MedWorm: Angelman Syndrome

TDP-43 pathology in a case of hereditary spastic paraplegia with a NIPA1/SPG6 mutation

Acta Neuropathologica — Thu, 02 Feb 2012 18:15:30 +0100

We present the first neuropathological description of a patient with a NIPA1 mutation, and clinical phenotype of complicated HSP with motor neuron disease-like syndrome and cognitive decline. Postmortem examination revealed degeneration of lateral corticospinal tracts and dorsal columns with motor neuron loss. TDP-43 immunostaining showed widespread spinal cord and cerebral skein-like and round neuronal cytoplasmic inclusions. We ruled out NIPA1 mutations in 419 additional cases of motor neuron disease. These findings suggest that hereditary spastic paraplegia due to NIPA1 mutations could represent a TDP-43 proteinopathy. Content Type Journal ArticleCategory Case ReportsPages 1-7DOI 10.1007/s00401-012-0947-yAuthors Maria Martinez-Lage, Department of Pathology and Laboratory Medi...

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UNC Study Could Lead To A Treatment For Angelman Syndrome

Health News from Medical News Today — Sun, 01 Jan 2012 08:00:00 +0100

Results of a new study from the University of North Carolina at Chapel Hill may help pave the way to a treatment for a neurogenetic disorder often misdiagnosed as cerebral palsy or autism. Known as Angelman syndrome, or AS, its most characteristic feature is the absence or near absence of speech throughout the person's life. Occurring in one in 15,000 live births, other AS characteristics include intellectual and developmental delay, severe intellectual disability, seizures, sleep disturbance, motor and balance disorders... (Source: Health News from Medical News Today)

Transcription Is Required to Establish Maternal Imprinting at the Prader-Willi Syndrome and Angelman Syndrome Locus

PLoS Genetics — Thu, 29 Dec 2011 05:00:00 +0100

by Emily Y. Smith, Christopher R. Futtner, Stormy J. Chamberlain, Karen A. Johnstone, James L. Resnick The Prader-Willi syndrome (PWS [MIM 17620]) and Angelman syndrome (AS [MIM 105830]) locus is controlled by a bipartite imprinting center (IC) consisting of the PWS-IC and the AS-IC. The most widely accepted model of IC function proposes that the PWS-IC activates gene expression from the paternal allele, while the AS-IC acts to epigenetically inactivate the PWS-IC on the maternal allele, thus silencing the paternally expressed genes. Gene order and imprinting patterns at the PWS/AS locus are well conserved from human to mouse; however, a murine AS-IC has yet to be identified. We investigated a potential regulatory role for transcription from the Snrpn alternative upstream exons in sil...

[News & Analysis] Neurodevelopmental Disorders: New Hope for a Devastating Neurological Disorder

Science: Current Issue — Fri, 23 Dec 2011 06:32:20 +0100

Scientists have identified a drug that, in mice, fixes the genetic defect behind Angelman syndrome, which robs victims of speech and leaves them with intellectual disabilities, movement and balance problems.Author: Greg Miller (Source: Science: Current Issue)

Angelman syndrome: Drugs to awaken a paternal gene

Nature AOP — Wed, 21 Dec 2011 05:00:00 +0100

Nature advance online publication 21 December 2011. doi:10.1038/nature10784 Author: Arthur L. Beaudet Mutations in the maternal copy of the UBE3A gene cause a neurodevelopmental disorder known as Angelman syndrome. Drugs that activate the normally silenced paternal copy of this gene may be of therapeutic value. (Source: Nature AOP)

Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons

Nature AOP — Wed, 21 Dec 2011 05:00:00 +0100

Authors: Hsien-Sung Huang, John A. Allen, Angela M. Mabb, Ian F. King, Jayalakshmi Miriyala, Bonnie Taylor-Blake, Noah Sciaky, J. Walter Dutton, Hyeong-Min Lee, Xin Chen, Jian Jin, Arlene S. Bridges, Mark J. Zylka, Bryan L. Roth & Benjamin D. Philpot Angelman syndrome is a severe neurodevelopmental disorder caused by deletion or mutation of the maternal allele of the ubiquitin protein ligase E3A (UBE3A). In neurons, the paternal allele of UBE3A is intact but epigenetically silenced, raising the possibility that Angelman syndrome could be treated by activating this silenced allele to restore functional UBE3A protein. Using an unbiased, high-content screen in primary cortical neurons from mice, we identify twelve topoisomerase I inhibitors and four topoisomerase II inhibitors that unsile...

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Angelman syndrome: Drugs to awaken a paternal gene

Nature — Wed, 21 Dec 2011 05:00:00 +0100

Authors: Arthur L. Beaudet Mutations in the maternal copy of the UBE3A gene cause a neurodevelopmental disorder known as Angelman syndrome. Drugs that activate the normally silenced paternal copy of this gene may be of therapeutic value. See Letter p.185 (Source: Nature)

Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons

Nature — Wed, 21 Dec 2011 05:00:00 +0100

Epilepsy in four genetically determined syndromes of intellectual disability

Journal of Intellectual Disability Research — Tue, 06 Dec 2011 05:00:00 +0100

Conclusions The annotation highlights research describing disturbances in excitatory and inhibitory neurotransmitter systems, neuronal ion channel and glial functions that provide possible explanations for the co‐occurrence of seizures within several ID syndromes, in some cases suggesting possible avenues for research into novel therapeutic targets. Phenotypic overlaps between syndromes may also relate to roles for the implicated genes in different disturbances in linked biochemical pathways. (Source: Journal of Intellectual Disability Research)

X-linked Angelman-like syndrome caused by Slc9a6 knockout in mice exhibits evidence of endosomal-lysosomal dysfunction

Brain — Wed, 09 Nov 2011 05:00:00 +0100

Mutations in solute carrier family 9 isoform 6 on chromosome Xq26.3 encoding sodium–hydrogen exchanger 6, a protein mainly expressed in early and recycling endosomes are known to cause a complex and slowly progressive degenerative human neurological disease. Three resulting phenotypes have so far been reported: an X-linked Angelman syndrome-like condition, Christianson syndrome and corticobasal degeneration with tau deposition, with each characterized by severe intellectual disability, epilepsy, autistic behaviour and ataxia. Hypothesizing that a sodium–hydrogen exchanger 6 deficiency would most likely disrupt the endosomal–lysosomal system of neurons, we examined Slc9a6 knockout mice with tissue staining and related techniques commonly used to study lysosomal storage dis...

Intragenic deletion of UBE3A gene in 2 sisters with Angelman syndrome detected by MLPA

American Journal of Medical Genetics Part A — Mon, 07 Nov 2011 05:00:00 +0100

(Source: American Journal of Medical Genetics Part A)

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

Journal of Intellectual Disability Research — Wed, 02 Nov 2011 04:00:00 +0100

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. (Source: Journal of Intellectual Disability Research)

A therapeutic trial of pro‐methylation dietary supplements in Angelman syndrome

American Journal of Medical Genetics Part A — Fri, 14 Oct 2011 04:00:00 +0100

AbstractAngelman syndrome (AS) is due to deficient ubiquitin protein ligase 3a, the gene for which (UBE3A) maps to chromosome 15q11–q13 and is imprinted such that only the maternally inherited gene is expressed. The paternally inherited UBE3A gene is silenced, a process mediated by an antisense transcript. We conducted a trial using methylation‐promoting dietary supplements (betaine, metafolin, creatine, and vitamin B12) in an attempt to reduce antisense transcript production, increase UBE3A expression, and ameliorate the symptoms of AS. Neuropsychological evaluations, biochemical testing, and assessment of DNA methylation were performed at the beginning and at the end of 1 year of supplementation. The primary outcome measures were changes in the level of developmental function (cognit...

Behavioral phenotypes of genetic syndromes with intellectual disability: Comparison of adaptive profiles

Psychiatry Research — Wed, 05 Oct 2011 03:45:59 +0100

Abstract: The study of distinctive and consistent behaviors in the most common genetic syndromes with intellectual disability is useful to explain abnormalities or associated psychiatric disorders. The behavioral phenotypes revealed outcomes totally or partially specific for each syndrome. The aim of our study was to compare similarities and differences in the adaptive profiles of the five most frequent genetic syndromes, i.e. Down syndrome, Williams syndrome, Angelman syndrome, Prader-Willi syndrome, and Fragile-X syndrome (fully mutated), taking into account the relation with chronological age and the overall IQ level. The research was carried out using the Vineland Adaptive Behavior Scale (beside the Wechsler Intelligence scales to obtain IQ) with a sample of 181 persons (107 males and ...

[Neurology of laughter and humour: pathological laughing and crying].

Revista de Neurologia — Fri, 30 Sep 2011 19:46:01 +0100

CONCLUSIONS. As human neurobiological phenomena, laughter and humour also belong to the field of clinical neurology; their processing is affected in a number of different diseases and, in certain cases, effective treatment can be established. PMID: 21948012 [PubMed - in process] (Source: Revista de Neurologia)

Angelman syndrome and prenatally diagnosed Prader–Willi syndrome in first cousins

American Journal of Medical Genetics Part A — Fri, 30 Sep 2011 04:00:00 +0100

We report on the diagnosis of a familial unbalanced 10;15 translocation causing AS in a child that led to the prenatal diagnosis of an unbalanced 10;15 translocation with resultant deletion of the Prader–Willi critical region in her maternal uncle's offspring. © 2011 Wiley Periodicals, Inc. (Source: American Journal of Medical Genetics Part A)

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Detecting and resolving position-dependent temperature effects in real-time quantitative polymerase chain reaction.

Analytical Biochemistry — Sat, 27 Aug 2011 04:00:00 +0100

Authors: von Kanel T, Gerber D, Wittwer CT, Hermann M, Gallati S Abstract Real-time quantitative polymerase chain reaction (qPCR) depends on precise temperature control of the sample during cycling. In the current study, we investigated how temperature variation in plate-based qPCR instruments influences qPCR results. Temperature variation was measured by amplicon melting analysis as a convenient means to assess well-to-well differences. Multiple technical replicates of several SYBR Green I-based qPCR assays allowed correlation of relative well temperature to quantification cycle. We found that inadequate template denaturation results in an inverse correlation and requires increasing the denaturation temperature, adding a DNA destabilizing agent, or pretreating with a restriction e...

Sudden Death and Angelman Syndrome.

Journal of Forensic Sciences — Thu, 18 Aug 2011 23:00:00 +0100

Authors: Herbst J, Byard RW Abstract Angelman syndrome is a condition characterized by developmental delay due to abnormalities in the maternally derived chromosome 15q11-q13. Typical features include impaired expressive language, an ataxic gait, and seizures. Hyperactivity may result in accidental bruises and abrasions, raising issues of possible inflicted injury. A fascination with water may predispose to drowning. A 5-year-old boy with an established diagnosis of Angelman syndrome is reported who died of upper airway obstruction due to massively enlarged tonsils complicating infectious mononucleosis. Assessment of the severity of underlying illness in developmentally delayed children may be difficult due to failure to vocalize worsening symptoms and distress. In addition, si...

