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Preview: MedWorm: Angelman Syndrome

MedWorm: Angelman Syndrome



MedWorm.com provides a medical RSS filtering service. Over 7000 RSS medical sources are combined and output via different filters. This feed contains the latest news and research in the Angelman Syndrome category.



Last Build Date: Tue, 22 Mar 2016 08:29:10 +0100

 



Gene-targeting pharmaceuticals for single-gene disorders

Mon, 21 Mar 2016 00:00:00 +0100

The concept of orphan drugs for treatment of orphan genetic diseases is perceived enthusiastically at present, and this is leading to research investment on the part of governments, disease-specific foundations and industry. This review attempts to survey the potential to use traditional pharmaceuticals as opposed to biopharmaceuticals to treat single-gene disorders. The available strategies include the use of antisense oligonucleotides (ASOs) to alter splicing or knock-down expression of a transcript, siRNAs to knock-down gene expression and drugs for nonsense mutation read-through. There is an approved drug for biallelic knock-down of the APOB gene as treatment for familial hypercholesterolemia. Both ASOs and siRNAs are being explored to knock-down the transthyretin gene to prevent the r...

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Reflex seizures in a patient with Angelman syndrome and trisomy 21

Mon, 14 Mar 2016 00:00:00 +0100

(Source: Neurological Sciences)



Protein Delivery of an Artificial Transcription Factor Restores Widespread Ube3a Expression in an Angelman Syndrome Mouse Brain

Tue, 08 Mar 2016 00:00:00 +0100

Authors: Barbara J Bailus, Benjamin Pyles, Michelle M McAlister, Henriette O'Geen, Sarah H Lockwood, Alexa N Adams, Jennifer Trang T Nguyen, Abigail Yu, Robert F Berman & David J Segal (Source: Molecular Therapy)



Diagnostics of common microdeletion syndromes using fluorescence in situ hybridization: single center experience in a developing country.

Sun, 06 Mar 2016 12:45:02 +0100

We report 4 patients with DiGeorge syndromes, 4 patients with Prader-Willi/Angelman, 4 patients with Wolf-Hirschhorn syndrome, and 3 patients with Williams syndrome in the analyzed 7 year period. Based on the positive FISH results for each syndrome, the incidence was calculated for the Federation of Bosnia and Herzegovina. These are the first reported frequencies of the microdeletion syndromes in the Federation of Bosnia and Herzegovina. PMID: 26937776 [PubMed - as supplied by publisher] (Source: Bosnian Journal of Basic Medical Sciences)



Sedation with dexmedetomidine for conducting electroencephalogram in a patient with Angelman syndrome: a case report

Sun, 06 Mar 2016 00:00:00 +0100

Conclusion Dexmedetomidine promoted satisfactory sedation, was well tolerated and enabled the interpretation of the electroencephalogram in a patient with Angelman syndrome and seizure disorder. (Source: Brazilian Journal of Anesthesiology)



Scrutinizing brain magnetic resonance imaging patterns in Angelman syndrome

Thu, 03 Mar 2016 00:00:00 +0100

Conclusion: The lack of specific changes in the brain MRI of children with AS observed in this case series rendered brain MRI a less helpful complementary test. Thus, a definitive diagnosis of AS could only be established on molecular biology that was undertaken based on the clinical suspicion of AS. (Source: Neurology India)

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Investigational new drugs for focal epilepsy.

Sun, 14 Feb 2016 14:09:02 +0100

Authors: Mula M Abstract For more than 30 years, antiepileptic drug development has been based on specific assumptions regarding the neurobiology of epilepsy but all marketed drugs have not changed the proportion of drug refractory patients. It is, therefore, evident that new molecular targets need to be identified. Advances in neurobiology and molecular pharmacology are bringing into the epilepsy field new neurochemical functions such as those modulated by cannabinoid, serotonin, melatonin and galanin receptors. Among all the different compounds, the melatonin type 3 receptor agonist beprodone and cannabidiol are those at the more advanced stage of development. Interestingly, despite the structural analogies with tetrahydrocannabinol, the anticonvulsant activity of cannabidiol is...



Description and Evaluation of a Home-Based, Parent-Administered Program for Teaching Enhanced Natural Gestures to Individuals With Angelman Syndrome.

Wed, 03 Feb 2016 00:00:00 +0100

Conclusions: ENGs may, in conjunction with other forms of augmentative and alternative communication, represent a viable method of communication for many individuals with Angelman syndrome. Further research is warranted to explore the feasibility of ENGs with other populations of individuals with severe disabilities and complex communication challenges. PMID: 26847597 [PubMed - as supplied by publisher] (Source: American Journal of Speech-Language Pathology)



Identification of copy number variations associated with congenital heart disease by chromosomal microarray analysis and next generation sequencing

Tue, 02 Feb 2016 00:00:00 +0100

ConclusionsCMA and CNV‐Seq arereliable and accurate prenatal techniques for identifying pathogenic fetal chromosomal abnormalities associated with cardiac defects prenatally. (Source: Prenatal Diagnosis)



Description and Evaluation of a Home-Based, Parent-Administered Program for Teaching Enhanced Natural Gestures to Individuals With Angelman Syndrome

Mon, 01 Feb 2016 00:00:00 +0100

Conclusions ENGs may, in conjunction with other forms of augmentative and alternative communication, represent a viable method of communication for many individuals with Angelman syndrome. Further research is warranted to explore the feasibility of ENGs with other populations of individuals with severe disabilities and complex communication challenges. (Source: American Journal of Speech-Language Pathology)



A structured assessment of motor function and behavior in patients with Kleefstra Syndrome.

Fri, 22 Jan 2016 00:00:00 +0100

In conclusion, patients with Kleefstra syndrome present with a broad range of clinical problems in all age groups and are therefore in need of a multidisciplinary follow-up also after their transition into adulthood. PMID: 26808425 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)

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Management of Sleep Disorders in Children With Neurodevelopmental Disorders: A Review

Thu, 21 Jan 2016 00:00:00 +0100

Neurodevelopmental disorders (NDDs) are defined as a group of disorders caused by changes in early brain development, resulting in behavioral and cognitive alterations in sensory and motor systems, speech, and language. NDDs affect approximately 1–2% of the general population. Up to 80% of children with NDDs are reported to have disrupted sleep; subsequent deleterious effects on daytime behaviors, cognition, growth, and overall development of the child are commonly reported. Examples of NDDs discussed in this review include autism spectrum disorder, cerebral palsy, Rett syndrome, Angelman syndrome, Williams syndrome, and Smith‐Magenis syndrome. The etiology of sleep disorders in children with NDDs is largely heterogeneous and disease specific. The diagnosis and management of sleep diso...



Pharmacological therapies for Angelman syndrome

Tue, 12 Jan 2016 00:00:00 +0100

Summary Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a loss of the maternally inherited UBE3A; the paternal UBE3A is silenced in neurons by a mechanism involving an antisense transcript (UBE3A-AS). We reviewed the published information on clinical trials that have been completed as well as the publicly available information on ongoing trials of therapies for AS. Attempts at hypermethylating the maternal locus through dietary compounds were ineffective. The results of a clinical trial using minocycline as a matrix metalloproteinase-9 inhibitor were inconclusive; another clinical trial is underway. Findings from a clinical trial using L-dopa to alter phosphorylation of calcium/calmodulin-dependent kinase II are awaited. Topoisomerase inhibitors and antise...



