acutely, with respect to sedative effects, and in long-term outcome, with respect to EEG and behavioral tests measured at 12–14 weeks of age. The EEG of control mice remained unaffected under all conditions, but the EEG of beta3 (−/−) injected with diazepam in week 1 was worsened, showing increased oscillatory activity at 5–6Hz, and more myoclonic jerks, particularly among males. For beta3 (−/−) injected with diazepam in week 2, the EEG was normalized in half the mice but worsened similarly to week 1 in the other half. Neonatal diazepam injection had a long-term normalizing effect on behavior of beta3 (−/−) mice injected in week 1, but diazepam treatment in week 2 did not affect the hyperactive and circling behavior characteristic of the beta3 knockout mouse. Diazepam treatment in postnatal week 2 significantly decreased anxiety in the adult beta3 group. Diazepam treatment in both postnatal weeks 1 and 2 improved the motor coordination of beta3 (−/−) on the rotarod, although performance of control mice injected with diazepam in postnatal week 2 was significantly impaired. The observed long-term outcome of neonatal diazepam injections may result from interference with developmental processes, and shows that enhancing GABAergic activity with diazepam during the period where GABA can be excitatory can produce narrow stage-related effects on brain development. [Copyright &y& Elsevier]

Genomic imprinting is a mechanism by which only one copy of a gene pair is expressed, and this expression is determined by the parental origin of the copy. The deregulation of imprinted genes has been implicated in a number of human diseases. The Imprinted Gene Catalogue now has more than 200 genes listed, and estimates based on mouse models suggest many more may exist in humans. Therefore, the development of methods to identify such genes is important. In this communication, we present a parametric model-based approach to analyzing arbitrary-sized pedigree data for genomic imprinting. We have modified widely used LINKAGE program to incorporate our proposed approach. In addition, our approach allows for the use of sex-specific recombinations in the analysis, which is of particular importance in a genome-wide analysis for imprinted genes. We compared our imprinting analysis approach to that implemented in the GENEHUNTER-IMPRINT program using simulation studies as well as by analyzing causal genes in Angelman’s syndrome families, which are known to be imprinted. These analyses showed that the proposed approach is very powerful for detecting imprinted genes in large pedigrees. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Peters SU, Beaudet AL, Madduri N, Bacino CA. Autism in Angelman's syndrome: implications for autism research.Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe mental retardation, ataxia, and a happy/sociable disposition. Maternally, but not paternally, derived defects, such as duplications, within the AS critical region result in autistic symptomatology, suggesting that theUBE3Agene might be implicated in the causation of autism. This study examined the prevalence of autism in AS in 19 children representing three known molecular classes of AS. Children were studied over the course of 1 year. Forty-two percent of this population, eight of 19 children, met criteria for autism according to the Autism Diagnostic Observation Schedule (ADOS). Parents of children who were diagnosed with autism according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria as well as the ADOS– Generic, Module 1 (ADOS-G) were administered the Autism Diagnostic Interview– Revised (ADI-R). Data from the ADI-R were convergent with data from the ADOS-G in all cases. 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 ofUBE3Amay play a role in the causation of autism. [ABSTRACT FROM AUTHOR]

The diagnostic features of 36 cases of Angelman's “happy puppet” syndrome are reported from the Hospital for Sick Children, Great Ormond Street, London.