Longitudinal follow‐up of autism spectrum features and sensory behaviors in Angelman syndrome by deletion class

Journal of Child Psychology and Psychiatry — Tue, 09 Aug 2011 23:00:00 +0100

Conclusions: Despite a lack of differences in cognition or adaptive behavior, individuals with Class I deletions have greater severity in ASD features and sensory aversions that remain over time. There are four genes (NIPA 1, NIPA 2, CYFIP1, and GCP5) missing in Class I and present in Class Il deletions, one or more of which may have a role in modifying the severity of social affect impairment, and level of restricted/repetitive behaviors in AS. Our results also suggest the utility of a dimensional, longitudinal approach to the assessment of ASD features in populations of individuals who are low functioning. (Source: Journal of Child Psychology and Psychiatry)

Are children with Angelman syndrome at high risk for anesthetic complications?

Pediatric Anesthesia — Tue, 02 Aug 2011 19:38:49 +0100

Conclusions: We found no data to suggest that these patients demonstrate exaggerated responses to GABA stimulating drugs. In fact, it appears that regardless of the anesthetic agent, the perioperative course was unremarkable. (Source: Pediatric Anesthesia)

A loss‐of‐function mutation in the SLC9A6 gene causes X‐linked mental retardation resembling Angelman syndrome

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics — Mon, 01 Aug 2011 23:00:00 +0100

AbstractSLC9A6 mutations have been reported in families in whom X‐linked mental retardation (XMR) mimics Angelman syndrome (AS). However, the relative importance of SLC9A6 mutations in patients with an AS‐like phenotype or XMR has not been fully investigated. Here, the involvement of SLC9A6 mutations in 22 males initially suspected to have AS but found on genetic testing not to have AS (AS‐like cohort), and 104 male patients with XMR (XMR cohort), was investigated. A novel SLC9A6 mutation (c.441delG, p.S147fs) was identified in one patient in the AS‐like cohort, but no mutation was identified in XMR cohort, suggesting mutations in SLC9A6 are not a major cause of the AS‐like phenotype or XMR. The patient with the SLC9A6 mutation showed the typical AS phenotype, further demonstrati...

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Association of Genetic Variants on 15q12 With Cortical Thickness and Cognition in Schizophrenia [Original Article]

Archives of General Psychiatry — Sun, 31 Jul 2011 23:00:00 +0100

Conclusion This genome-wide association study identifies a common genetic variant that contributes to the heritable reduction of cortical thickness in schizophrenia. These results highlight the usefulness of cortical thickness as an intermediate phenotype for neuropsychiatric diseases. Future independent replication studies are required to confirm these findings. (Source: Archives of General Psychiatry)

Are children with Angelman syndrome at high risk for anesthetic complications?

Paediatric Anaesthesia — Sun, 31 Jul 2011 23:00:00 +0100

Molecular and Clinical Aspects of Angelman Syndrome

Karger Publishers — Wed, 27 Jul 2011 21:56:50 +0100

Mol Syndromol (DOI:10.1159/000328837) (Source: Karger Publishers)

Defects in translational regulation contributing to human cognitive and behavioral disease.

Current Opinion in Genetics and Development — Thu, 14 Jul 2011 23:00:00 +0100

Authors: Darnell J Recent data suggest that the levels of many synaptic proteins may be tightly controlled by the opposing processes of new translation and protein turnover in neurons. Alterations in this balance or in the levels of such dosage-sensitive proteins that result in altered stoichiometry of protein complexes at developing and remodeling synapses may underlie several human cognitive diseases including Fragile X Syndrome, autism spectrum disorders, Angelman syndrome and non-syndromic mental retardation. While a significant amount is known about the transduction of membrane signals to the translational apparatus through kinase cascades acting on general translation factors, much less is understood about how such signals may influence the activity of mRNA-specific regulators, t...

UBE3A Regulates MC1R Expression: A Link to Hypopigmentation in Angelman Syndrome.

Pigment Cell and Melanoma Research — Tue, 05 Jul 2011 23:00:00 +0100

Authors: Low D, Chen KS Angelman syndrome (AS) is a neurogenetic disorder caused by the lack of functional ubiquitin-protein ligase E3A (UBE3A) that acts as an E3 ligase in the ubiquitin-proteosomal degradation pathway and/or as a transcriptional coactivator. Besides neurological deficit, hypopigmentation is another phenotype associated with AS patients currently attributed towards the hemizygosity of the type II oculocutaneous albinism (OCA2) gene. Here we show that the melanocortin-1-receptor (MC1R) is down-regulated in the skin of the Ube3a((-/-)) mice. Luciferase-reporter assay shows that UBE3A is able to induce MC1R promoter activity. Using chromatin immunoprecipitation assay, Ube3a was observed to be physically associated with the Mc1r promoter. Deletion of the E box/SP1 element ...

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Aberrant expression of genes necessary for neuronal development and notch signaling in an epileptic mind bomb zebrafish

Developmental Dynamics — Sun, 19 Jun 2011 07:38:32 +0100

In conclusion, these expression studies indicate a general down‐regulation of Notch signaling genes necessary for proper brain development and suggest that these mutant fish could provide valuable insights into neurological conditions, such as Angelman syndrome, associated with ubiquitin E3 ligase mutation. Developmental Dynamics, 2011. © 2011 Wiley‐Liss, Inc. (Source: Developmental Dynamics)

Subtle changes in two or more genes may cause some autism

Baylor College of Medicine News — Fri, 10 Jun 2011 05:00:00 +0100

Autism is often described as a spectrum – varying from severe syndromes in which the symptoms of autism are only part of the problem to the more classic autism characterized by impaired social skills, delayed language development, and repetitive or stereotyped behaviors. The genetic origin of the disorder may also occur along a spectrum. On one hand, a severe mutation affecting a particular gene gives rise to syndromic autism, a form of the disorder that occurs along with other problems including physical and facial abnormalities, including Rett, Angelman and Fragile X syndromes. On the other hand, a new study from researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children's Hospital proposes that several subtle mutati...

Fetal pads as a clue to the diagnosis of Pitt–Hopkins syndrome

American Journal of Medical Genetics Part A — Thu, 09 Jun 2011 23:00:00 +0100

AbstractPitt–Hopkins syndrome (PHS) is characterized by severe mental retardation, characteristic facial features including a wide mouth and intermittent overbreathing. It is due to abnormalities of the TCF4 gene at 18q21.1 and over 50 cases have now been reported in the literature. The clinical features overlap significantly with those of Angelman, Rett, and Mowat–Wilson syndromes. We have observed prominent fetal pads as a feature in several individuals with PHS and suggested that this is a useful clinical sign which helps to distinguish PHS from other conditions in the differential diagnosis and may guide genetic testing. © 2011 Wiley‐Liss, Inc. (Source: American Journal of Medical Genetics Part A)

The role of imprinted genes in fetal growth abnormalities

Birth Defects Research Part A: Clinical and Molecular Teratology — Sun, 05 Jun 2011 23:00:00 +0100

AbstractEpigenetics, and in particular imprinted genes, have a critical role in the development and function of the placenta, which in turn has a central role in the regulation of fetal growth and development. A unique characteristic of imprinted genes is their expression from only one allele, maternal or paternal and dependent on parent of origin. This unique expression pattern may have arisen as a mechanism to control the flow of nutrients from the mother to the fetus, with maternally expressed imprinted genes reducing the flow of resources and paternally expressed genes increasing resources to the fetus. As a result, any epigenetic deregulation affecting this balance can result in fetal growth abnormalities. Imprinting‐associated disorders in humans, such as Beckwith‐Wiedemann and A...

The Pitt‐Hopkins syndrome: Report of 16 new patients and clinical diagnostic criteria

American Journal of Medical Genetics Part A — Tue, 31 May 2011 23:00:00 +0100

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UBE3A Regulates MC1R Expression: A Link to Hypopigmentation in Angelman Syndrome

Pigment Cell Research — Tue, 31 May 2011 23:00:00 +0100

SummaryAngelman syndrome (AS) is a neurogenetic disorder caused by the lack of functional ubiquitin‐protein ligase E3A (UBE3A) that acts as an E3 ligase in the ubiquitin‐proteosomal degradation pathway and/or as a transcriptional coactivator. Besides neurological deficit, hypopigmentation is another phenotype associated with AS patients currently attributed towards the hemizygosity of the type II oculocutaneous albinism (OCA2) gene. Here we show that the melanocortin‐1‐receptor (MC1R) is down‐regulated in the skin of the Ube3a(‐/‐) mice. Luciferase‐reporter assay shows that UBE3A is able to induce MC1R promoter activity. Using chromatin immunoprecipitation assay, Ube3a was observed to be physically associated with the Mc1r promoter. Deletion of the E box/SP1 element in the ...

Rett syndrome: A study of the face

American Journal of Medical Genetics Part A — Thu, 26 May 2011 23:00:00 +0100

AbstractRett syndrome is a unique disorder of neurodevelopment that is characterized by an evolving behavioral and developmental phenotype, which emerges after an apparently normal early infantile period. It almost exclusively affects females. The face of Rett syndrome is said to resemble that of Angelman syndrome, although there seems little objective support for this impression and it is not a concept with universal support. This observational and anthropometric study was carried out to define the key facial characteristics of females with Rett syndrome and to evaluate whether any changes of significance occur with age. Thirty‐seven affected Caucasian females, from 2 to 20 years of age, were evaluated. Thirty‐five of them had a documented mutation in MECP2 while the remaining two ful...

HERC2 Stimulates E6AP-mediated Ubiquitination [Protein Synthesis and Degradation]

Journal of Biological Chemistry — Thu, 26 May 2011 23:00:00 +0100

In this study, we report that the giant protein HERC2, which is like E6AP a member of the HECT family of ubiquitin-protein ligases, binds to E6AP. The interaction is mediated by the RCC1-like domain 2 of HERC2 and a region spanning amino acid residues 150–200 of E6AP. Furthermore, we provide evidence that HERC2 stimulates the ubiquitin-protein ligase activity of E6AP in vitro and within cells and that this stimulatory effect does not depend on the ubiquitin-protein ligase activity of HERC2. Thus, the data obtained indicate that HERC2 acts as a regulator of E6AP. (Source: Journal of Biological Chemistry)

Our patients’ stories: Looking towards the future of Angelman syndrome

Thrive, Children's Hospital Boston — Mon, 23 May 2011 13:42:06 +0100

Michelle and Dustin Sclater’s son Jake was born with Angelman syndrome, a genetic condition that affects about 1 in every 10,000 people. Raising a child with a rare medical issue feels isolating at times, but the Sclaters are determined to raise awareness about the condition, both in the medical community and the world at-large. Sclater family. (Jake is featured in center) Jake Sclater loves Tater tots. He can’t ask for them by name, but sitting across from him at a table at Children’s Hospital Boston’s cafeteria, it’s easy to tell he’s ready for a few more of his favorite treats; with a friendly smile a quick point of his finger, Jake lets his mother Michelle know that lunch isn’t over just yet. Jake can’t ask for more tots because he has Angelman syndrome (AS), a rar...

Establishment of the first WHO international genetic reference panel for Prader Willi and Angelman syndromes

European Journal of Human Genetics — Tue, 17 May 2011 23:00:00 +0100

Authors: Jennifer Boyle, Malcolm Hawkins, David E Barton, Karen Meaney, Miriam Guitart, Anna O'Grady, Simon Tobi, Simon C Ramsden, Rob Elles, Elaine Gray, Paul Metcalfe & J Ross Hawkins (Source: European Journal of Human Genetics)

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Drosophila modeling of heritable neurodevelopmental disorders.