A Case Report of an Infant with Robertsonian Translocation (15;22)(q10;q10) and Literature Review.

Fri, 01 Jan 2016 00:00:00 +0100

We describe a case with rob(15;22) in which the phenotype includes generalized hypotonia, respiratory distress, tent shaped upper lips, hyporeflexia and single umbilical artery. Chromosome analysis with peripheral blood was performed, while the karyotype was interpreted as 45,XX,der(15;22)(q10;q10). In Prader-Willi/Angelman Syndrome FISH studies, deletion of the SNRPN gene was not observed, but deletion of 15p11.2 was noted. Prader-Willi/Angelman Syndrome methylation-specific polymerase chain reaction and chromosomal microarrays showed negative findings. Molecular studies associated with spinal muscular atrophy and progressive muscular dystrophy also showed negative findings. We suggest that rob(15;22) and deletion of 15p11.2 could be related to clinical presentation like this case. P...



The Impact of Menstrual Issues on Young Women with Angelman Syndrome

Mon, 21 Dec 2015 00:00:00 +0100

Characterize menstrual health issues and their impact in young women with Angelman Syndrome (AS). Our Secondary objective is to compare them with young women with Autism Spectrum Disorders (ASD). (Source: Journal of Pediatric and Adolescent Gynecology)



Epigenetic imprinting during assisted reproductive technologies: The effect of temporal and cumulative fluctuations in methionine cycling on the DNA methylation state

Fri, 11 Dec 2015 00:00:00 +0100

This article is protected by copyright. All rights reserved (Source: Molecular Reproduction and Development)

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Whole Exome Sequencing and Heterologous Cellular Electrophysiology Studies Elucidate a Novel Loss-of-Function Mutation in the Encoded Neuronal P/Q-Type Calcium Channel in a Child with Congenital Hypotonia and Developmental Delay

Fri, 06 Nov 2015 00:00:00 +0100

A 4-year-old boy born at 37-weeks’ gestation with intrauterine grown restriction presented with developmental delay with pronounced language and gross motor delay, axial hypotonia, and dynamic hyper-tonicity of the extremities. Investigations including the Minnesota Newborn Screen, thyroid stimulating hormone/thyroxin (TSH/T4), and inborn errors of metabolism screening were negative. Cerebral magnetic resonance imaging and spectroscopy were normal. Genetic testing was negative for coagulopathy, Smith-Lemli-Opitz, Fragile X, and Prader-Willi/Angelman syndromes. (Source: Pediatric Neurology)



Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model

Wed, 21 Oct 2015 00:30:03 +0100

Angelman syndrome (AS) is a severe neurological disorder that is associated with prominent movement and balance impairments that are widely considered to be due to defects of cerebellar origin. Here, using the cerebellar-specific vestibulo-ocular reflex (VOR) paradigm, we determined that cerebellar function is only mildly impaired in the Ube3am–/p+ mouse model of AS. VOR phase-reversal learning was singularly impaired in these animals and correlated with reduced tonic inhibition between Golgi cells and granule cells. Purkinje cell physiology, in contrast, was normal in AS mice as shown by synaptic plasticity and spontaneous firing properties that resembled those of controls. Accordingly, neither VOR phase-reversal learning nor locomotion was impaired following selective deletion of Ube3a...



Long contiguous stretches of homozygosity spanning shortly the imprinted loci are associated with intellectual disability, autism and/or epilepsy

Thu, 15 Oct 2015 00:00:00 +0100

Conclusions: This study demonstrates that shorter LCSH at chromosomes 7q21.3, 7q31.2, 11p15.5, and 15p11.2 occur with a frequency of about 5 % in the children with intellectual disability, autism, congenital malformations and/or epilepsy. Consequently, this type of epigenetic mutations appears to be the most common one among children with neurodevelopmental diseases. Finally, since LCSH less than 2.5–10 Mb in size are generally ignored in diagnostic SNP microarray studies, one can conclude that an important epigenetic cause of intellectual disability, autism or epilepsy is actually overlooked. (Source: Molecular Cytogenetics)



Angelman Syndrome

Tue, 06 Oct 2015 19:19:24 +0100

NASHVILLE, Tenn. (Ivanhoe Newswire) -- What would you do if your son was born with a serious disorder and there was no cure? Terry Jo Bichell, Vanderbilt University researcher in Nashville, Tennessee, knew what she had to do: find one. (Source: Medical Headlines From Ivanhoe.com)



Angelman Syndrome: A Review Highlighting Musculoskeletal and Anatomical Aberrations

Thu, 01 Oct 2015 00:00:00 +0100

This article is protected by copyright. All rights reserved. (Source: Clinical Anatomy)

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Neurodevelopmental disease: A molecular tightrope

Wed, 30 Sep 2015 00:00:00 +0100

Authors: Ype Elgersma The identification of a regulatory site on the UBE3A protein that can be phosphorylated to alter its enzymatic activity provides insight into the aetiology of two human neurodevelopmental diseases, Angelman syndrome and autism. (Source: Nature)



Epigenetic mechanisms in diurnal cycles of metabolism and neurodevelopment

Wed, 16 Sep 2015 00:00:00 +0100

The circadian cycle is a genetically encoded clock that drives cellular rhythms of transcription, translation and metabolism. The circadian clock interacts with the diurnal environment that also drives transcription and metabolism during light/dark, sleep/wake, hot/cold and feast/fast daily and seasonal cycles. Epigenetic regulation provides a mechanism for cells to integrate genetic programs with environmental signals in order produce an adaptive and consistent output. Recent studies have revealed that DNA methylation is one epigenetic mechanism that entrains the circadian clock to a diurnal environment. We also review recent circadian findings in the epigenetic neurodevelopmental disorders Prader–Willi, Angelman and Rett syndromes and hypothesize a link between optimal brain develo...



Prevalence of selected congenital anomalies in Saudi children: a community-based study

Thu, 03 Sep 2015 14:26:00 +0100

CONCLUSION: The data suggest a significant decline in the prevalence of Down syndrome; however, the prevalence of other anomalies like congenital deafness is still high.    (Source: Annals of Saudi Medicine)



Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis

Wed, 02 Sep 2015 00:00:00 +0100

Publication date: Available online 1 September 2015 Source:The Lancet Psychiatry Author(s): Caroline Richards, Christopher Jones, Laura Groves, Jo Moss, Chris Oliver Background Autism spectrum disorder (ASD) phenomenology is reported to be more common in individuals with some genetic syndromes than in the general population; however, no meta-analysis has provided prevalence data within and between syndromes. In this systematic review and meta-analysis, we aimed to synthesise data from a wide range of papers to provide accurate estimates about ASD phenomenology in genetic and metabolic syndromes. Methods We identified syndromes reported as most likely to be associated with ASD. We searched Ovid PsycINFO, Ovid MEDLINE, Ovid Embase, and PubMed Central for English-language papers publi...



Comparative molecular approaches in Prader-Willi Syndrome diagnosis.

Mon, 31 Aug 2015 00:00:00 +0100

Authors: Botezatu A Abstract Prader-Willi and Angelman syndromes are two distinct neurogenetic disorders caused by chromosomal deletions, uniparental disomy or loss of the imprinted gene expression in the 15q11-q13 region. PWS results from the lack of the paternally expressed gene contribution in the region. The aim of our study was to compare a new molecular approach based on the quantification of the expression of non-imprinted bi-allelic gene (NIPA1 and OCA2) with in house MS-PCR and the MS-MLPA test. Blood samples were collected from 12 patients, clinical criteria positives for Prader-Willi syndrome. DNA and RNA samples were isolated from white blood cells. Epigenetic changes at SNRPN gene locus were evaluated by MS-PCR technique. The expression levels of two non-imprinted gene...

