MedWorm: Angelman Syndrome

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)

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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)

Loss Of Enzyme Reduces Neural Activity In Angelman Syndrome

Pediatrics News From Medical News Today — Sat, 06 Mar 2010 08:00:00 +0100

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)

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)

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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...

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)

Angelman Syndrome Foundation Request for Proposals

ScanGrants feed — Wed, 10 Jun 2009 04:00:00 +0100

Application Submission Deadline: July 15, 2009The Angelman Syndrome Foundation announces the availability of up to $670,000 (USD) to be awarded in support of research on Angelman syndrome.Angelman syndrome is a neurodevelopmental disorder caused by deficiency of the ubiquitin protein ligase UBE3A in the brain. Applications related to any areas of research involving Angelman syndrome will be considered.Highest priority will be given to pilot projects to test new ideas about pathogenesis and therapeutics of Angelman syndrome. Researchers from all countries are encouraged to apply.One- or two-year grants will be awarded for amounts of up to $100,000 per year. The application should include the following:• Cover letter with title of proposal and name of principal investigator• One-...

[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)

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

European Journal of Human Genetics — Tue, 26 May 2009 23:00:00 +0100

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

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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)

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)

Angelman syndrome (AS, MIM 105830)

European Journal of Human Genetics — Tue, 19 May 2009 23:00:00 +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)

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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)

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...

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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...

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...

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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...

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...

Angelman Syndrome Foundation Request for Behavioral Research Proposals

ScanGrants feed — Wed, 18 Feb 2009 05:00:00 +0100

Application Submission Deadline: May 1, 2009 The Angelman Syndrome Foundation announces the availability of up to $200,000 to be awarded in support of research aimed at providing improved understanding, identification and effective therapeutic strategies for the behavioral difficulties known to occur in the Angelman syndrome. Proposals are encouraged to concentrate on practical treatment strategies that may be implemented in the home and school setting. Examples of priority areas for funding include strategies targeted toward improving: Nonverbal communication skills Self-injurious behaviors Hyperactivity and inattention problems Sleep disorders Eating and nutritional difficulties School-based behavioral disruptions Highest priority will be given to pilot projects that address new ideas a...

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)

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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)

[Original articles] Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number

Journal of Medical Genetics — Fri, 30 Jan 2009 05:00:00 +0100

Conclusion: Our findings suggest that genetic copy number changes combined with additional genetic or environmental influences on epigenetic mechanisms impact outcome and clinical heterogeneity of 15q11–13 duplication syndromes. (Source: Journal of Medical Genetics)

Identification of CpG methylation of the SNRPN gene by methylation-specific multiplex PCR

Electrophoresis — Fri, 09 Jan 2009 05:00:00 +0100

In this article, we show that methylation-specific multiplex PCR (MS-multiplex PCR) is a sensitive and specific single assay for detecting CpG methylation status as well as copy number aberrations. We used MS-multiplex PCR to simultaneously amplify three sequences: the 3[prime] ends of the SNRPN gene (for unmethylated sequences), the KRITI gene (as internal control), and the promoter of the SNRPN gene containing CpG islands (for methylated sequences) after digestion with a methylation-sensitive restriction enzyme (HhaI). We established this duplex assay for the analysis of 38 individuals with Prader-Willi syndrome, 2 individuals with Angelman syndrome, and 28 unaffected individuals. By comparing the copy number of the three regions, the methylation status and the copy number changes can be...

A multiplex molecular assay for the detection of uniparental disomy for human chromosome 15

Electrophoresis — Wed, 03 Dec 2008 05:00:00 +0100

Uniparental disomy (UPD) describes the inheritance of both homologues of a pair of chromosomes from only one parent. During the last two decades, the clinical impact of UPD and associated imprinting disorders, such as Prader-Willi syndrome (PWS) and Angelman syndrome (AS) increasingly have come to our attention. About 25% of PWS and 3%-5% of AS are a consequence of UPD with the resulting phenotype generated from the parent of origin of the disomic pair of chromosomes 15. Chromosome 15 UPD testing is relevant in various prenatal diagnostic conditions including apparent confined placental mosaicism, homologous and nonhomologous Robertsonian translocations involving chromosome 15 and 14, and as genomic biomarker for detecting chromosome origin. In this work we developed and validated a two fl...