Current Opinion in Neurobiology — Mon, 16 May 2011 23:00:00 +0100

Authors: Gatto CL, Broadie K Heritable neurodevelopmental disorders are multifaceted disease conditions encompassing a wide range of symptoms including intellectual disability, cognitive dysfunction, autism and myriad other behavioral impairments. In cases where single, causative genetic defects have been identified, such as Angelman syndrome, Rett syndrome, Neurofibromatosis Type 1 and Fragile X syndrome, the classical Drosophila genetic system has provided fruitful disease models. Recent Drosophila studies have advanced our understanding of UBE3A, MECP2, NF1 and FMR1 function, respectively, in genetic, biochemical, anatomical, physiological and behavioral contexts. Investigations in Drosophila continue to provide the essential mechanistic understanding required to facilitate the conc...

Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes.

Trends in Neurosciences — Sun, 15 May 2011 23:00:00 +0100

Authors: Mabb AM, Judson MC, Zylka MJ, Philpot BD Angelman syndrome (AS) is a severe genetic disorder caused by mutations or deletions of the maternally inherited UBE3A gene. UBE3A encodes an E3 ubiquitin ligase that is expressed biallelically in most tissues but is maternally expressed in almost all neurons. In this review, we describe recent advances in understanding the expression and function of UBE3A in the brain and the etiology of AS. We highlight current AS model systems, epigenetic mechanisms of UBE3A regulation, and the identification of potential UBE3A substrates in the brain. In the process, we identify major gaps in our knowledge that, if bridged, could move us closer to identifying treatments for this debilitating neurodevelopmental disorder. PMID: 21592595 [PubMed - ...

Age related change in social behavior in children with Angelman syndrome

American Journal of Medical Genetics Part A — Wed, 11 May 2011 23:00:00 +0100

AbstractWe investigated the relationship between age and laughing and smiling in children with Angelman syndrome. Twenty‐four children with Angelman syndrome were exposed to three experimentally manipulated conditions: proximity only, restricted social interaction, and social interaction. Children smiled the most in the social interaction condition and the least in the proximity only condition confirming the effect of social interaction on these behaviors. There was a decline in smiling and laughing in the oldest group (13.4–15.9 years) only in the social interaction condition. This trajectory of a decline in resource soliciting behaviors with age is consistent with predictions based on kinship theory. © 2011 Wiley‐Liss, Inc. (Source: American Journal of Medical Genetics Part A)

Hexasomy of the Prader-Willi/Angelman critical region, including the OCA2 gene, in a patient with pigmentary dysplasia: Case report.

European Journal of Medical Genetics — Thu, 05 May 2011 23:00:00 +0100

This report supports the previous observations assuming that severity of phenotype in patients with inv dup(15) depends on the dosage of the PWACR and that skin pigmentation is correlated to OCA2 gene copy number. PMID: 21621018 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)

Pharmacological inactivation of the small GTPase Rac1 impairs long-term plasticity in the mouse hippocampus.

Neuropharmacology — Wed, 04 May 2011 23:00:00 +0100

Authors: Martinez LA, Tejada-Simon MV Neuronal development involves several discrete morphological steps requiring migration of newborn neurons to characteristic locations, extension of axons and dendrites into proper target regions, and formation of synapses with appropriate partners. Small GTPases such as Rac1, are believed to be critical regulators of these processes. We have previously reported that Rac1 is highly expressed in mouse hippocampus, where NMDA receptor activation causes Rac1 to translocate to the membrane in a manner similar to that observed in other non-neuronal cells. Additionally Rac1 has been seen to play a role in activation of signal transduction pathways associated with hippocampal learning and memory. Because of the established role of LTP and LTD in learning a...

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Complex chromosome rearrangements related 15q14 microdeletion plays a relevant role in phenotype expression and delineates a novel recurrent syndrome

Orphanet Journal of Rare Diseases — Mon, 18 Apr 2011 23:00:00 +0100

Complex chromosome rearrangements are constitutional structural rearrangements involving three or more chromosomes or having more than two breakpoints. These are rarely seen in the general population but their frequency should be much higher due to balanced states with no phenotypic presentation. These abnormalities preferentially occur de novo during spermatogenesis and are transmitted in families through oogenesis.Here, we report a de novo complex chromosome rearrangement that interests eight chromosomes in eighteen-year-old boy with an abnormal phenotype consisting in moderate developmental delay, cleft palate, and facial dysmorphisms.Standard G-banding revealed four apparently balanced traslocations involving the chromosomes 1;13, 3;19, 9;15 and 14;18 that appeared to be reciprocal. Ar...

Abnormal Language Pathway in Children With Angelman Syndrome

Pediatric Neurology — Tue, 12 Apr 2011 19:03:00 +0100

We examined the basis for severe language delay in patients with Angelman syndrome by diffusion tensor imaging. Magnetic resonance imaging/diffusion tensor imaging was performed in 7 children with genetically confirmed Angelman syndrome (age 70 ± 26 months, 5 boys) and 4 age-matched control children to investigate the microstructural integrity of arcuate fasciculus and other major association tracts. Six of 7 children with Angelman syndrome had unidentifiable left arcuate fasciculus, while all control children had identifiable arcuate fasciculus. The right arcuate fasciculus was absent in 6 of 7 children with Angelman syndrome and 1 of 4 control children. Diffusion tensor imaging color mapping suggested aberrant morphology of the arcuate fasciculus region. Other association tracts, inclu...

Maternally Derived Microduplications at 15q11-q13: Implication of Imprinted Genes in Psychotic Illness [Articles]

Am J Psychiatry — Wed, 06 Apr 2011 23:00:00 +0100

Conclusions: These findings suggest that the presence of two maternal copies of a fragment of chromosome 15q11.2-q13.1 that overlaps with the Prader-Willi/Angelman syndrome critical region may be a rare risk factor for schizophrenia and other psychoses. Given that maternal duplications of this region are among the most consistent cytogenetic observations in autism, the findings provide further support for a shared genetic etiology between autism and psychosis. (Source: Am J Psychiatry)

The expression and assessment of emotions and internal states in individuals with severe or profound intellectual disabilities.

Clinical Psychology Review — Thu, 31 Mar 2011 23:00:00 +0100

Authors: Adams D, Oliver C The expression of emotions and internal states by individuals with severe or profound intellectual disabilities is a comparatively under-researched area. Comprehensive or standardized methods of assessing or understanding the emotions and internal states within this population, whose ability to communicate is significantly compromised, do not exist. The literature base will be discussed and compared to that applicable to the general population. Methods of assessing broader internal states, notably depression, anxiety, and pain within severe or profound intellectual disabilities are also addressed. Finally, this review will examine methods of assessing internal states within genetic syndromes, including hunger, social anxiety, and happiness within Prader-Willi...

Ophthalmic findings in Angelman syndrome

Journal of AAPOS — Thu, 31 Mar 2011 23:00:00 +0100

Conclusions: Ophthalmic alterations in AS were observed more frequently than has been previously reported, except for ocular hypopigmentation, which was observed less frequently. (Source: Journal of AAPOS)

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[Anesthesia and Angelman syndrome.]

Der Anaesthesist — Wed, 16 Mar 2011 00:00:00 +0100

Authors: Witte W, Nobel C, Hilpert J Angelman syndrome (AS) is a rare neurodevelopmental disorder with an incidence of 1:10,000-1:40,000 caused by deficient genetic imprinting in the chromosomal segment 15q11-q13. Experimental data suggest that the gamma-aminobutyric acid A (GABA(A)) receptor as well as the N-methyl-D-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors may be affected by this condition. The first description of the syndrome goes back to 1965 when the British pediatrician Harry Angelman (1915-1996) recognized similar clinical features in three children. Angelman's description of puppet children was changed to happy puppet syndrome 2 years later before this euphemistic denotation was replaced by the concept Angelman syndrome over ...

[15Q11.2 (BP1-BP2) microdeletion, a new syndrome with variable expressivity.]

Anales de Pediatria — Wed, 16 Mar 2011 00:00:00 +0100

Authors: Sempere Pérez A, Manchón Trives I, Palazón Azorín I, Alcaraz Más L, Pérez Lledó E, Galán Sánchez F The case of a boy with psychomotor retardation and dysmorphic features is presented. He has a 1.5 Mb 15q11.2 microdeletion of paternal origin diagnosed by aCGH. The deletion is located between breakpoints BP1 and BP2 of the Prader-Willi/Angelman syndromes critical region. Clinical features in our patient fit well with those described in ten cases of pure BP1-BP2 deletion published to date. PMID: 21419731 [PubMed - as supplied by publisher] (Source: Anales de Pediatria)

Novel deletion encompassing exons 5-12 of the UBE3A gene in a girl with Angelman Syndrome.

European Journal of Medical Genetics — Wed, 09 Mar 2011 00:00:00 +0100

We report a novel deletion encompassing the exons 5-12 of the UBE3A gene in a girl with AS, identified by MLPA (Multiplex Ligation-dependent Probe Amplification), which was not detected by the conventional diagnostic protocol. We propose that copy number analysis of the UBE3A gene should be considered in individuals whose clinical examination is strongly suggestive of AS, after more common mechanisms have been excluded. PMID: 21397058 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)

Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay

Human Genetics — Sat, 26 Feb 2011 21:42:14 +0100

We present a large cohort of subjects with copy number alteration of BP1 to BP2 with common phenotypic features. These include autism, developmental delay, motor and language delays, and behavioral problems, which were present in both cytogenetic groups. Parental studies demonstrated phenotypically normal carriers in several instances, and mildly affected carriers in others, complicating phenotypic association and/or causality. Possible explanations for these results include reduced penetrance, altered gene dosage on a particular genetic background, or a susceptibility region as reported for other areas of the genome implicated in autism and behavior disturbances. Content Type Journal ArticlePages 1-12DOI 10.1007/s00439-011-0970-4Authors Rachel D. Burnside, Laboratory Corporati...

Assessing Joint Attention Responding and Initiation in Children with Angelman Syndrome

Journal of Applied Research in Intellectual Disabilities — Wed, 23 Feb 2011 02:53:26 +0100

Conclusions Differences in children’s response patterns are discussed in relation to their characteristics on measures of cognitive, adaptive and language functioning as well as on a measure of autistic symptomatology. A better understanding of the nature of joint attention deficits in children with AS may assist with developing remedial approaches to improve their communication and social skills. (Source: Journal of Applied Research in Intellectual Disabilities)

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Ras and Rap Signaling in Synaptic Plasticity and Mental Disorders

The Neuroscientist — Tue, 22 Feb 2011 00:00:00 +0100

The Ras family GTPases (Ras, Rap1, and Rap2) and their downstream mitogen-activated protein kinases (ERK, JNK, and p38MAPK) and PI3K signaling cascades control various physiological processes. In neuronal cells, recent studies have shown that these parallel cascades signal distinct forms of AMPA-sensitive glutamate receptor trafficking during experience-dependent synaptic plasticity and adaptive behavior. Interestingly, both hypo- and hyperactivation of Ras/ Rap signaling impair the capacity of synaptic plasticity, underscoring the importance of a "happy-medium" dynamic regulation of the signaling. Moreover, accumulating reports have linked various genetic defects that either up- or down-regulate Ras/Rap signaling with several mental disorders associated with learning disability (e.g., Alz...