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Filicide-Suicide: Case Series and Review of the Literature

Sat, 15 Aug 2015 11:05:37 +0100

We present 3 cases of filicide-suicide. In case 1, a divorced mother with schizophrenia and bipolar disorder shot her son and herself. In case 2, a father shot his son and himself while involved in a child-custody dispute. In case 3, a father, experiencing a divorce and financial difficulties, and his daughter with Angelman syndrome succumbed to carbon monoxide poisoning. The forensic pathologist should be aware of the psychosocial dynamics that interplay in filicide-suicide. Diligent attention to a parent's life stressors may aid in determining risk factors for filicide-suicide. (Source: The American Journal of Forensic Medicine and Pathology)



Expanding the Scope of Noninvasive Prenatal Testing: Detection of Fetal Microdeletion Syndromes

Sat, 01 Aug 2015 05:00:00 +0100

This study estimates the success of a single-nucleotide polymorphism (SNP) approach to analyzing maternal cell-free DNA in detecting 5 fetal microdeletion syndromes. Genomic DNA was isolated from 40 characterized cell lines for initial validation studies to show that SNP-targeted assay could detect the presence of 22q11.2, 1p36, cri-du-chat, Angelman, and Prader-Willi deletions. A cohort of 496 test samples, including 352 unaffected pregnancy plasmas, 111 artificial DNA mixtures representing microdeletions, and 6 maternal plasma samples from women pregnant with a fetus with a microdeletion were studied. All samples, as well as maternal and, if available, paternal samples, were sequenced and underwent targeted multiplex polymerase chain reaction. The NExt Generation Aneuploidy Test using SN...



Mosaic paternal genome‐wide uniparental isodisomy with Down syndrome

Thu, 30 Jul 2015 00:54:48 +0100

We report on a 6‐month‐old girl with two apparent cell lines; one with trisomy 21, and the other with paternal genome‐wide uniparental isodisomy (GWUPiD), identified using single nucleotide polymorphism (SNP) based microarray and microsatellite analysis of polymorphic loci. The patient has Beckwith‐Wiedemann syndrome (BWS) due to paternal uniparental disomy (UPD) at chromosome location 11p15 (UPD 11p15), which was confirmed through methylation analysis. Hyperinsulinemic hypoglycemia is present, which is associated with paternal UPD 11p15.5; and she likely has medullary nephrocalcinosis, which is associated with paternal UPD 20, although this was not biochemically confirmed. Angelman syndrome (AS) analysis was negative but this testing is not completely informative; she has no speci...



The neurobehavioral and molecular phenotype of Angelman syndrome

Wed, 29 Jul 2015 00:00:00 +0100

In this study we aim to contribute to understanding of the neurobehavioral phenotype of AS with particular focus on the neuropsychiatric presentation of the disorder. We also undertake initial exploration of brain‐derived neurotrophic factor (BDNF) plasma levels in AS. Twelve individuals ages 3 years or older with a confirmed genetic diagnosis of AS underwent detailed medical history, phenotypic characterization, and BDNF plasma sampling. The results of this study demonstrate that individuals with AS suffer from significant developmental delay, impaired adaptive behavior, and sleep disruption. Additionally, hyperactivity/impulsivity appears to be the primary behavioral domain noted in these individuals. The majority of individuals in this project met criteria for autism spectrum disorder...



Routine Chromosomal Microarray Analysis is Necessary in Korean Patients With Unexplained Developmental Delay/Mental Retardation/Autism Spectrum Disorder.

Sun, 26 Jul 2015 03:53:51 +0100

CONCLUSIONS: Our findings suggest the necessity of CMA as a routine diagnostic test for unexplained DD, MR, and ASD in Korea. PMID: 26206688 [PubMed - in process] (Source: Annals of Laboratory Medicine)

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Model mice for 15q11-13 duplication syndrome exhibit late-onset obesity and altered lipid metabolism

Thu, 23 Jul 2015 00:00:00 +0100

Copy number variations on human chromosome 15q11–q13 have been implicated in several neurodevelopmental disorders. A paternal loss or duplication of the Prader–Willi syndrome/Angelman syndrome (PWS/AS) region confers a risk of obesity, although the mechanism remains a mystery due to a lack of an animal model that accurately recreates the obesity phenotype. We performed detailed analyses of mice with duplication of PWS/AS locus (6 Mb) generated by chromosome engineering and found that animals with a paternal duplication of this region (patDp/+) show late-onset obesity, high sensitivity for high-fat diet, high levels of blood leptin and insulin without an increase in food intake. We show that prior to becoming obese, young patDp/+ mice already had enlarged white adipocytes. Trans...



Uncovering a Role for SK2 in Angelman Syndrome

Wed, 22 Jul 2015 00:00:00 +0100

Publication date: 21 July 2015 Source:Cell Reports, Volume 12, Issue 3 Author(s): Sofia B. Lizarraga, Eric M. Morrow Angelman syndrome is a severe neurodevelopmental disorder caused by mutations in UBE3A. Sun et al. (2015) report SK2 as a UBE3A substrate and provide insight into the molecular mechanisms that might underlie impaired neuronal function in individuals affected by Angelman syndrome. (Source: Cell Reports)



Rapid Diagnosis of Imprinting Disorders Involving Copy Number Variation and Uniparental Disomy Using Genome-Wide SNP Microarrays

Wed, 15 Jul 2015 22:46:36 +0100

In conclusion, SNP-based microarray is an efficient alternative method for quickly and precisely diagnosing PWS, AS, BWS, and other imprinted gene-associated disorders when considering aberrations due to CNVs and most types of UPD.Cytogenet Genome Res (Source: Cytogenetic and Genome Research)



UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis

Sat, 11 Jul 2015 00:00:00 +0100

We report here that synaptic SK2 levels are regulated by the E3 ubiquitin ligase UBE3A, whose deficiency results in Angelman syndrome and overexpression in increased risk of autistic spectrum disorder. UBE3A directly ubiquitinates SK2 in the C-terminal domain, which facilitates endocytosis. In UBE3A-deficient mice, increased postsynaptic SK2 levels result in decreased NMDA receptor activation, thereby impairing hippocampal long-term synaptic plasticity. Impairments in both synaptic plasticity and fear conditioning memory in UBE3A-deficient mice are significantly ameliorated by blocking SK2. These results elucidate a mechanism by which UBE3A directly influences cognitive function. Graphical abstract Teaser Sun et al. show that UBE3A, an ubiquitin E3 ligase whose deficiency results in Angel...



Anaesthesia and orphan disease: marked attenuation of motor evoked potentials by high-dose dexmedetomidine in a child with Angelman syndrome undergoing scoliosis surgery: A case report with pharmacokinetic analysis

Fri, 03 Jul 2015 18:49:24 +0100

No abstract available (Source: European Journal of Anaesthesiology)

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Yin-and-Yang of mTORC1/C2 in Angelman syndrome mice.