Angelman syndrome and anesthesia.

Paediatric Anaesthesia — Mon, 01 Dec 2008 05:00:00 +0100

Authors: Patil JJ, Sindhakar S PMID: 19076580 [PubMed - in process] (Source: Paediatric Anaesthesia)

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The Prevalence and Phenomenology of Repetitive Behavior in Genetic Syndromes.

Journal of Autism and Developmental Disorders — Thu, 27 Nov 2008 05:00:00 +0100

Authors: Moss J, Oliver C, Arron K, Burbidge C, Berg K We investigated the prevalence and phenomenology of repetitive behavior in genetic syndromes to detail profiles of behavior. The Repetitive Behaviour Questionnaire (RBQ) provides fine-grained identification of repetitive behaviors. The RBQ was employed to examine repetitive behavior in Angelman (N = 104), Cornelia de Lange (N = 101), Cri-du-Chat (N = 58), Fragile X (N = 191), Prader-Willi (N = 189), Lowe (N = 56) and Smith-Magenis (N = 42) syndromes and individuals with intellectual disability of heterogeneous aetiology (N = 56). Repetitive behavior was variable across syndromes. Fragile X syndrome scored highly on all subscales. Angelman syndrome demonstrated a significantly lowered probability for most behaviors. Prader-Willi, Cr...

The inv dup (15) or idic (15) syndrome (Tetrasomy 15q)

Orphanet Journal of Rare Diseases — Wed, 19 Nov 2008 05:00:00 +0100

The inv dup(15) or idic(15) syndrome displays distinctive clinical findings represented by early central hypotonia, developmental delay and intellectual disability, epilepsy, and autistic behaviour. Incidence at birth is estimated at 1 in 30,000 with a sex ratio of almost 1:1. Developmental delay and intellectual disability affect all individuals with inv dup(15) and are usually moderate to profound. Expressive language is absent or very poor and often echolalic. Comprehension is very limited and contextual. Intention to communicate is absent or very limited. The distinct behavioral disorder shown by children and adolescents has been widely described as autistic or autistic-like. Epilepsy with a wide variety of seizure types can occur in these individuals, with onset between 6 months and 9...

A review of known imprinting syndromes and their association with assisted reproduction technologies

Human Reproduction — Mon, 17 Nov 2008 05:00:00 +0100

An association between assisted reproduction technologies (ART) and abnormal genomic imprinting in humans has been recognized for several years; however, the magnitude of this risk and the spectrum of imprinting syndromes to which the risk applies remains unknown. Nine human imprinting syndromes have been identified but current evidence links ART with only three: Beckwith–Wiedemann syndrome, Angelman syndrome and the newly described maternal hypomethylation syndrome. There is currently a lack of evidence linking ART with the remaining six imprinting syndromes: Prader–Willi syndrome, Russell–Silver syndrome, maternal and paternal uniparental disomy of chromosome 14, pseudohypoparathyroidism type 1b and transient neonatal diabetes. Evidence from clinical reports suggests th...

[Causes and clinical implications of sperm DNA damages.]

Gynecologie, Obstetrique & Fertilite — Mon, 27 Oct 2008 04:00:00 +0100

Authors: Hazout A, Menezo Y, Madelenat P, Yazbeck C, Selva J, Cohen-Bacrie P Numerous recent studies involve DNA damages associated with poor fertilization rates, early embryo development defect, and poor quality of conceptus following Assisted Reproductive Technologies (ART). The authors denounce a particularly high rate of miscarriages and childhood cancer or dominant genetic mutations such as achondroplasia, Apert syndrome or aberrant gene imprinting such as Angelman and Beckwith Wiedeman syndromes. Gametes DNA defects have numerous origins which are difficult to determine; they are known to involve hypomethylation, oxydative stress and environmental factors.(adducts formation). DNA defect is also linked to a more or less delayed apoptotic phenomenon. Exposure to radiations or radio...

Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: Efficient identification of known microduplications and identification of a novel microduplication in ASMT

BMC Medical Genomics — Thu, 16 Oct 2008 04:00:00 +0100

Conclusions: MLPA proves to be an efficient method to screen for chromosomal abnormalities. We identified duplications in 15q11-q13 and in 22q11, including new de novo small duplications, as likely contributing to ASD in the current sample by increasing liability and/or exacerbating symptoms. Our data indicate that duplications in the TM4SF2 are not associated with the phenotype given their presence in controls. The results in PAR1/PAR2 are the first large-scale studies of gene dosage in these regions, and the findings at the ASMT locus indicate that further studies of the duplication of the ASMT gene are needed in order to gain insight into its potential involvement in ASD. Our studies also identify some limitations of MLPA, where single base changes in probe binding sequences alter resul...

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[Parental imprinting related to Assisted Reproductive Technologies.]

Gynecologie, Obstetrique & Fertilite — Mon, 13 Oct 2008 04:00:00 +0100

Authors: Fauque P, Jouannet P, Jammes H Until the introduction of Assisted Reproductive Technologies (ART), many studies were conducted in order to evaluate their impact upon the children's health born in such a way. The epigenetic-risk notion was invoked and a link between ART and diseases associated with imprinting alterations was suggested with different examples, such as Beckwith-Wiedemann syndrome (BWS), Angelman syndrome (AS) and Silver-Russell syndrome (SRS). The epigenetic "life cycle" of imprinting (germline erasure, germline establishment, and somatic maintenance) concerns all the phases from gametogenesis, gamete maturation, fertilization, to early embryo development and appears particularly vulnerable to perturbations induced by superovulation, in vitro fertilization, embry...

Functional characterization of NIPA2, a selective Mg2+ transporter

AJP: Cell Physiology — Thu, 09 Oct 2008 04:00:00 +0100

We used microarray analysis to identify renal cell transcripts that were upregulated with low magnesium. One transcript, identified as NIPA2 (nonimprinted in Prader-Willi/Angelman syndrome) subtype 2, was increased over twofold relative to cells cultured in normal magnesium. The deduced sequence comprises 129 amino acids with 8 predicted transmembrane regions. As the secondary structure of NIPA2 conformed to a membrane transport protein, we expressed it in Xenopus oocytes and determined that it mediated Mg2+ uptake with two-electrode voltage-clamp and fluorescence studies. Mg2+ transport was electrogenic, voltage dependent, and saturable, demonstrating a Michaelis affinity constant of 0.31 mM. Unlike other reported Mg2+ transporters, NIPA2 was very selective for the Mg2+ cation. NIPA2 mRNA...

What would the brain look like in Angelman syndrome?

European Journal of Paediatric Neurology — Fri, 26 Sep 2008 04:00:00 +0100

Authors: Dan B, Pelc K, Christophe C PMID: 18824378 [PubMed - as supplied by publisher] (Source: European Journal of Paediatric Neurology)

Ubiquitin ligase E6-AP and its role in human disease.

Biochemical Society Transactions — Wed, 17 Sep 2008 17:10:03 +0100

Authors: Matentzoglu K, Scheffner M The ubiquitin ligase E6-AP (E6-associated protein) represents a prime example for the notion that deregulated modification of proteins with ubiquitin contributes to the development of human disease: loss of E6-AP function by mutation is responsible for the development of AS (Angelman syndrome), a neurological disorder, and unscheduled activation of E6-AP by complex formation with the E6 oncoprotein of HPVs (human papillomaviruses) contributes to cervical carcinogenesis. However, while there is a considerable amount of data concerning the oncogenic properties of the E6-E6-AP complex, only little is known about the function(s) of E6-AP in neurons. This is mainly due to the fact that although some E6-AP substrates have been identified, it is at present ...

Genomic imprinting in the development and evolution of psychotic spectrum conditions

Biological Reviews — Tue, 09 Sep 2008 04:00:00 +0100

I review and evaluate genetic and genomic evidence salient to the hypothesis that the development and evolution of psychotic spectrum conditions have been mediated in part by alterations of imprinted genes expressed in the brain. Evidence from the genetics and genomics of schizophrenia, bipolar disorder, major depression, Prader-Willi syndrome, Klinefelter syndrome, and other neurogenetic conditions support the hypothesis that the etiologies of psychotic spectrum conditions commonly involve genetic and epigenetic imbalances in the effects of imprinted genes, with a bias towards increased relative effects from imprinted genes with maternal expression or other genes favouring maternal interests. By contrast, autistic spectrum conditions, including Kanner autism, Asperger syndrome, Rett syndr...