Psychological well‐being in parents of children with Angelman, Cornelia de Lange and Cri du Chat syndromes

Journal of Intellectual Disability Research — Tue, 15 Feb 2011 00:00:00 +0100

Conclusions Parents of children with rare genetic syndromes are at risk for high levels of stress and mental health problems. Methodological issues and the practical applications of these results are discussed. (Source: Journal of Intellectual Disability Research)

Maternally Derived Microduplications at 15q11-q13: Implication of Imprinted Genes in Psychotic Illness.

The American Journal of Psychiatry — Tue, 15 Feb 2011 00:00:00 +0100

Effects of adult familiarity on social behaviours in Angelman syndrome

Journal of Intellectual Disability Research — Mon, 24 Jan 2011 08:25:24 +0100

Conclusions In Angelman syndrome, looking at adults, laughing and smiling appear to be unaffected by the familiarity of the adult. However, approach behaviours are more common with mothers than strangers. The function of the approach behaviours might be to increase investment from the primary caregiver. (Source: Journal of Intellectual Disability Research)

Normal social seeking behavior, hypoactivity and reduced exploratory range in a mouse model of Angelman syndrome

BMC Genetics - Latest articles — Fri, 14 Jan 2011 00:00:00 +0100

Conclusions: Although hyperactivity and social-seeking behavior are characteristic phenotypes of Angelman Syndrome in humans, the Ube3a deficient mouse model does not reproduce these phenotypes in comparison to their wild-type littermates. These phenotypic differences may be explained by differences in the size of the genetic defect as ~70% of AS patients have a deletion that includes several other genes surrounding the UBE3A locus. (Source: BMC Genetics - Latest articles)

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Genome-Wide Association Study Identifies Two Major Loci Affecting Calving Ease and Growth-Related Traits in Cattle [Genetics of complex traits]

Genetics — Tue, 11 Jan 2011 00:00:00 +0100

Identifying quantitative trait loci (QTL) underlying complex, low-heritability traits is notoriously difficult. Prototypical for such traits, calving ease is an important breeding objective of cattle (Bos taurus)-improving programs. To identify QTL underlying calving ease, we performed a genome-wide association study using estimated breeding values (EBVs) as highly heritable phenotypes for paternal calving ease (pCE) and related traits. The massively structured study population consisted of 1800 bulls of the German Fleckvieh (FV) breed. Two pCE-associated regions on bovine chromosomes (BTA) 14 and 21 (P = 5.72 x 10–15 and P = 2.27 x 10–8, respectively) were identified using principal components analysis to correct for population stratification. The two most significantly associ...

An atypical case of hypomethylation at multiple imprinted loci

European Journal of Human Genetics — Wed, 05 Jan 2011 00:00:00 +0100

Authors: Emma L Baple, Rebecca L Poole, Sahar Mansour, Catherine Willoughby, I Karen Temple, Louise E Docherty, Rohan Taylor & Deborah J G Mackay (Source: European Journal of Human Genetics)

Angelman syndrome: Mutations influence features in early childhood

American Journal of Medical Genetics Part A — Wed, 29 Dec 2010 01:21:56 +0100

We present baseline data from 92 children with a molecular diagnosis of AS between 5 and 60 months old who are enrolled in the National Institutes of Health Rare Diseases Clinical Research Network Angelman Syndrome Natural History Study from January 2006 to March 2008. Seventy‐four percent of participants had deletions, 14% had either uniparental disomy (UPD) or imprinting defects, and 12% had UBE3A mutations. Participants with UPD/imprinting defects were heavier (P = 0.0002), while those with deletions were lighter, than the general population (P < 0.0001). Twenty out of 92 participants were underweight, all of whom had deletions or UBE3A mutations. Eight out of 92 participants (6/13 (46%) with UPD/imprinting defects and 2/11 (18%) with UBE3A mutations) were obese. Seventy‐...

Neuroscience: Angelman syndrome connections

Nature — Wed, 15 Dec 2010 00:00:00 +0100

Authors: Peter Scheiffele & Asim A. Beg Neuronal networks in the brain that develop early in life underlie our ability to learn, remember and communicate. Genetic defects that perturb the fine-tuning of such neuronal connectivity can cause disease. (Source: Nature)

Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism.

Neurobiology of Disease — Fri, 10 Dec 2010 00:00:00 +0100

Authors: Ferdousy F, Bodeen W, Summers K, Doherty O, Wright O, Elsisi N, Hilliard G, O'Donnell JM, Reiter LT The underlying defects in Angelman syndrome (AS) and autism spectrum disorder (ASD) may be in part due to basic defects in synaptic plasticity and function. In some individuals serotonin reuptake inhibitors, which decrease pre-synaptic re-uptake of serotonin, can ameliorate symptoms, as can resperidone, which blocks both dopamine and serotonin receptors. Loss of maternal UBE3A expression causes AS, while maternal duplications of chromosome 15q11.2-q13 that include the UBE3A gene cause ASD, implicating the maternally expressed UBE3A gene in the ASD phenotype. In a Drosophila screen for proteins regulated by UBE3A, we identified a key regulator of monoamine synthesis, the gene Pun...

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Familial partial trisomy 15q11-13 presenting as intractable epilepsy in the child and schizophrenia in the mother.

European Journal of Paediatric Neurology — Tue, 07 Dec 2010 00:00:00 +0100

We report a ten year-old girl with normal intelligence prior to the onset of seizures, who developed severe intractable epilepsy at the age of seven years. Family history was significant for a mother with recurrent episodes of acute psychosis. The patient's and mother's karyotype revealed 47,XX+m. Array comparative genomic hybridization (A-CGH) identified a gain of 13 BAC clones from 15q11.2 through 15q13.1, which was then confirmed by FISH to be part of the marker chromosome. This duplicated region contains the SNRPN/UBE3A locus. This case demonstrates that a duplication of 15q11-13 can present differently in the same family either as intractable epilepsy or as a psychiatric illness and that intelligence can be preserved. We suggest that CGH microarray should be performed in cases with in...

Alterations in white matter pathways in Angelman syndrome

Developmental Medicine and Child Neurology — Wed, 01 Dec 2010 00:00:00 +0100

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 9...

Angelman Syndrome

Journal of Paediatrics and Child Health — Wed, 01 Dec 2010 00:00:00 +0100

(Source: Journal of Paediatrics and Child Health)

Delineation of Behavioral Phenotypes in Genetic Syndromes: Characteristics of Autism Spectrum Disorder, Affect and Hyperactivity.

Journal of Autism and Developmental Disorders — Tue, 16 Nov 2010 00:00:00 +0100

Authors: Oliver C, Berg K, Moss J, Arron K, Burbidge C We investigated autism spectrum disorder (ASD) symptomatology, hyperactivity and affect in seven genetic syndromes; Angelman (AS; n = 104), Cri du Chat (CdCS; 58), Cornelia de Lange (CdLS; 101), Fragile X (FXS; 191), Prader-Willi (PWS; 189), Smith-Magenis (SMS; 42) and Lowe (LS; 56) syndromes (age range 4-51). ASD symptomatology was heightened in CdLS and FXS. High levels of impulsivity were seen in SMS, AS, CdCS, FXS and adults with CdLS. Negative affect was prominent in adults with CdLS, while positive affect was prominent in adults with AS and FXS. Heightened levels of overactivity and impulsivity were identified in FXS, AS and SMS while low levels were identified in PWS. These findings confirm and extend previously reported b...

Novel deletion of the UBE3A gene detected by MLPA in a patient with Angelman syndrome.

exp Mol Med — Thu, 11 Nov 2010 00:00:00 +0100

In this study, we have used for the first time Multiplex Ligation-dependent Probe Amplification (MLPA) and Comparative Multiplex Dosage Analysis (CMDA) to search for large deletions affecting the UBE3A gene. Using this approach, we identified a novel causative deletion involving exon 8 in an affected sibling. Based on our results, we propose the use of MLPA as a fast, accurate and inexpensive test to detect large deletions in the UBE3A gene in a small but significant percentage of AS patients. PMID: 21072004 [PubMed - as supplied by publisher] (Source: exp Mol Med)

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Imprinting disorders and assisted reproductive technology

Current Opinion in Endocrinology, Diabetes and Obesity — Mon, 01 Nov 2010 10:53:16 +0100

Purpose of review: To summarize current evidence in the association of imprinting disorders and assisted reproductive technology. Recent findings: The worldwide usage of assisted reproductive technology (ART) has continued to increase since the first successful birth of a human after IVF. Since 2002, several reports have raised concerns that children conceived by ART are at increased risk of having imprinting disorders. The majority of published studies have examined DNA methylation in children conceived by ART, but results are conflicting. Beckwith–Wiedemann syndrome and Angelman syndrome are the most extensively studied imprinting disorders and multiple case series and reports have been published on ART-conceived children with these syndromes. Overall the majority of reports suggest t...

Update on Clinical Features and Brain Abnormalities in Neurogenetics Syndromes

Journal of Applied Research in Intellectual Disabilities — Mon, 01 Nov 2010 00:00:00 +0100

This article reviews the clinical features and highlights studies with a focus on the relevant gene–brain–behaviour connections observed in neurogenetic syndromes, such as Williams, Rett, Fragile X, Prader‐Willi, Angelman, Down and velocardiofacial (22q11.2 deletion) syndromes. The relationship of altered brain regions and activation patterns are discussed for each syndrome, as well as the clinical, cognitive and behavioural correlates of these neuroimaging findings. (Source: Journal of Applied Research in Intellectual Disabilities)

The behavioral phenotype of the Angelman syndrome

American Journal of Medical Genetics Part C: Seminars in Medical Genetics — Fri, 29 Oct 2010 23:36:40 +0100

Abstract (Source: American Journal of Medical Genetics Part C: Seminars in Medical Genetics)

Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader-Willi syndromes [Genetics]

Proceedings of the National Academy of Sciences — Tue, 12 Oct 2010 16:27:00 +0100

Angelman syndrome (AS) and Prader–Willi syndrome (PWS) are neurodevelopmental disorders of genomic imprinting. AS results from loss of function of the ubiquitin protein ligase E3A (UBE3A) gene, whereas the genetic defect in PWS is unknown. Although induced pluripotent stem cells (iPSCs) provide invaluable models of human disease, nuclear reprogramming could limit the usefulness of iPSCs from patients who have AS and PWS should the genomic imprint marks be disturbed by the epigenetic reprogramming process. Our iPSCs derived from patients with AS and PWS show no evidence of DNA methylation imprint erasure at the cis-acting PSW imprinting center. Importantly, we find that, as in normal brain, imprinting of UBE3A is established during neuronal differentiation of AS iPSCs, with the patern...

Parental origin and functional relevance of a de novo UBE3A variant.

European Journal of Medical Genetics — Tue, 05 Oct 2010 23:00:00 +0100

In conclusion, our results strongly suggest that the 3 bp deletion is a loss-of-function mutation of the maternal UBE3A allele that has caused Angelman syndrome in our patient. Our study may serve as a paradigm to determine the parental origin of a de novo mutation. PMID: 20933619 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)

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Ketogenic diet in a patient with Angelman syndrome

Pediatrics International — Thu, 30 Sep 2010 17:45:50 +0100

(Source: Pediatrics International)

Adaptive behaviour in Angelman syndrome: its profile and relationship to age

Journal of Intellectual Disability Research — Mon, 20 Sep 2010 11:07:32 +0100

Abstract (Source: Journal of Intellectual Disability Research)

Methylation profiling in individuals with uniparental disomy identifies novel differentially methylated regions on chromosome 15 [METHOD]

Genome Research — Wed, 01 Sep 2010 14:02:24 +0100

The maternal and paternal genomes possess distinct epigenetic marks that distinguish them at imprinted loci. In order to identify imprinted loci, we used a novel method, taking advantage of the fact that uniparental disomy (UPD) provides a system that allows the two parental chromosomes to be studied independently. We profiled the paternal and maternal methylation on chromosome 15 using immunoprecipitation of methylated DNA and hybridization to tiling oligonucleotide arrays. Comparison of six individuals with maternal versus paternal UPD15 revealed 12 differentially methylated regions (DMRs). Putative DMRs were validated by bisulfite sequencing, confirming the presence of parent-of-origin-specific methylation marks. We detected DMRs associated with known imprinted genes within the Prader-W...