Mon, 29 Jun 2015 23:46:04 +0100

Authors: Bi X, Sun J, Baudry M PMID: 26116835 [PubMed - as supplied by publisher] (Source: Oncotarget)



Partial tetrasomy of the proximal long arm of chromosome 15 in two patients: the significance of the gene dosage in terms of phenotype

Thu, 25 Jun 2015 00:00:00 +0100

Conclusions: Dosage effect of some genes in the concerned genomic region is known, but several genes have no evidence to have dosage dependence. Our results expanded the previous literature data. We assume dosage dependence in the case of CHRNA7 and OTUD7A, which might be involved in growth regulation. On the other hand increased dosage of the KLF13 gene seems to have no direct causal relationship with heart morphology. The genomic environment of the affected genes may be responsible for the observed phenotype. (Source: Molecular Cytogenetics)



Angelman syndrome presenting with a rare seizure type in a patient with 15q11.2 deletion: a case report

Tue, 16 Jun 2015 00:00:00 +0100

Conclusions Angelman syndrome due to a microdeletion of the chromosome 15q11.2 region is often not diagnosed in infancy. Extensor and flexor spasms are not typically described seizure types in Angelman syndrome, and our patient’s seizures responded well to a combination of valproic acid and clonazepam. Clinicians should suspect other possible seizure types in patients with Angelman syndrome and should treat the patient appropriately. (Source: Journal of Medical Case Reports)



Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings

Thu, 11 Jun 2015 00:00:00 +0100

Conclusions Updated information regarding the early diagnosis and management of individuals with Prader-Willi syndrome is important for all physicians and will be helpful in anticipating and managing or modifying complications associated with this rare obesity-related disorder. (Source: Journal of Endocrinological Investigation)



Angelman Syndrome

Thu, 04 Jun 2015 00:00:00 +0100

Abstract In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder,...

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Angelman syndrome imprinting center [Colloquium Paper]

Tue, 02 Jun 2015 00:00:00 +0100

Clusters of imprinted genes are often controlled by an imprinting center that is necessary for allele-specific gene expression and to reprogram parent-of-origin information between generations. An imprinted domain at 15q11–q13 is responsible for both Angelman syndrome (AS) and Prader–Willi syndrome (PWS), two clinically distinct neurodevelopmental disorders. Angelman syndrome arises from... (Source: Proceedings of the National Academy of Sciences)



Correction for Lewis et al., Angelman syndrome imprinting center encodes a transcriptional promoter [Correction]

Tue, 02 Jun 2015 00:00:00 +0100

COLLOQUIUM Correction for “Angelman syndrome imprinting center encodes a transcriptional promoter,” by Michael W. Lewis, Jason O. Brant, Joseph M. Kramer, James I. Moss, Thomas P. Yang, Peter Hansen, R. Stan Williams, and James L. Resnick, which appeared in issue 22, June 2, 2015, of Proc Natl Acad Sci USA... (Source: Proceedings of the National Academy of Sciences)



Of mothers and myelin: Aberrant myelination phenotypes in mouse model of Angelman Syndrome are dependent on maternal and dietary influences.

Thu, 28 May 2015 00:00:00 +0100

Authors: Grier MD, Carson RP, Lagrange AH Abstract Angelman Syndrome (AS) is a neurodevelopmental disorder characterized by a number of neurological problems, including developmental delay, movement disorders and epilepsy. AS results from the loss of UBE3A (an imprinted gene) expressed from the maternal chromosome in neurons. Given the ubiquitous expression of Ube3a and the devastating nature of AS, the role of environmental and maternal effects has been largely ignored. Severe ataxia, anxiety-like behaviors and learning deficits are well-documented in patients and AS mice. More recently, clinical imaging studies of AS patients suggest myelination may be delayed or reduced. Utilizing a mouse model of AS, we found disrupted expression of cortical myelin proteins, the magnitude of wh...



The E3 ligase ube3a is required for learning in Drosophila melanogaster.

Wed, 29 Apr 2015 00:00:00 +0100

Authors: Chakraborty M, Paul BK, Nayak T, Das A, Jana NR, Bhutani S Abstract Angelman syndrome and autism are neurodevelopmental disorders linked to mutations and duplications of an E3 ligase called ube3a respectively. Since cognitive deficits and learning disabilities are hallmark symptoms of both these disorders, we investigated a role for dube3a in the learning ability of flies using the aversive phototaxis suppression assay. We show that down and up-regulation of dube3a are both detrimental to learning in larvae and adults. Using conditional gene expression we found that dube3a is required for normal brain development and during adulthood. Furthermore, we suggest that dube3a could be interacting with other learning and memory genes such as derailed. Along with firmly establishi...



Sleep in Children with Neurodevelopmental Disabilities

Tue, 28 Apr 2015 00:00:00 +0100

NeuropediatricsDOI: 10.1055/s-0035-1550151This review describes recent research in pediatric sleep disorders associated with neurodevelopmental disabilities (NDDs) and their treatment. NDDs affect more than 2% of the general population and represent more than 35% of the total cases of children referred to a neuropsychiatric center for sleep problems. Specific clinical and therapeutic aspects of sleep disorders associated with Down syndrome, Fragile X syndrome, Prader–Willi syndrome, Angelman syndrome, Rett syndrome, Smith–Magenis syndrome, cerebral palsy, and autism spectrum disorders are described. Furthermore, the drugs commonly used for sleep disorders in children with NDDs are described. The review clearly highlighted that children with NDDs are often affected by sleep disorders th...

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Prader-Willi, Angelman, and 15q11-q13 Duplication Syndromes

Wed, 22 Apr 2015 00:00:00 +0100

This article discusses the clinical background, genetic cause, diagnostic strategy, and management of each of these 3 disorders. (Source: Pediatric Clinics of North America)



Mild Angelman syndrome phenotype due to a mosaic methylation imprinting defect

Tue, 21 Apr 2015 00:00:00 +0100

We present a girl with AS due to a mosaic ImpD who has relatively high developmental function (VABS‐II composite score of 76) and communication skills (as demonstrated in supplemental video links). Given the patient's relatively mild developmental impairment, without clinical evidence of seizures, gait disturbance or inappropriate laughter, the diagnosis of AS was not initially suspected. Initial laboratory testing for AS was inconclusive but additional studies suggested mosaic ImpD and characteristic EEG findings provided further support for the clinical diagnosis. Our patient, along with other case reports of children with AS and relatively mild phenotypes, raises the question as to whether there exists an undiagnosed group of individuals with mild intellectual disability and expressiv...



Reducing Arc reverses seizures in Angelman mouse [Medical Sciences]

Tue, 21 Apr 2015 00:00:00 +0100

Angelman syndrome (AS) is a neurodevelopmental disorder arising from loss-of-function mutations in the maternally inherited copy of the UBE3A gene, and is characterized by an absence of speech, excessive laughter, cognitive delay, motor deficits, and seizures. Despite the fact that the symptoms of AS occur in early childhood, behavioral characterization... (Source: Proceedings of the National Academy of Sciences)



Girl, aged 5, raises $25,000 selling lemonade for disabled brother

Tue, 14 Apr 2015 14:38:02 +0100

A five-year-old girl from Toronto, has raised $25, 000 in the hope that a cure can be found for her brother's disability (Source: Telegraph Health)



Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model

Tue, 14 Apr 2015 06:50:03 +0100

Angelman syndrome (AS) is a severe neurodevelopmental disorder that results from loss of function of the maternal ubiquitin protein ligase E3A (UBE3A) allele. Due to neuron-specific imprinting, the paternal UBE3A copy is silenced. Previous studies in murine models have demonstrated that strategies to activate the paternal Ube3a allele are feasible; however, a recent study showed that pharmacological Ube3a gene reactivation in adulthood failed to rescue the majority of neurocognitive phenotypes in a murine AS model. Here, we performed a systematic study to investigate the possibility that neurocognitive rescue can be achieved by reinstating Ube3a during earlier neurodevelopmental windows. We developed an AS model that allows for temporally controlled Cre-dependent induction of the maternal ...