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TCF4 Deletions in Pitt-Hopkins Syndrome

Human Mutation — Tue, 09 Sep 2008 04:00:00 +0100

In this report, we also further specify the phenotypic spectrum of PHS, enlarged to behavior, with aim to increase the rate and specificity of PHS diagnosis. © 2008 Wiley-Liss, Inc. (Source: Human Mutation)

Genomic imprinting in the development and evolution of psychotic spectrum conditions.

Biological Reviews of the Cambridge Philosophical Society — Tue, 09 Sep 2008 04:00:00 +0100

Authors: Crespi B I review and evaluate genetic and genomic evidence salient to the hypothesis that the development and evolution of psychotic spectrum conditions have been mediated in part by alterations of imprinted genes expressed in the brain. Evidence from the genetics and genomics of schizophrenia, bipolar disorder, major depression, Prader-Willi syndrome, Klinefelter syndrome, and other neurogenetic conditions support the hypothesis that the etiologies of psychotic spectrum conditions commonly involve genetic and epigenetic imbalances in the effects of imprinted genes, with a bias towards increased relative effects from imprinted genes with maternal expression or other genes favouring maternal interests. By contrast, autistic spectrum conditions, including Kanner autism, Asperge...

[Genetic and clinical diagnosis of Angelman syndrome. Case Reviews.]

Anales de Pediatria — Mon, 01 Sep 2008 04:00:00 +0100

CONCLUSIONS: The phenotypical characteristics of the syndrome should be known before requesting specific genetic testing and to make a diagnosis even in cases with negative genetic. The phenotype characteristics that describe Angelman syndrome were verified. Deletion cases had a worse outcome. PMID: 18775268 [PubMed - in process] (Source: Anales de Pediatria)

Evolution of Genomic Imprinting with Biparental Care: Implications for Prader-Willi and Angelman Syndromes

PLoS Biology: Archived Table of Contents — Wed, 27 Aug 2008 08:02:30 +0100

A familial structure of fathers contributing resources to their offspring may result in a reversal of the expected imprinting pattern and may provide an evolutionary explanation for the striking bi-phasic phenotype of patients with Prader-Willi syndrome. (Source: PLoS Biology: Archived Table of Contents)

Prader-Willi Syndrome Gives Genetic Insight On Imprinting

Genetics News From Medical News Today — Tue, 26 Aug 2008 07:00:00 +0100

Important findings related to the birth defects Prader-Willi Syndrome (PWS) and Angelman Syndromes, discussed in an article released on August 25, 2008 in PLoS Biology, may help explain imprinted genes in humans. In humans, two copies of each gene are contributed to a child: one from the mother and one from the father. (Source: Genetics News From Medical News Today)

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[Genetics] A Drosophila model for Angelman syndrome

Proceedings of the National Academy of Sciences — Tue, 26 Aug 2008 04:00:00 +0100

Angelman syndrome is a neurological disorder whose symptoms include severe mental retardation, loss of motor coordination, and sleep disturbances. The... (Source: Proceedings of the National Academy of Sciences)

Gender influences monoallelic expression of ATP10A in human brain

Human Genetics — Sun, 24 Aug 2008 16:40:13 +0100

In this study, we examined allelic expression of ATP10A transcript in 16 control brain samples, and found that 10/16 exhibited biallelic expression while only 6/16 showed monoallelic expression. Contrary to the expectation for a maternally expressed imprinted gene, quantitative RT-PCR revealed significantly reduced ATP10A transcript in Prader-Willi syndrome brains with two maternal chromosomes due to uniparental disomy (PWS UPD). Furthermore, a PWS UPD brain sample with monoallelic ATP10A expression demonstrated that monoallelic expression can be independent of imprinting. Investigation of factors that may influence allelic ATP10A expression status revealed that gender has a major affect, as females were significantly more likely to have monoallelic ATP10A expression than males. Regul...