Epilepsy in Prader-Willi syndrome: Clinical characteristics and correlation to genotype.

Epilepsy and Behaviour — Tue, 17 Aug 2010 23:00:00 +0100

Authors: Vendrame M, Maski KP, Chatterjee M, Heshmati A, Krishnamoorthy K, Tan WH, Kothare SV Prader-Willi syndrome (PWS) is a genomic imprinting disease secondary to the loss of a functional paternal copy of 15q11-q13. Unlike its related imprinting disorder, Angelman syndrome, PWS has not been regarded as a risk factor for epilepsy. A retrospective analysis of 92 patients with PWS identified 24 (26%) with seizures. Twenty-two of these (92%) were affected by focal epilepsy and only two (8%) had generalized epilepsy. The most common seizure type was staring spells (67%). Correlation to genotype analysis showed deletions were more common in patients with epilepsy than in patients without epilepsy. The epilepsy syndromes were easy to control with a single antiepileptic drug in most cases....

Prader–Willi syndrome and Angelman syndrome

American Journal of Medical Genetics Part C: Seminars in Medical Genetics — Sat, 14 Aug 2010 23:00:00 +0100

Abstract (Source: American Journal of Medical Genetics Part C: Seminars in Medical Genetics)

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Side-by-Side Comparison of Five Commercial Media Systems in a Mouse Model: Suboptimal In Vitro Culture Interferes with Imprint Maintenance.

Biology of Reproduction — Tue, 10 Aug 2010 23:00:00 +0100

In this study, we performed side-by-side comparisons of five commercial embryo culture systems (KSOMaa, global, human tubal fluid, preimplantation 1/multiblast, and G1v5PLUS/G2v5PLUS) in relation to a best case (in vivo-derived embryos) and a worst case scenario (Whittens culture). Imprinted DNA methylation and expression were examined at three well-studied loci, H19, Peg3 and Snrpn, in mouse embryos cultured from the 2-cell to the blastocyst stage. We show that embryo culture in all commercial media systems resulted in imprinted methylation loss compared to in vivo-derived embryos, although some media systems were able to maintain imprinted methylation levels more similar to in vivo-derived embryos in comparison to embryos cultured in Whittens medium. However, all media systems exhibited ...

Loss of dopaminergic neurons and resulting behavioural deficits in mouse model of Angelman syndrome.

Neurobiology of Disease — Thu, 05 Aug 2010 23:00:00 +0100

Authors: Mulherkar SA, Jana NR E6 associated protein is an E3 ubiquitin ligase encoded by the gene Ube3a. Deletion or loss of function of the maternally inherited allele of Ube3a leads to Angelman syndrome. In the present study, we show that maternal loss of Ube3a (Ube3a(m-/p+)) in the mouse model leads to motor deficits that could be attributed to the dysfunction of the nigrostriatal pathway. The number of tyrosine hydroxylase positive neurons in the substantia nigra was significantly reduced in Ube3a(m-/p+) mice as compared to the wild type counterparts. The Ube3a(m-/p+) mice performed poorly in behavioural paradigms sensitive to nigrostriatal dysfunction. Even though the tyrosine hydroxylase staining was apparently the same in the striatum of both genotypes, the presynaptic and post...

Refractive lens exchange with intraocular lens implantation in hyperopic eyes of a patient with Angelman syndrome

Journal of Cataract and Refractive Surgery — Tue, 27 Jul 2010 06:23:36 +0100

We describe a patient with Angelman syndrome with severe developmental delay who was visually impaired by uncorrected high hyperopia and poor control of accommodation. Refractive lens exchange with intraocular lens implantation was performed in both eyes when the patient was 22 years of age. Satisfactory anatomical and functional outcomes were achieved and maintained during 3 years of follow-up. Refractive lens exchange can be useful in patients with severe neurobehavioral disorders in the presence of high refractive error and poor accommodative control.Financial Disclosure: Neither author has a financial or proprietary interest in any material or method mentioned. (Source: Journal of Cataract and Refractive Surgery)

Double-blind therapeutic trial in Angelman syndrome using betaine and folic acid

American Journal of Medical Genetics Part A — Wed, 14 Jul 2010 23:00:00 +0100

We report herein the data on 48 children with AS who were enrolled in a double-blind placebo-controlled protocol using betaine and folic acid for 1 year. There were no statistically significant changes between treated and untreated children; however, in a small subset of patients we observed some positive trends. © 2010 Wiley-Liss, Inc. (Source: American Journal of Medical Genetics Part A)

Methylation profiling in individuals with uniparental disomy identifies novel differentially methylated regions on chromosome 15 [METHOD]

Genome Research — Wed, 14 Jul 2010 15:00:04 +0100

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Partial hexasomy for the Prader-Willi-Angelman syndrome critical region due to a maternally inherited large supernumerary marker chromosome

American Journal of Medical Genetics Part A — Thu, 01 Jul 2010 23:00:00 +0100

We report on a 15-year-old girl referred for developmental delay and seizures with a mosaic tricentric small marker chromosome (SMC) 15 identified by routine G-banding chromosome studies. C-banding and FISH confirmed the presence of three chromosome 15 centromeres as well as four copies of the PWASCR on the SMC in approximately 60% of interphase cells. Microsatellite genotyping documented maternal inheritance of the SMC, and methylation-sensitive multiplex ligation-dependent PCR amplification (MS-MLPA) showed that the extra copies of the PWASCR contained on the marker chromosome bear a methylation pattern similar to a normal maternal chromosome, implying maternal inheritance. These findings are consistent with the patient's phenotype as paternal inheritance of such a marker chromosome is t...

Anesthetic management in a child with Angelman syndrome.

Paediatric Anaesthesia — Wed, 30 Jun 2010 23:00:00 +0100

Authors: Mayhew JF PMID: 20642665 [PubMed - in process] (Source: Paediatric Anaesthesia)

Quantitative 1-Step DNA Methylation Analysis with Native Genomic DNA as Template [Molecular Diagnostics and Genetics]

Clinical Chemistry — Mon, 28 Jun 2010 19:01:45 +0100

Conclusions: Our novel DNA methylation assay reduces both the hands-on time and errors caused by handling and pipetting and allows methylation analyses to be completed within 90 min after DNA extraction. Combined with its precision and reliability, these features make the assay well suited for diagnostic procedures as well as high-throughput analyses. (Source: Clinical Chemistry)

De novo interstitial duplication of the 15q11.2-q14 PWS/AS region of maternal origin: Clinical description, array CGH analysis, and review of the literature

American Journal of Medical Genetics Part A — Wed, 23 Jun 2010 23:00:00 +0100

We present a 6-month-old girl carrying a de novo duplication of maternal origin of the 15q11.2-q14 PWS/AS region (17.73 Mb in size) [46,XX,dup(15)(q11.2-q14)] detected with a high-resolution microarray-based comparative genomic hybridization (array-CGH). The patient is characterized by severe hypotonia, obesity, microstomia, long eyelashes, hirsutism, microretrognathia, short nose, severe psychomotor retardation, and multiple episodes of drug-resistant epileptic seizures, while her brain magnetic resonance imaging (MRI) documented partial corpus callosum dysplasia. In our patient the duplicated region is quite large extending beyond the Prader-Willi-Angelman critical region (PWACR), containing a number of genes that have been shown to be involved in ASD, exhibiting a severe phenotype, beyo...

Genome-wide gene expression profiling of the Angelman syndrome mice with Ube3a mutation

European Journal of Human Genetics — Tue, 22 Jun 2010 23:00:00 +0100

Authors: Daren Low & Ken-Shiung Chen (Source: European Journal of Human Genetics)

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Epilepsy caused by CDKL5 mutations.

European Journal of Paediatric Neurology — Tue, 18 May 2010 23:00:00 +0100

Authors: CastrÃ©n M, Gaily E, TengstrÃ¶m C, LÃ¤hdetie J, Archer H, Ala-Mello S Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been identified in female patients with early onset epileptic encephalopathy and severe mental retardation with a Rett-like phenotype. Subsequently CDKL5 mutations were shown to be associated with more diverse phenotypes including mild epilepsy and autism without epilepsy. Furthermore, CDKL5 mutations were found in patients with Angelman-like phenotype. The severity of epilepsy associated with CDKL5 mutations was recently shown to correlate with the type of CDKL5 mutations and epilepsy was identified to involve three distinct sequential stages. Here, we describe the phenotype of a severe form of neurodevelopmental disease in a female pat...

Practice guidelines for the molecular analysis of Prader-Willi and Angelman syndromes

BMC Medical Genetics - Latest articles — Mon, 10 May 2010 23:00:00 +0100

Conclusion: An agreed set of practice guidelines has been developed for the diagnostic molecular genetic testing of PWS and AS. (Source: BMC Medical Genetics - Latest articles)

Phenotype-genotype correlation of a patient with a "balanced" translocation 9;15 and cryptic 9q34 duplication and 15q21q25 deletion

American Journal of Medical Genetics Part A — Mon, 10 May 2010 23:00:00 +0100

We report on a 2-year-old boy with intellectual disabilities, distinctive facies, hypotonia, cardiac, and renal malformations. During his infancy he had recurrent episodes of apnea, cyanosis, and bradycardia. Chromosomal analysis showed a de novo apparently balanced translocation 46,XY,t(9;15)(q31;q26)dn. The use of array-comparative genomic hybridization (CGH) however, revealed the presence of additional cryptic complex chromosomal rearrangements involving a [sim]5-5.8 Mb distal duplication on chromosome 9 (9q34.1 [rarr] 9q34.3), and deletions on three separate regions of chromosome 15 adding to [sim]8.1-12.2 Mb (15q21.2 [rarr] 15q21.3, 15q22.31 [rarr] 15q23, 15q25.1 [rarr] 15q25.2). During confirmation with fluorescence in situ hybridization (FISH) an inversion was unexpectedly revealed ...

Molecular Cause of Mental Retardation Traced in Angelman Syndrome

Focus Newsletter — Fri, 23 Apr 2010 22:00:00 +0100

Clues to Autism, Related Diseases Emerge (Source: Focus Newsletter)

Epilepsy in patients with Angelman syndrome

Italian Journal of Pediatrics — Thu, 15 Apr 2010 23:00:00 +0100

Angelman syndrome (AS) is a neuro-behavioural, genetically determined condition, characterized by ataxic jerky movements, happy sociable disposition and unprovoked bouts of laughter in association with seizures, learning disabilities and language impairment. Most of the cases are hardly diagnosed during infancy as jerky movements, the cardinal sign, appear later in childhood.AS is caused by a variety of genetic mechanisms involving the 15q 11-13 chromosome. About 70% of cases are due to a "de novo" interstitial deletion in the long arm region, arising on the maternally inherited chromosome. The diagnosis is confirmed by methylation test or by mutation analysis of UBE3A gene. The deletion phenotype is generally linked to a more severe clinical picture in that 95% of patients manifest more s...