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Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome

Mon, 13 Apr 2015 00:00:00 +0100

In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus‐dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post‐mortem human brain. Angelman syndrome (AS) is a devastating monogenic human disorder that is nicely recapitulated in a mouse model. Reelin is an extracellular matrix protein that signals through specific lipoprotein receptors in the CNS and modifies synaptic function and memory formation. Reelin injected into the ventricles of the AS mouse model results in a recovery of th...



Angelman Syndrome due to familial translocation: unexpected additional results characterized by Microarray-based Comparative Genomic Hybridization

Thu, 09 Apr 2015 00:00:00 +0100

Conclusions: This report demonstrates the usefulness of array CGH for a detailed characterization of familial translocations, including the detection of submicroscopic copy number variations, which would otherwise be missed by karyotype analysis alone. Our report also expands two molecularly characterized rare patient cohorts: Angelman Syndrome patients due to familial translocations and patients with 15q11.2 duplications of paternal origin. (Source: Molecular Cytogenetics)



Angelman syndrome: The blurred lines of interpretation in cognitive defects

Thu, 02 Apr 2015 00:00:00 +0100

We report a case of Angelman syndrome with initial diagnostic confusion with multiple associated pathologies. A holistic evaluation and management of such patients is necessary. (Source: Journal of Pediatric Neurosciences)



Phenotype of a child with Angelman syndrome born to a woman with Prader–Willi syndrome

Wed, 01 Apr 2015 00:00:00 +0100

This report describes the phenotype, from early childhood to adolescence, of a girl with Angelman syndrome (AS) born following a maternal transmission of a germline paternal 15q11.2‐q13 deletion. During early childhood, she showed a typical AS phenotype, such as jerky movements, poor sleep, high voltage electroencephalography pattern, epilepsy, and a severe developmental disability. As she grew older, indications of phenotypical traits similar to Prader–Willi syndrome (PWS) appeared, in particular hyperphagic behavior and a body fat distribution similar to that reported in PWS. She generally showed cheerful AS behavior and had the characteristic outbursts of laughter, but her attitude to other people did not reflect the usual shared enjoyment of interaction seen in children with AS. In...



Parent stress across molecular subtypes of children with Angelman syndrome

Wed, 01 Apr 2015 00:00:00 +0100

ConclusionsHow parents react to stress depends, in part, on children's AS molecular subtype. Despite falling under the larger umbrella term of AS, it is important to acknowledge the unique aspects associated with children's molecular subtype. Identifying these factors can lead to tailored interventions that fit the particular needs of families of children with different AS subtypes. (Source: Journal of Intellectual Disability Research)

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Angelman syndrome and isovaleric acidemia: What is the link?

Mon, 30 Mar 2015 00:00:00 +0100

We report a toddler affected with Angelman syndrome and isovaleric acidemia (IVA). Such association was due to paternal uniparental isodisomy (UPD) of chromosome 15 in which the proband inherited two paternal copies of an IVA gene point mutation. As both diseases may have severe impact on neurodevelopment, adequate treatment of IVA should be discussed. In our patient however, the variant identified likely causes asymptomatic organic aciduria. Such findings emphasize that paternal UPD 15 can rarely lead to co-occurrence of Angelman syndrome and potentially treatable inborn errors of metabolism. (Source: Molecular Genetics and Metabolism Reports)



Brief Report: A Longitudinal Study of Excessive Smiling and Laughing in Children with Angelman Syndrome.

Sat, 07 Mar 2015 00:00:00 +0100

This study compares levels of laughing and smiling in 12 participants across three experimental conditions [full social interaction (with eye contact), social interaction with no eye contact, proximity only] at two data points. No differences were noted in frequency of laughing and smiling over time in any condition. However, with age as a covariate, the frequency of laughing and smiling decreased over time in the full social interaction (with eye contact) condition only. As this is the first longitudinal study to explore these behaviors in Angelman syndrome, the results suggest a gene-environment-time interaction within the behavioral phenotype. PMID: 25749713 [PubMed - as supplied by publisher] (Source: Journal of Autism and Developmental Disorders)



Autism and the synapse: emerging mechanisms and mechanism-based therapies

Thu, 05 Mar 2015 16:48:15 +0100

Purpose of review: Recent studies have implicated hundreds of genetic variants in the cause of autism spectrum disorder (ASD). Genes involved in ‘monogenic’ forms of syndromic ASD converge on common pathways that are involved in synaptic development, plasticity and signaling. In this review, we discuss how these ‘developmental synaptopathies’ inform our understanding of the molecular disease in ASD and highlight promising approaches that have bridged the gap between the bench and the clinic. Recent findings: Accumulating evidence suggests that synaptic deficits in syndromic and nonsyndromic ASD can be mapped to gene mutations in pathways that control synaptic protein synthesis and degradation, postsynaptic scaffold architecture and neurotransmitter receptors. This is recapitulated ...



Genetic Variations in Magnesium-Related Ion Channels May Affect Diabetes Risk among African American and Hispanic American Women [Biochemical, Molecular, and Genetic Mechanisms]

Mon, 02 Mar 2015 00:00:00 +0100

Conclusions: Our findings suggest important associations between genetic variations in magnesium-related ion channel genes and T2D risk in AA and HA women that vary by amount of magnesium intake. (Source: Journal of Nutrition)



Circadian biology: rhythms leave their imprint.

Mon, 02 Mar 2015 00:00:00 +0100

Authors: Ray DW Abstract A recent study has revealed that loss of neuronal expression of the paternally imprinted gene Ube3a in Angelman syndrome results in selective neuronal loss of robust circadian oscillations, with a resulting behavioural phenotype, and adipose tissue accumulation. PMID: 25734270 [PubMed - in process] (Source: Current Biology)

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Are Angelman and Prader‐Willi syndromes more similar than we thought? Food‐related behavior problems in Angelman, Cornelia de Lange, Fragile X, Prader‐Willi and 1p36 deletion syndromes

Wed, 18 Feb 2015 00:00:00 +0100

Food‐related behavior problems are well documented in Prader–Willi syndrome (PWS), with impaired satiety, preoccupation with food and negative food‐related behaviors (such as taking and storing food) frequently reported as part of the behavioral phenotype of older children and adults. Food‐related behavior problems in other genetic neurodevelopmental syndromes remain less well studied, including those seen in Angelman Syndrome (AS), the ‘sister imprinted disorder’ of PWS. Food‐related behavior problems were assessed in 152 participants each with one of five genetic neurodevelopmental syndromes – PWS, AS, 1p36 deletion, Cornelia de Lange, and fragile X. Predictably, levels of food‐related behavior problems reported in participants with PWS significantly exceeded those of a...



Administration of CoQ10 analogue ameliorates dysfunction of the mitochondrial respiratory chain in a mouse model of Angelman syndrome.