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Regulation of the polycomb protein Ring1B by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome [Biochemistry]

Proceedings of the National Academy of Sciences — Tue, 13 Apr 2010 17:22:31 +0100

The polycomb repressive complex (PRC) 1 protein Ring1B is an ubiquitin ligase that modifies nucleosomal histone H2A, a modification which... (Source: Proceedings of the National Academy of Sciences)

A de novo 15q13.2q13.3 deletion in a boy with an Angelman syndrome like phenotype.

European Journal of Medical Genetics — Wed, 07 Apr 2010 23:00:00 +0100

We report on a 11-year-old boy investigated for a clinical suspicion of Angelman syndrome (AS) (OMIM 105830) who was found to carry a de novo interstitial deletion of chromosome 15q13.2q13.3. The deletion overlaps the critical region for the newly recognized recurrent 15q13.3 deletion syndrome. This is the first report of a patient with 15q13.3 deletion syndrome with clinical features similar to that of AS, thus broadening the phenotypic spectrum associated with the 15q13.3 microdeletion syndrome. PMID: 20382277 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)

Epilepsy in Angelman Syndrome and Response to Treatment

AAP Grand Rounds — Wed, 31 Mar 2010 19:04:35 +0100

(Source: AAP Grand Rounds)

Neurodevelopmental disorders: Mechanistic insights into Angelman's syndrome

Nature Reviews Neuroscience — Tue, 30 Mar 2010 23:00:00 +0100

Nature Reviews Neuroscience 11, 298 (2010). doi:10.1038/nrn2837 Author: Cristian Bodo ARC-mediated downregulation of AMPA receptors at the synapse may explain the abnormal CNS development in Angelman's syndrome. (Source: Nature Reviews Neuroscience)

Mutations affecting GABAergic signaling in seizures and epilepsy.

Pflugers Archiv : European Journal of Physiology — Mon, 29 Mar 2010 23:00:00 +0100

Authors: Galanopoulou AS The causes of epilepsies and epileptic seizures are multifactorial. Genetic predisposition may contribute in certain types of epilepsies and seizures, whether idiopathic or symptomatic of genetic origin. Although these are not very common, they have offered a unique opportunity to investigate the molecular mechanisms underlying epileptogenesis and ictogenesis. Among the implicated gene mutations, a number of GABA(A) receptor subunit mutations have been recently identified that contribute to several idiopathic epilepsies, febrile seizures, and rarely to certain types of symptomatic epilepsies, like the severe myoclonic epilepsy of infancy. Deletion of GABA(A) receptor genes has also been linked to Angelman syndrome. Furthermore, mutations of proteins controlling...

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Neurodevelopmental disorders involving genomic imprinting at human chromosome 15q11-q13.

Neurobiology of Disease — Thu, 18 Mar 2010 00:00:00 +0100

Authors: Chamberlain SJ, Lalande M Human chromosome 15q11-q13 is subject to regulation by genomic imprinting, an epigenetic process by which genes are expressed in a parent-of-origin specific manner. Three neurodevelopmental disorders, Prader-Willi syndrome, Angelman syndrome, and 15q duplication syndrome, result from aberrant expression of imprinted genes in this region. Here, we review the current literature pertaining to mouse models and recently identified patients with atypical deletions, which shed light on the epigenetic regulation of the chromosome 15q11-q13 subregion and the genes that are responsible for the phenotypic outcomes of these disorders. PMID: 20304067 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)

Loss of enzyme reduces neural activity in Angelman syndrome

ScienceDaily Headlines — Wed, 10 Mar 2010 07:00:00 +0100

Angelman syndrome (AS) is a debilitating neurological disorder characterized by mental retardation and a high frequency of autism. Researchers have now found that the gene mutation underlying AS appears to affect the ability of neurons to communicate and to properly develop during the first few years of life, a time when brain activity is "rewired" by external stimuli. (Source: ScienceDaily Headlines)

Loss Of Enzyme Reduces Neural Activity In Angelman Syndrome

Health News from Medical News Today — Sat, 06 Mar 2010 08:00:00 +0100

Angelman Syndrome is a rare but serious genetic disorder that causes a constellation of developmental problems in affected children, including mental retardation, lack of speech, and in some cases, autism. Over a decade ago, researchers found that AS was caused by mutation in a single gene, but no one had been able to explain how this defect resulted in the debilitating neurological symptoms of the disease... (Source: Health News from Medical News Today)

The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc

Cell — Fri, 05 Mar 2010 04:00:45 +0100

Paul L. Greer, Rikinari Hanayama, Brenda L. Bloodgood, Alan R. Mardinly, David M. Lipton, Steven W. Flavell, Tae-Kyung Kim, Eric C. Griffith, Zachary Waldon, Rene Maehr, Hidde L. Ploegh, Shoaib Chowdhury, Paul F. Worley, Judith Steen, Michael E. Greenberg. Angelman Syndrome is a debilitating neurological disorder caused by mutation of the E3 ubiquitin ligase Ube3A, a gene whose mutation has also recently been associated with autism spectrum d.... (Source: Cell)

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Angelman Syndrome: Finding the Lost Arc

Cell — Fri, 05 Mar 2010 04:00:44 +0100

Hwan-Ching Tai, Erin M. Schuman. Angelman syndrome is a neurodevelopmental disorder caused by mutations in the maternally inherited UBE3A gene, which encodes a ubiquitin ligase. Greer et al. (2010) now identify a UBE3A sub.... (Source: Cell)

Loss of enzyme reduces neural activity in Angelman syndrome

EurekAlert! - Medicine and Health — Thu, 04 Mar 2010 05:00:00 +0100

(Harvard Medical School) Angelman syndrome (AS) is a debilitating neurological disorder characterized by mental retardation and a high frequency of autism. Researchers have now found that the gene mutation underlying AS appears to affect the ability of neurons to communicate and to properly develop during the first few years of life, a time when brain activity is "rewired" by external stimuli. (Source: EurekAlert! - Medicine and Health)

Parents' Priorities for AAC and Related Instruction for their Children with Angelman Syndrome.

Augmentative and Alternative Communication — Mon, 01 Mar 2010 00:00:00 +0100

Authors: Calculator SN, Black T This investigation examined the extent to which a set of 98 best practices in AAC, previously agreed upon by a panel of experts in AAC and inclusive education, reflected the actual preferences of 32 parents of children diagnosed with Angelman Syndrome. Parents' responses were examined in relation to whether their children were currently in mostly integrated (MI) settings with children without disabilities, or mostly segregated settings with other children with disabilities. With two exceptions, both groups, regardless of their children's current placements, viewed the practices favorably. When asked to prioritize the most important communication skills they wished their children to attain, all of the most frequently cited priorities were reflected in ite...

A “Happy” Toddler Presenting With Sudden, Life-Threatening Seizures

Seminars in Pediatric Neurology — Mon, 01 Mar 2010 00:00:00 +0100

Angelman syndrome is often associated with medically refractory epilepsy. Here, we report the case of a young girl with Angelman syndrome who experienced frequent and prolonged atonic seizures associated with dysautonomia and was unresponsive to multiple antiepileptic drugs, but who responded dramatically to the ketogenic diet. Clinicians are encouraged to consider the ketogenic diet early in the treatment course of patients with Angelman syndrome. (Source: Seminars in Pediatric Neurology)

Double‐blind therapeutic trial in Angelman syndrome using betaine and folic acid

American Journal of Medical Genetics Part A — Fri, 01 Jan 2010 00:00:00 +0100

(Source: American Journal of Medical Genetics Part A)

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Partial hexasomy for the Prader–Willi–Angelman syndrome critical region due to a maternally inherited large supernumerary marker chromosome

American Journal of Medical Genetics Part A — Fri, 01 Jan 2010 00:00:00 +0100

(Source: American Journal of Medical Genetics Part A)

Tyrosinemia type 1 and Angelman syndrome due to paternal uniparental isodisomy 15

Journal of Inherited Metabolic Disease — Wed, 23 Dec 2009 22:57:20 +0100

Abstract Uniparental isodisomy arises when an individual inherits two copies of a specific chromosome from a single parent, which can unmask a recessive mutation or cause a problem of genetic imprinting. Here we describe an exceptional case in which the patient simultaneously presents tyrosinemia type 1 and Angelman syndrome. The genetic studies showed that the patient presents paternal uniparental isodisomy of chromosome 15, with absence of the maternal homolog. As a consequence of this isodisomy, the patient is homozygous for the mutation IVS12+5G>A in the FAH gene, located in the chromosomal region 15q23-25, causing tyrosinemia type 1. The mutation was inherited from his father in double dosage, whereas the mother is not a carrier, which implies that the recurrence ri...

Imprinting Disorders and Assisted Reproductive Technology

Medscape Today Headlines — Mon, 21 Dec 2009 12:04:43 +0100

What is the current evidence concerning an association between assisted reproductive technology and retinoblastoma, Beckwith-Wiedemann, Angelman, Silver-Russell and maternal hypomethylation syndromes? Seminars in Reproductive Medicine (Source: Medscape Today Headlines)

Angelman syndrome: Therapies focus on managing the condition

MayoClinic.com Full Feed — Fri, 18 Dec 2009 06:00:00 +0100

Angelman syndrome — Comprehensive overview covers symptoms, causes, treatment of this rare genetic disorder. Sponsored by:Chemotherapy.com - http://www.chemotherapy.com (Source: MayoClinic.com Full Feed)

2q23.1 microdeletion identified by array comparative genomic hybridisation: an emerging phenotype with Angelman-like features?

Journal of Medical Genetics — Tue, 01 Dec 2009 18:04:20 +0100

Discussion: Haploinsufficiency of one of the deleted genes (MBD5 or EPC2) could be responsible for the common clinical features observed in the 2q23.1 microdeletion syndrome, and this hypothesis needs further investigation. (Source: Journal of Medical Genetics)

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Atp10a, a gene adjacent to the PWS/AS gene cluster, is not imprinted in mouse and is insensitive to the PWS-IC

Neurogenetics — Thu, 05 Nov 2009 18:57:51 +0100

We report that Atp10a is biallelically expressed in both the newborn and adult brain, and Atp10a allelic expression is insensitive to deletion or mutation of the PWS imprinting center. The CpG island associated with Atp10a is hypomethylated, a result consistent with the notion that Atp10a is not an imprinted gene. Content Type Journal ArticleCategory ORIGINAL ARTICLEDOI 10.1007/s10048-009-0226-9Authors Amanda J. DuBose, University of Florida College of Medicine Department of Molecular Genetics and Microbiology Gainesville Florida 32610-0266 USAKaren A. Johnstone, Peninsula Medical School, University of Exeter Institute of Biomedical and Clinical Sciences Exeter EX2 5DW UKEmily Y. Smith, University of Florida College of Medicine Department of Molecular Genetics and Microbiology Gainesv...

Genomic imprinting disorders in humans: a mini-review

Journal of Assisted Reproduction and Genetics — Wed, 21 Oct 2009 05:58:10 +0100

Abstract Mammals inherit two complete sets of chromosomes, one from the father and one from the mother, and most autosomal genes are expressed from both maternal and paternal alleles. Imprinted genes show expression from only one member of the gene pair (allele) and their expression are determined by the parent during production of the gametes. Imprinted genes represent only a small subset of mammalian genes that are present but not imprinted in other vertebrates. Genomic imprints are erased in both germlines and reset accordingly; thus, reversible depending on the parent of origin and leads to differential expression in the course of development. Genomic imprinting has been studied in humans since the early 1980’s and accounts for several human disorders. The first repo...

Prader–Willi and Angelman syndromes: genetic counseling

European Journal of Human Genetics — Tue, 06 Oct 2009 23:00:00 +0100

Prader–Willi and Angelman syndromes: genetic counseling European Journal of Human Genetics advance online publication, October 7, 2009. doi:10.1038/ejhg.2009.170 Authors: Cristina Camprubí, Maria Dolors Coll, Elisabeth Gabau & Míriam Guitart (Source: European Journal of Human Genetics)

Impaired hippocampal plasticity and altered neurogenesis in adult Ube3a maternal deficient mouse model for Angelman syndrome.

Experimental Neurology — Wed, 23 Sep 2009 23:00:00 +0100

Authors: Mardirossian S, Rampon C, Salvert D, Fort P, Sarda N Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by mental retardation, seizures and sleep disturbances. It results from lack of the functional maternal allele of UBE3A gene. Ube3a maternal-deficient mice (Ube3a m-/p+), animal models for AS, are impaired in hippocampal-dependent learning tasks as compared with control (Ube3a m+/p+) mice. We first examined the basal expression of immediate early genes which expression is required for synaptic plasticity and memory formation. We found that basal expression of c-fos and Arc genes is reduced in the DG of Ube3a maternal deficient mice compared to their non-transgenic littermates. We then examined whether adult hippocampal neurogenesis, which likely ser...

A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease [METHODS]

Genome Research — Mon, 31 Aug 2009 23:00:00 +0100

Copy-number variants (CNVs) are substantial contributors to human disease. A central challenge in CNV-disease association studies is to characterize the pathogenicity of rare and possibly incompletely penetrant events, which requires the accurate detection of rare CNVs in large numbers of individuals. Cost and throughput issues limit our ability to perform these studies. We have adapted the Illumina BeadXpress SNP genotyping assay and developed an algorithm, SNP-Conditional OUTlier detection (SCOUT), to rapidly and accurately detect both rare and common CNVs in large cohorts. This approach is customizable, cost effective, highly parallelized, and largely automated. We applied this method to screen 69 loci in 1105 children with unexplained intellectual disability, identifying pathogenic var...

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Abnormal myelination in Angelman syndrome.

European Journal of Paediatric Neurology — Fri, 28 Aug 2009 23:00:00 +0100

Authors: Castro-Gago M, Gómez-Lado C, Eirís-Puñal J, Rodríguez-Mugico VM PMID: 19720548 [PubMed - as supplied by publisher] (Source: European Journal of Paediatric Neurology)

Imprinting Disorders and Assisted Reproductive Technology

Seminars in Reproductive Medicine — Thu, 27 Aug 2009 13:12:35 +0100

Semin Reprod Med 2009; 27: 417-428DOI: 10.1055/s-0029-1237430ABSTRACTWorldwide use of assisted reproductive technology (ART) accounts for an estimated 1 to 3% of births. Since 2002, a series of reports have suggested an increased risk of imprinting disorders (Beckwith-Wiedemann syndrome and Angelman syndrome) in children conceived by ART. Definitive conclusions are difficult to substantiate due to the rarity of imprinting disorders and the variability in ART protocols. Despite these limitations, there is biological plausibility for alteration in nongenomic inheritance caused by ART. Animal studies have shown that ART procedures can alter normal imprinting, specifically DNA methylation patterns. Collectively, studies suggest an association between ART and loss of maternal methylation. More ...

Autism spectrum disorders in genetic syndromes: implications for diagnosis, intervention and understanding the wider autism spectrum disorder population

Journal of Intellectual Disability Research — Tue, 25 Aug 2009 23:00:00 +0100

Conclusions There is a need for caution in interpreting the significance of superficial similarities between ASD and the behavioural phenotypes of certain genetically determined syndromes. However, recognition of ASD-like characteristics (even where a true diagnosis of ASD may not be relevant) in individuals with genetic syndromes is crucial in ensuring that individuals receive appropriate behavioural management and educational placement. Further research in this field requires fine-grained investigation of behavioural phenomenology within individual syndrome groups. (Source: Journal of Intellectual Disability Research)

Supernumerary marker chromosome 15 in a male with azoospermia and open bite deformity.

Asian Journal of Andrology — Sun, 23 Aug 2009 23:00:00 +0100

Authors: Koç A, Onur SO, Ergün MA, Perçin EF Supernumerary marker chromosome 15 (sSMC[15]) is the most frequent marker chromosome, and it is generally regarded as unimportant if it does not contain the Prader-Willi/Angelman syndrome critical region (PWACR). The clinical importance of the larger markers in association with the critical region is mentioned in almost all reports related to marker chromosome 15, and smaller markers are solely associated with minor dysmorphic features, azoospermia and recurrent miscarriages. However, these small sSMC(15)s without the PWACR may also determine a specific phenotype. A dysmorphic examination of an azoospermic patient in a genetics clinic was performed and was followed by a peripheral blood lymphocyte chromosomal analysis accordin...

Form and Function of Communicative Behaviours in Individuals with Angelman Syndrome

Journal of Applied Research in Intellectual Disabilities — Tue, 04 Aug 2009 23:00:00 +0100

There are only a few studies that have attempted to systematically document the communicative forms and functions in the repertoires of individuals with Angelman syndrome (AS). In the present study, we sent the Inventory of Potential Communicative Acts (IPCA) (Sigafoos et al. 2000a,b) to 136 families of children with AS. The IPCA aims to provide a systematic inventory and objective description of the communication forms and functions present in the child's repertoire. Seventy-nine surveys were returned and analyzed to determine differences in the number and types of communicative forms and functions in relation to the child's setting, genetic subtype, presence of epilepsy, age, and level of intellectual disability. The results showed significant differences in the forms and functions of re...

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The ubiquitin proteasome system in neuropathology

Acta Neuropathologica — Tue, 14 Jul 2009 09:56:41 +0100

Abstract The ubiquitin proteasome system (UPS) orchestrates the turnover of innumerable cellular proteins. In the process of ubiquitination the small protein ubiquitin is attached to a target protein by a peptide bond. The ubiquitinated target protein is subsequently shuttled to a protease complex known as the 26S proteasome and subjected to degradative proteolysis. The UPS facilitates the turnover of proteins in several settings. It targets oxidized, mutant or misfolded proteins for general proteolytic destruction, and allows for the tightly controlled and specific destruction of proteins involved in development and differentiation, cell cycle progression, circadian rhythms, apoptosis, and other biological processes. In neuropathology, alteration of the UPS, or mutations ...

[METHODS] A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease

Genome Research — Tue, 07 Jul 2009 23:00:00 +0100

A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease [METHODS]

Genome Research — Tue, 07 Jul 2009 23:00:00 +0100

Health Needs Annual Evidence Update 2009 - Epilepsy

Neurological Conditions Specialist Library — Tue, 07 Jul 2009 16:56:53 +0100

The prevalence rate of epilepsy amongst people with learning disabilities is suggested as 22% compared to 0.4%-1% for the general population. Epilepsy occurs 15-30 times as often in people with learning disabilities (van Schrojenstein Lantman- Valk 2000; Espie et al 2003).The prevalence of epilepsy has been found to vary with the age of patients and aetiology of learning disability. There has been one new review published since January 2008 (Amiet et al 2008), a meta analysis which looked at epilepsy in autism and its association with learning disability and gender. Looking at published reports between 1963-2006 the authors compared the prevalence of epilepsy among autistic patients with learning disabilities versus autistic patients without learning disabilities and among male versus...

UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27.

Neurobiology of Disease — Mon, 06 Jul 2009 23:00:00 +0100

Authors: Mishra A, Godavarthi SK, Jana NR The UBE3A/E6-AP is known to function both as an E3 ubiquitin ligase of the ubiquitin proteasome system and as a transcriptional coactivator. E6-AP shows brain-specific imprinting and loss of function of maternally inherited E6-AP causes Angelman syndrome. However, how the loss of function of E6-AP causes disease pathogenesis is poorly understood. Here, we show that E6-AP interacts with and promotes proteasome-mediated degradation of cyclin-dependent kinase inhibitor p27. E6-AP also directly ubiquitinates p27 in an in vitro ubiquitination assay. Partial knockdown of E6-AP increases the level of p27 leading to cell cycle arrest. Interestingly, partial knockdown also increases the transcription of p27. Finally, we have demonstrated the increased l...

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[Genetics] Protein-binding elements establish in the oocyte the primary imprint of the Prader-Willi/Angelman syndromes domain

Proceedings of the National Academy of Sciences — Mon, 22 Jun 2009 23:00:00 +0100

Imprinting of the PWS/AS 2.4 Mb domain in the human is controlled by a paternally active imprinting center (PWS-IC). PWS-IC... (Source: Proceedings of the National Academy of Sciences)

[METHODS AND RESOURCES] A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease

Genome Research — Mon, 08 Jun 2009 04:00:00 +0100

Copy-number variants (CNVs) are substantial contributors to human disease A central challenge in CNV-disease association studies is to characterize the pathogenicity of rare and possibly incompletely penetrant events - a task that requires the accurate detection of rare CNVs in large numbers of cases and controls. The high cost, low throughput, and inflexibility of currently available technologies limit our ability to perform these studies. We have adapted the Illumina BeadXpress SNP genotyping assay and developed an algorithm, Snp-Conditional OUTlier detection (SCOUT), to rapidly and accurately detect both rare and common CNVs in large sample collections. This approach is customizable, cost-effective, highly parallelized, and largely automated. We applied this method to screen 69 loci in...

Mutation in the SLC9A6 gene is not a frequent cause of sporadic Angelman-like syndrome

European Journal of Human Genetics — Wed, 27 May 2009 04:00:00 +0100

Authors: Yann Fichou, Nadia Bahi-Buisson, Juliette Nectoux, Jamel Chelly, Delphine Héron, Laurence Cuisset & Thierry Bienvenu (Source: European Journal of Human Genetics)

Neurogenetics: Protecting plasticity

Nature — Wed, 20 May 2009 04:00:00 +0100

Nature 459, 303 (2009). doi:10.1038/459303b Nature Neurosci. doi:10.1038/nn.2327 (2009)Angelman syndrome is a form of mental retardation caused by mutations in the gene UBE3A. Scientists have discovered a role for the Ube3A protein that might explain the learning deficits associated with the disorder.Benjamin (Source: Nature)

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Angelman syndrome (AS, MIM 105830)

European Journal of Human Genetics — Wed, 20 May 2009 04:00:00 +0100

Authors: Griet Van Buggenhout & Jean-Pierre Fryns (Source: European Journal of Human Genetics)

Epilepsy and the sleep–wake patterns found in Angelman syndrome

Epilepsia — Mon, 11 May 2009 23:00:00 +0100

This study examines seizure variables and sleep in a large AS cohort. Sleep disturbances and epilepsy were assessed in 290 individuals with AS using two questionnaires, including the Behavioral Evaluation of Disorders of Sleep (BEDS). Sensitivity to the sleeping environment, decreased nightly hours of sleep, and a difficulty initiating sleep were significantly correlated with the presence of epilepsy, particularly focal seizures. Use of multiple anticonvulsant drugs was shown to affect sleep. No significant associations were present between molecular subtypes of AS and individual sleep factors. Sleep problems appeared to be associated with epilepsy in individuals with AS, especially with focal and absence seizures and multiple seizure types. Results were consistent with those of prior stud...