Thu, 12 Feb 2015 00:00:00 +0100

Authors: Llewellyn KJ, Nalbandian A, Gomez A, Wei D, Walker N, Kimonis VE Abstract Genetic defects in the UBE3A gene, which encodes for the imprinted E6-AP ubiquitin E3 ligase (UBE3A), is responsible for the occurrence of Angelman syndrome (AS), a neurodegenerative disorder which arises in 1 out of every 12,000-20,000 births. Classical symptoms of AS include delayed development, impaired speech, and epileptic seizures with characteristic electroencephalography (EEG) readings. We have previously reported impaired mitochondrial structure and reduced complex III in the hippocampus and cerebellum in the Ube3a(m-/p+) mice. CoQ10 supplementation restores the electron flow to the mitochondrial respiratory chain (MRC) to ultimately increase mitochondrial antioxidant capacity. A number of r...



Link Between Circadian Clock and Angelman Syndrome Established

Fri, 06 Feb 2015 12:46:56 +0100

(Source: News from NIGMS Funded Institutions)



Circadian clock linked to Angelman syndrome

Thu, 05 Feb 2015 17:27:31 +0100

Biologists have found a direct link between the biological clock and Angelman syndrome, a neurogenetic disorder that occurs in more than one in every 15,000 live births. The link may provide a valuable way to judge the effectiveness of the first experimental drugs under development for treating the syndrome. (Source: ScienceDaily Headlines)



Ube3a Imprinting Impairs Circadian Robustness in Angelman Syndrome Models.

Wed, 04 Feb 2015 00:00:00 +0100

CONCLUSIONS: Ube3a expression constitutes a direct mechanistic connection between symptoms of a human neurological disorder and the central circadian clock mechanism. The lengthened circadian period leads to delayed phase, which could explain the short sleep duration and increased sleep onset latency of AS subjects. Moreover, we report the pharmacological rescue of an AS phenotype, in this case, altered circadian period. These findings reveal potential treatments for sleep disorders in AS patients. PMID: 25660546 [PubMed - as supplied by publisher] (Source: Current Biology)

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Angelman syndrome-associated ubiquitin ligase UBE3A/E6AP mutants interfere with the proteolytic activity of the proteasome

Thu, 29 Jan 2015 00:00:00 +0100

Angelman syndrome-associated ubiquitin ligase UBE3A/E6AP mutants interfere with the proteolytic activity of the proteasome Cell Death and Disease 6, e1625 (January 2015). doi:10.1038/cddis.2014.572 Authors: V Tomaić & L Banks (Source: Cell death and disease)



Common Genetic and Epigenetic Syndromes

Thu, 22 Jan 2015 00:00:00 +0100

This article reviews some of the more common genetic syndromes. (Source: Pediatric Clinics of North America)



A retrospective review to assess whether spinal fusion and scoliosis correction improved activity and participation for children with Angelman syndrome: Brief report

Tue, 30 Dec 2014 15:40:03 +0100

Developmental Neurorehabilitation, Ahead of Print. (Source: Developmental Neurorehabilitation)



Electroencephalogram (EEG) Duration Needed to Detect Abnormalities in Angelman Syndrome: Is 1 Hour of Overnight Recording Sufficient?

Tue, 23 Dec 2014 00:00:00 +0100

Approximately, 90% of patients with Angelman syndrome present with epileptic seizures. Obtaining an electroencephalogram (EEG) with sleep improves the chances of detecting ictal, interictal, and benign abnormal rhythms in Angelman syndrome. However, electroencephalograms, even when obtained during sleep, can be challenging in this population because of tactile sensitivities as well as anxiety related to a novel environment. We tested the hypothesis that 1 hour of sleep on an electroencephalogram would provide as much information as an entire night of electroencephalogram recording, yet more than a routine electroencephalogram conducted during the day. Overnight polysomnograms were collected in 14 children with Angelman syndrome seen at Vanderbilt University. All patients who obtained sleep...



Obesity possible sign of Angelman syndrome in infants, toddlers

Mon, 22 Dec 2014 00:00:00 +0100

(Source: American Journal of Medical Genetics Part A)

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Neurodevelopmental disorders: Unmuting Ube3a in mice alleviates Angelman syndrome

Tue, 16 Dec 2014 00:00:00 +0100

Nature Reviews Neurology 11, 66 (2015). doi:10.1038/nrneurol.2014.240 Author: Hemi Malkki Harnessing the silenced, but functional, paternal copy of the UBE3A gene via antisense oligonucleotides (ASOs) might provide a way to alleviate symptoms of Angelman syndrome. According to new research published in Nature, unsilencing paternal Ube3a in a mouse model of Angelman syndrome (Source: Nature Reviews Neurology)



An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome

Wed, 10 Dec 2014 00:00:00 +0100

Conclusion: The clinical and neuropsychological measures suggest minocycline was well tolerated and causes improvements in the adaptive behaviors of this sample of children with Angelman syndrome. While the optimal dosage and the effects of long-term use still need to be determined, these findings suggest further investigation into the effect minocycline has on patients with Angelman syndrome is warranted.Trial registrationNCT01531582 ? clinicaltrials.gov (Source: BMC Neurology)



Disease genetics: Therapeutic targeting of a long non-coding RNA

Tue, 09 Dec 2014 00:00:00 +0100

Nature Reviews Genetics 16, 2 (2015). doi:10.1038/nrg3879 Author: Linda Koch Antisense oligonucleotides (ASOs) against the long non-coding RNA UBE3A antisense transcript (UBE3A-ATS) could represent a feasible therapy for the monogenic disorder Angelman syndrome, a new study reports. The disease results from loss of expression of the maternal UBE3A allele in the presence (Source: Nature Reviews Genetics)



False deletion of the D15S986 maternal allele in a suspected case of Angelman syndrome.

Thu, 04 Dec 2014 21:55:09 +0100

CONCLUSIONS: An alternative primer set was developed, for which the segregation pattern of D15S986 in the proband extended family was normal. It can replace the currently used set. PMID: 25451953 [PubMed - in process] (Source: International Journal of Clinical Chemistry)



Towards a therapy for Angelman syndrome by targeting a long non-coding RNA

Mon, 01 Dec 2014 00:00:00 +0100

Authors: Linyan Meng, Amanda J. Ward, Seung Chun, C. Frank Bennett, Arthur L. Beaudet & Frank Rigo Angelman syndrome is a single-gene disorder characterized by intellectual disability, developmental delay, behavioural uniqueness, speech impairment, seizures and ataxia. It is caused by maternal deficiency of the imprinted gene UBE3A, encoding an E3 ubiquitin ligase. All patients carry at least one copy of paternal UBE3A, which is intact but silenced by a nuclear-localized long non-coding RNA, UBE3A antisense transcript (UBE3A-ATS). Murine Ube3a-ATS reduction by either transcription termination or topoisomerase I inhibition has been shown to increase paternal Ube3a expression. Despite a clear understanding of the disease-causing event in Angelman syndrome and the potential to harnes...

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Angelman Syndrome: A Case Series Assessing Neurological Issues in Adulthood

Fri, 28 Nov 2014 17:14:08 +0100

This study aimed to evaluate the clinical symptoms of Angelman syndrome (AS) in adults and to identify the neurological pathways affected in this disease. AS is a neurogenetic disorder resulting due to the deletion or inactivation of the ubiquitin-protein-ligase E3A gene on maternal chromosome 15. Summary: A retrospective analysis of data from six adults patients with clinical, electroencephalographic and genetic confirmation of AS was performed. Movement disorders of the hands and mouth, laughing spells, severe expressive speech disorders, a happy nature, hyposomnia and anxiety are the major neurological characteristics of AS in adulthood. Cerebellar ataxia, muscle hypotonia and tremor, though constant in childhood, tend to be attenuated in adulthood. Epilepsy, one of the most frequent sy...



Angelman syndrome in adulthood

Wed, 26 Nov 2014 00:00:00 +0100

Angelman syndrome (AS) is a neurogenetic disorder. The goal of this study was to investigate the primary health issues affecting adults with AS and to further characterize the natural history and genotype–phenotype correlations. Standardized phone interviews with caregivers for 110 adolescents and adults with AS were conducted. The impact of age, sex, and genotype on specific outcomes in neurology, orthopedics, internal medicine, and psychiatry were investigated. The mean age of individuals with AS was 24 years (range 16–50y). Active seizures were present in 41% of individuals, and 72% had sleep dysfunction. Significant constipation was present in 85%, and 32% were overweight or obese, with obesity disproportionately affecting women. Scoliosis affected 50% with a mean age at diagnosis ...



Increased body mass in infancy and early toddlerhood in Angelman syndrome patients with uniparental disomy and imprinting center defects

Mon, 17 Nov 2014 20:07:20 +0100

We report on 16 infants and toddlers (ages 6 to 44 months; 6 female, and 10 male) with severe developmental delay. Birth weights were appropriate for gestational age in most cases, >97th% in one case and not available in four cases. The molecular subclass case distribution consisted of: UPD (n = 2), IC defect (n = 3), UPD or IC defect (n = 3), and UBE3A mutation (n = 8). Almost all (7 out of 8) UPD, IC and UPD/IC cases went on to exhibit >90th% age‐ and gender‐appropriate weight for height or BMI within the first 44 months. In contrast, no UBE3A mutation cases exhibited obesity or pre‐obesity measures (percentiles ranged from <3% to 55%). These findings demonstrate that increased body mass may be evident as early as the first year of life and highlight the ut...



Behavioural effects of imprinted genes

Sun, 02 Nov 2014 00:00:00 +0100

Publication date: April 2015 Source:Current Opinion in Behavioral Sciences, Volume 2 Author(s): Jennifer R Davies , Claire L Dent , Gráinne I McNamara , Anthony R Isles The importance of imprinted gene effects on brain and behaviour is becoming increasingly clear. In addition to roles in neurodevelopmental disorders such as Prader–Willi and Angelman syndromes, changes in expression of imprinted genes contribute to neuropsychiatric illness more generally. Imprinted genes are also critical for placental function, and can influence adult behavioural outcomes via effects on the supply and demand of nutrients from the mother. Finally, the high level of epigenetic regulation and parental specific monoallelic expression make this subset of mammalian genes candidates for mediating the behavio...

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A suspicious case of mosaic Prader–Willi and Angelman syndromes

Sat, 01 Nov 2014 00:00:00 +0100

Publication date: December 2013 Source:Egyptian Journal of Forensic Sciences, Volume 3, Issue 4 Author(s): Suha Alfehaid , Osama Al Madani , Magdy Karoshah , Manal Bamousa , Madadin Mohammed Prader–Willi and Angelman syndromes are both rare diseases. Having both syndromes is even rarer, and only a handful of case reports describe a mosaic between both diseases, all of which were made based on antemortem descriptions. A description of these syndromes post-mortem can provide good information about such syndromes as an entity; even if the autopsy and histopathology did not add any further information from what was described clinically, they can still provide good negative value. (Source: Egyptian Journal of Forensic Sciences)



Molecular classes in 209 patients with Prader–Willi or Angelman syndromes: Lessons for genetic counseling

Wed, 01 Oct 2014 00:00:00 +0100

(Source: American Journal of Medical Genetics Part A)



Abstract 2751: ASPM, a cell cycle regulated gene and silencing its splicing variant as a molecular target in hepatocellular carcinoma

Tue, 30 Sep 2014 00:00:00 +0100

In this study, we figured out there were two transcripts (full length/ NM_018136.4 and variant #1/ NM_001206846.1) in human liver tissue. To further elucidate the role of ASPM in liver cancer cells, we used RNAi knockdown to investigate its biological functions in HCC cells. We selected two 21-mers-RNAi oligos named si-482 (at nt5125/exon 18) and si-945 (at nt9977/exon 25) of ASPM mRNA (full length), respectively. Using the RT-PCR detection, the full length ASPM transcript could partially downregulation by both RNAi oligos. However, the ASPM variant#1 transcript only downregulated by the ASPM si-945 RNAi oligos, but could not down-regulate by ASPM si-482 RNAi oligos. Knockdown of ASPM mRNA expression by ASPM si-482 and si-945 RNAi oligos in HuH-7, Ha22T and HCC36 cells and exhibited dramat...



Severe epilepsy in an adult with partial trisomy 18q

Wed, 24 Sep 2014 00:00:00 +0100

Epilepsy is one of the most common presentations associated with chromosome aberrations. Detailed descriptions of some aberration‐specific epileptic and electroencephalographic (EEG) phenotypes have been reported (i.e., Angelman syndrome, ring 20 etc.). However there is limited and mixed information about the characteristics of epilepsy related to trisomy 18. Thus a common seizure phenotype has not been characterized yet. Here we describe in detail a patient with refractory epilepsy and partial 18q trisomy. © 2014 Wiley Periodicals, Inc. (Source: American Journal of Medical Genetics Part A)



Seizures and EEG features in 74 patients with genetic‐dysmorphic syndromes

Wed, 24 Sep 2014 00:00:00 +0100

Epilepsy is one of the most common findings in chromosome aberrations. Types of seizures and severity may significantly vary both between different conditions and within the same aberration. Hitherto specific seizures and EEG patterns are identified for only few syndromes. We studied 74 patients with defined genetic‐dysmorphic syndromes with and without epilepsy in order to assess clinical and electroencephalographic features, to compare our observation with already described electro‐clinical phenotypes, and to identify putative electroencephalographic and/or seizure characteristics useful to address the diagnosis. In our population, 10 patients had chromosomal disorders, 19 microdeletion or microduplication syndromes, and 32 monogenic syndromes. In the remaining 13, syndrome diagnosis...

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Genetic Forms of Epilepsies and Other Paroxysmal Disorders

Fri, 05 Sep 2014 00:00:00 +0100

Semin Neurol 2014; 34: 266-279DOI: 10.1055/s-0034-1386765Genetic mechanisms explain the pathophysiology of many forms of epilepsy and other paroxysmal disorders, such as alternating hemiplegia of childhood, familial hemiplegic migraine, and paroxysmal dyskinesias. Epilepsy is a key feature of well-defined genetic syndromes including tuberous sclerosis complex, Rett syndrome, Angelman syndrome, and others. There is an increasing number of single-gene causes or susceptibility factors associated with several epilepsy syndromes, including the early-onset epileptic encephalopathies, benign neonatal/infantile seizures, progressive myoclonus epilepsies, genetic generalized and benign focal epilepsies, epileptic aphasias, and familial focal epilepsies. Molecular mechanisms are diverse, and a singl...