Epilepsy in Angelman syndrome: A questionnaire-based assessment of the natural history and current treatment options

Epilepsia — Mon, 11 May 2009 23:00:00 +0100

Discussion: This is the largest study to date assessing epilepsy in AS. Although epilepsy in AS is considered a generalized epilepsy, there was a high prevalence of partial seizures. There are few previous data regarding the use of newer AED in AS, and the results of this study suggest that these newer agents, specifically levetiracetam and lamotrigine, may have efficacy similar to that of valproic acid and clonazepam, and that they appear to have similar or better side-effect profiles. Nonpharmacologic therapies such as dietary therapy and vagus nerve stimulation (VNS) also suggest favorable efficacy and tolerability, although further studies are needed. (Source: Epilepsia)

Preclinical Work Shows How One Gene Causes Severe Mental Retardation

Health News from Medical News Today — Mon, 11 May 2009 08:00:00 +0100

Researchers at Duke University Medical Center and the University of North Carolina have discovered in mice how a single disrupted gene can cause a form of severe mental retardation known as Angelman syndrome. (Source: Health News from Medical News Today)

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Preclinical work shows how one gene causes severe mental retardation

EurekAlert! - Medicine and Health — Sun, 10 May 2009 04:00:00 +0100

(Duke University Medical Center) Researchers at Duke University Medical Center and the University of North Carolina have discovered in mice how a single disrupted gene can cause a form of severe mental retardation known as Angelman syndrome. In a Nature Neuroscience study, they found that the gene is needed so that neurons in the brain can form and adjust their connections to other neurons for storing sensory information. When the mice were deprived of sensory stimulation, the brain connections could be recovered, so treatments may be possible. (Source: EurekAlert! - Medicine and Health)

UNC-Duke study: Impaired brain plasticity linked to Angelman syndrome learning deficits

EurekAlert! - Medicine and Health — Sun, 10 May 2009 04:00:00 +0100

(University of North Carolina School of Medicine) How might disruption of a single gene in the brain cause the severe cognitive deficits associated with Angelman syndrome, a neurogenetic disorder? Researchers at the University of North Carolina at Chapel Hill School of Medicine and Duke University now believe they have the answer: impaired brain plasticity. (Source: EurekAlert! - Medicine and Health)

Impaired Brain Plasticity Linked To Angelman Syndrome Learning Deficits

ScienceDaily Headlines — Sun, 10 May 2009 04:00:00 +0100

How might disruption of a single gene in the brain cause the severe cognitive deficits associated with Angelman syndrome, a neurogenetic disorder? Researchers now believe they have the answer: impaired brain plasticity. (Source: ScienceDaily Headlines)

[Protein Synthesis, Post-Translational Modification, and Degradation] The Ubiquitin Ligase E6-AP Is Induced and Recruited to Aggresomes in Response to Proteasome Inhibition and May Be Involved in the Ubiquitination of Hsp70-bound Misfolded Proteins

Journal of Biological Chemistry — Fri, 10 Apr 2009 04:00:00 +0100

Cells are equipped with an efficient quality control system to selectively eliminate abnormally folded and damaged proteins. Initially the cell tries to refold the unfolded proteins with the help of molecular chaperones, and failure to refold leads to their degradation by the ubiquitin proteasome system. But how this proteolytic machinery recognizes the abnormally folded proteins is poorly understood. Here, we report that E6-AP, a HECT domain family ubiquitin ligase implicated in Angelman syndrome, interacts with the substrate binding domain of Hsp70/Hsc70 chaperones and promotes the degradation of chaperone bound substrates. The expression of E6-AP was dramatically induced under a variety of stresses, and overexpression of E6-AP was found to protect against endoplasmic reticulum stress-in...

Split hand-foot malformation, tetralogy of Fallot, mental retardation and a 1 Mb 19p deletion - evidence for further heterogeneity?

American Journal of Medical Genetics Part A — Tue, 07 Apr 2009 04:00:00 +0100

We report on a male patient with SHFM, tetralogy of Fallot and a clinical phenotype suggestive of Angelman syndrome. Using array based genome analysis (3K BACs and 500K SNPs), we identified a de novo deletion of chromosome 19p13.11, confirmed by Fluorescent In Situ Hybridization analysis. The deletion is 0.99 Mb in size and contains 28 genes. The proximal breakpoint of the deletion is in EPS15L1, which may be involved in vertebrate limb development. Subsequent screening of 21 syndromic and nonsyndromic SHFM patients (TP73L mutation negative) for rearrangements using Multiplex Ligation-dependent Probe Amplification did not detect other deletions or duplications in chromosome 19. These findings suggest that our patient may have a new contiguous gene syndrome and indicates that SHFM is geneti...

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43. EEG in the early diagnosis of Angelman syndrome

Clinical Neurophysiology — Wed, 01 Apr 2009 04:00:00 +0100

lntroduction: Angelman Syndrome is a genetic disorder characterized clinically by psychomotor retardation, craniofacial dysmorphism, ataxia or puppet gait, prolonged and inappropriate paroxysms of laughter and epileptic seizures. The average age at diagnosis is six. Some specific EEG patterns have been described. (Source: Clinical Neurophysiology)

Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances.

European Journal of Medical Genetics — Fri, 27 Mar 2009 04:00:00 +0100

We describe nine cases with a microdeletion at 15q11.2 between BP1-BP2, thus having a haploinsufficiency for TUBGCP5, NIPA1, NIPA2, and CYFIP1 without Prader-Willi/Angelman syndrome. The clinical significance of a pure BP1-BP2 microdeletion has been debated, however, our patients shared several clinical features, including delayed motor and speech development, dysmorphisms and behavioural problems (ADHD, autism, obsessive-compulsive behaviour). Although the deletion often appeared to be inherited from a normal or mildly affected parent, it was de novo in two cases and we did not find it in 350 healthy unrelated controls. Our results suggest a pathogenic nature for the BP1-BP2 microdeletion and, although there obviously is an incomplete penetrance, they support the existence of a novel micr...

Genetic Imprinting: The Paradigm of Prader-Willi and Angelman Syndromes.

Endocrine Development — Fri, 20 Mar 2009 18:07:48 +0100

Authors: Gurrieri F, Accadia M Imprinted genes are expressed from only one of the two parental alleles. A consequence of genomic imprinting is that viable embryos must receive two haploid genome complements from parents of opposite sex. The parental-specific expression is obtained through epigenetic modifications (DNA methylation, histone tail modifications) which alter the conformation of chromatin fiber and there-fore regulate the expression of the underlying genes. Deletions, duplication, mutations or alterations of imprinting of the only active allele, as well as uniparental disomy or loss of imprinting of the inactive allele lead to an unbalance (loss of function or gain of function) in the dosage of the gene product and may have phenotypic consequences. Two such examples in human...

Two distinctive classic genetic syndromes, 22q11.2 deletion syndrome and Angelman syndrome, occurring within the same family

American Journal of Medical Genetics Part A — Fri, 13 Mar 2009 04:00:00 +0100

We document a sib pair born to a mother with a reciprocal translocation, t(15;22)(q13;q11.2): the daughter had the Angelman syndrome phenotype associated with a maternally derived 15q deletion, and the son had a phenotype associated with a 22q deletion. Adjacent two-type segregation during gametogenesis in the mother can account for the unbalanced karyotypes of the siblings. From a tetravalent chromatid formed by normal chromosome 15, derivative chromosome 15, normal chromosome 22, and derivative chromosome 22, the daughter inherited chromosome 22 and derivative chromosome 22 and the son inherited chromosome 15 and derivative chromosome 15. The family is unique in that two distinctive genetic syndromes, 22q11.2 deletion syndrome and Angelman syndrome, occurred within the same family. The f...

Screening for Genomic Rearrangements and Methylation Abnormalities of the 15q11-q13 Region in Autism Spectrum Disorders

Biological Psychiatry — Thu, 12 Mar 2009 00:00:00 +0100

Conclusions: Our results show that abnormalities of the 15q11-q13 region are a significant cause of ASD, accounting for approximately 1% of cases. Maternal interstitial 15q11-q13 duplications, previously reported to be present in 1% of patients with ASD, were not detected in our sample. Although paternal duplications of chromosome 15 remain phenotypically silent in the majority of patients, they can give rise to developmental delay and ASD in some subjects, suggesting that paternally expressed genes in this region can contribute to ASD, albeit with reduced penetrance compared with maternal duplications. These findings indicate that patients with ASD should be routinely screened for 15q genomic imbalances and methylation abnormalities and that MLPA is a reliable, rapid, and cost-effective m...

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Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes

Neurogenetics — Wed, 25 Feb 2009 10:35:04 +0100

Abstract It has been found that CDKL5 gene mutations are responsible for early-onset epilepsy and drug resistance. We screened a population of 92 patients with classic/atypical Rett syndrome, 17 Angelman/Angelman-like patients and six idiopathic autistic patients for CDKL5 mutations and exon deletions and identified seven novel mutations: six in the Rett subset and one in an Angelman patient. This last, an insertion in exon 11, c.903_904 dupGA, p.Leu302Aspfx49X, is associated with a relatively mild clinical presentation as the patient is the only one capable of sitting and walking alone. Of the six mutations, two are de novo missense changes affecting highly conserved aminoacid residues, c.215 T > C p.Ile72Thr and c.380A > G p.His127Arg (present in a mosa...

Novel UBE3A mutations causing Angelman syndrome: Different parental origin for single nucleotide changes and multiple nucleotide deletions or insertions

American Journal of Medical Genetics Part A — Wed, 11 Feb 2009 05:00:00 +0100

Angelman syndrome (AS) is a genetic disorder caused by a deficiency of UBE3A imprinted gene expression from the maternal chromosome 15. In 10% of AS cases the genetic cause is a mutation affecting the maternal copy of the UBE3A gene. In two large Spanish series of clinically stringently selected and nonstringently selected patients, we have identified 11 pathological mutations - eight of them novel mutations - and 14 sequence changes considered polymorphic variants. Remarkably, single nucleotide substitutions are more likely to be inherited, while multiple nucleotide deletions or insertions are less frequently inherited, thus indicating that single nucleotide substitutions are more likely to originate from the paternal germline. Additionally, there seems to be a different distribution of n...

Imprinting disorders and assisted reproductive technology

Fertility and Sterility — Sun, 01 Feb 2009 05:00:00 +0100

Conclusion(s): Because the absolute incidence of imprinting disorders is small ( (Source: Fertility and Sterility)

Comparing Two Diagnostic Laboratory Tests for Several Microdeletions Causing Mental Retardation Syndromes: Multiplex Ligation-Dependent Amplification vs Fluorescent In Situ Hybridization.

The Korean Journal of Laboratory Medicine — Sun, 01 Feb 2009 05:00:00 +0100

CONCLUSIONS: On the basis of these results, we conclude that MLPA is an accurate, reliable, and cost-effective alternative to FISH in the screening for microdeletion syndromes. PMID: 19262082 [PubMed - in process] (Source: The Korean Journal of Laboratory Medicine)