Abnormalities of the DNA Methylation Mark and Its Machinery: An Emerging Cause of Neurologic Dysfunction

Fri, 05 Sep 2014 00:00:00 +0100

Semin Neurol 2014; 34: 249-257DOI: 10.1055/s-0034-1386763Recently, Mendelian disorders of the DNA methylation machinery have been described which demonstrate the complex roles of epigenetics in neurodevelopment and disease. For example, defects of DNMT1, the maintenance methyltransferase, lead to adult-onset progressive neurologic disorders, whereas defects of the de novo methyltransferases DNMT3A and DNMT3B lead to nonprogressive neurodevelopmental conditions. Furthermore, patients with DNMT3A deficiency demonstrate overgrowth, a feature common to disorders of histone machinery and imprinting disorders, highlighting the interconnectedness of the many epigenetic layers. Disorders of the DNA methylation machinery include both the aforementioned “writers” and also the “readers” of th...



Paroxysmal tonic upgaze complicating Angelman syndrome

Wed, 03 Sep 2014 00:00:00 +0100

Paroxysmal tonic upgaze is a childhood oculomotor syndrome characterized by episodes of conjugate upward deviation of the eyes. Its pathogenesis is unknown and the etiology is heterogeneous. (Source: Pediatric Neurology)



Paroxysmal Tonic Upward Gaze Complicating Angelman Syndrome

Wed, 03 Sep 2014 00:00:00 +0100

Paroxysmal tonic upward gaze is a childhood oculomotor syndrome characterized by episodes of conjugate upward deviation of the eyes. Its pathogenesis is unknown, and the etiology is heterogeneous. (Source: Pediatric Neurology)

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Mutation Update for UBE3A Variants in Angelman Syndrome

Mon, 01 Sep 2014 00:00:00 +0100

This article is protected by copyright. All rights reserved (Source: Human Mutation)



Diagnosis of an imprinted‐gene syndrome by a novel bioinformatics analysis of whole‐genome sequences from a family trio

Tue, 26 Aug 2014 00:00:00 +0100

We describe a unique bioinformatic analysis of whole‐genome sequences from a family trio designed to identify imprinted gene mutations that are often overlooked by inheritance‐based analyses. Application of this approach to whole‐genome sequencing data from a family with an affected child for whom multiple lines of investigation were nonexplanatory identified a CDKN1C mutation, thereby providing a diagnosis of IMAGe syndrome for the proband. (Source: Molecular Genetics & Genomic Medicine)



Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1

Wed, 20 Aug 2014 00:00:00 +0100

Conclusions Chromatin structure may influence gene expression across the 15q11-q13.1 region in neurons. Genome-wide analyses suggest that common neuronal pathways may be disrupted in both the Angelman and Dup15q syndromes. These data demonstrate that our disease-specific stem cell models provide a new tool to decipher the underlying cellular and genetic disease mechanisms of ASD and may also offer a pathway to novel therapeutic intervention in Dup15q syndrome. (Source: Molecular Autism)



Deletion of UBE3A in brothers with Angelman syndrome at the breakpoint with an inversion at 15q11.2

Wed, 06 Aug 2014 00:00:00 +0100

This report describes a rare type of familial AS detected using the D15S10 FISH test. © 2014 Wiley Periodicals, Inc. (Source: American Journal of Medical Genetics Part A)



Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome

Mon, 14 Jul 2014 00:00:00 +0100

Abstract Objective: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X‐linked Na+/H+ Exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. Methods: Twelve independent pedigrees (14 boys, ages 4 to 19) with mutations in NHE6 were administered standardized research assessments and mutations were characterized. Results: The mutational spectrum was composed of 9 single nucleotide variants (SNVs), 2 indels and 1 CNV deletion. All mutations were protein‐truncating or splicing mutations. We identified two recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, seven of 12 mutations (58%) were de novo, in contrast to prior literature wherein...

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Investigation of Microdeletions in Syndromic Intellectual Disability by MLPA in Iranian Population.

Tue, 01 Jul 2014 00:00:00 +0100

CONCLUSION: Our MLPA results indicate a high degree of concordance between the clinical data and the genotype. We suggest MLPA as the first screening method for children suffering from MR with normal karyotypes. In those cases where clinical findings were not compatible with the microdeletion syndrome identified by MLPA investigation, further studies such as FISH and aCGH were performed. PMID: 24979557 [PubMed - in process] (Source: Archives of Iranian Medicine)



Sodium-potassium ATPase emerges as a player in hippocampal phenotypes of Angelman syndrome mice

Tue, 01 Jul 2014 00:00:00 +0100

Angelman syndrome is a neurodevelopmental disorder characterized by intellectual disabilities, ataxia, and unusually happy affect. The hippocampal pyramidal cells of Angelman syndrome model mice have altered intrinsic membrane properties, which Kaphzan et al. (Cell Rep 4: 405–412, 2013) demonstrate can be corrected by genetic reduction of the α1-subunit of the sodium-potassium ATPase. Intriguingly, this manipulation also restores hippocampal long-term potentiation and learning. In this Neuro Forum, we discuss translational implications of this work and remaining questions left in its wake. (Source: Journal of Neurophysiology)



Does parent of origin matter? Methylation studies should be performed on patients with multiple copies of the Prader–Willi/Angelman syndrome critical region

Thu, 26 Jun 2014 00:00:00 +0100

Deletion of 15q11.2‐q13 results in either Prader–Willi syndrome (PWS) or Angelman syndrome (AS) depending on the parent of origin. Duplication of the PWS/AS critical region (PWASCR) has also been reported in association with developmental delay and autism, and it has been shown that they also show a parent‐of‐origin effect. It is generally accepted that maternal duplications are pathogenic. However, there is conflicting evidence as to the pathogenicity of paternal duplications. We have identified 35 patients with gain of the PWASCR using array comparative genomic hybridization. Methylation testing was performed to determine parent of origin of the extra copies. Of the 35 cases, 22 had a supernumerary marker chromosome 15 (SMC15), 12 had a tandem duplication, and 1 had a tandem trip...



Computer-aided diagnosis of rare genetic disorders from family snaps

Tue, 24 Jun 2014 13:33:22 +0100

Computer analysis of photographs could help doctors diagnose which condition a child with a rare genetic disorder has, say researchers. The researchers have come up with a computer program that recognizes facial features in photographs; looks for similarities with facial structures for various conditions, such as Down's syndrome, Angelman syndrome, or Progeria; and returns possible matches ranked by likelihood. (Source: ScienceDaily Headlines)



How a family photo could soon diagnose some of the rarest genetic diseases

Tue, 24 Jun 2014 00:44:41 +0100

Many genetic conditions such as Down’s syndrome and Angelman syndrome are associated with changes in facial appearance, say the Oxford and Edinburgh researchers. (Source: the Mail online | Health)



The prospect of molecular therapy for Angelman syndrome and other monogenic neurologic disorders

Thu, 19 Jun 2014 00:00:00 +0100

Angelman syndrome is a monogenic neurologic disorder that affects 1 in 15,000 children, and is characterized by ataxia, intellectual disability, speech impairment, sleep disorders, and seizures. The disorder is caused by loss of central nervous system expression of UBE3A, a gene encoding a ubiquitin ligase. Current treatments focus on the management of symptoms, as there have not been therapies to treat the underlying molecular cause of the disease. However, this outlook is evolving with advances in molecular therapies, including artificial transcription factors a class of engineered DNA-binding proteins that have the potential to target a specific site in the genome. Here we review the recent progress and prospect of targeted gene expression therapies. Three main issues that must be addre...