Model For Angelman Syndrome Developed By University Of Texas At Austin Biologists

Genetics News From Medical News Today — Sat, 16 Aug 2008 07:00:00 +0100

A model for studying the genetics of Angelman syndrome, a neurological disorder that causes mental retardation and other symptoms in one out of 15,000 births, has been developed by biologists at The University of Texas at Austin. Their research demonstrates that when a particular fruit fly gene, dube3a, is altered, the mutant flies show behavioral dysfunctions similar to those experienced by humans whose UBE3A gene doesn't function normally. (Source: Genetics News From Medical News Today)

Model For Neurological Disorder 'Angelman Syndrome' Developed

ScienceDaily Headlines — Fri, 15 Aug 2008 18:00:00 +0100

New model for studying the genetics of Angelman syndrome

News-Medical News Feed — Fri, 15 Aug 2008 04:39:00 +0100

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Model for Angelman syndrome developed by University of Texas at Austin biologists

EurekAlert! - Biology — Thu, 14 Aug 2008 04:00:00 +0100

(University of Texas at Austin) A model for studying the genetics of Angelman syndrome, a neurological disorder that causes mental retardation and other symptoms in one out of 15,000 births, has been developed by biologists at the University of Texas at Austin. (Source: EurekAlert! - Biology)

Cowden’s disease with a defined genetic alteration—Chromosomal duplication at 15q11–q13

Journal of Gastroenterology — Wed, 30 Jul 2008 08:24:16 +0100

We report a case of Cowden’s disease in which karyotype analysis revealed a small duplication (about 1 Mb) at 15q11–q13. This part of the genome is a region that is deleted in the Prader-Willi/Angelman syndrome and is a “hot spot” of chromosomal duplication. Content Type Journal ArticleCategory Case ReportDOI 10.1007/BF02934124Authors Takehisa Suzuki, The University of Tokyo First Department of Internal Medicine, Faculty of Medicine 7-3-1 Hongo, Bunkyo-ku 113 Tokyo JapanMasao Ichinose, The University of Tokyo First Department of Internal Medicine, Faculty of Medicine 7-3-1 Hongo, Bunkyo-ku 113 Tokyo JapanYasuo Matsubara, The University of Tokyo First Department of Internal Medicine, Faculty of Medicine 7-3-1 Hongo, Bunkyo-ku 113 Tokyo JapanNaohisa Yahagi, The University of T...

Functional Characterization of NIPA2, a Selective Mg2+ Transporter.

American Journal of Physiology. Cell Physiology — Wed, 30 Jul 2008 04:00:00 +0100

Authors: Goytain A, Hines RM, Quamme GA We used microarray analysis to identify renal cell transcripts that were upregulated with low magnesium. One transcript, identified as NIPA2 (nonimprinted in Prader-Willi/Angelman syndrome) subtype 2, was increased over 2-fold relative to cells cultured in normal magnesium. The deduced sequence comprises 129 amino acids with 8 predicted transmembrane regions. As the secondary structure of NIPA2 conformed to a membrane transport protein, we expressed it in Xenopus oocytes and determined that it mediated Mg(2)uptake with two-electrode voltage-clamp and fluorescence studies. Mg(2+) transport was electrogenic, voltage-dependent and saturable, demonstrating a Michaelis affinity constant (Km) of 0.31 mM. Unlike other reported Mg(2+) transporters, NIPA2...

Proximal 15q familial euchromatic variant and PWS/AS critical region duplication in the same patient: A cytogenetic pitfall.

European Journal of Medical Genetics — Tue, 22 Jul 2008 04:00:00 +0100

This report emphasizes the importance to distinguish proximal 15q polymorphic variants from clinically significant duplications. In any patient with inherited 15q proximal variant but unexplained developmental delay suggesting 15q11-q13 pathology, a pathogenic rearrangement has to be searched with adapted strategies, in order to detect deletions as well as duplications of this region. PMID: 18692163 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)

Mechanisms of imprinting of the Prader-Willi/Angelman region

American Journal of Medical Genetics Part A — Mon, 14 Jul 2008 04:00:00 +0100

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two distinct neurodevelopmental disorders, each caused by several genetic and epigenetic mechanisms involving the proximal long arm of chromosome 15. Lack of a functional paternal copy of 15q11-q13 causes PWS; lack of a functional maternal copy of UBE3A, a gene within 15q11-q13, causes AS. This region of chromosome 15 contains a number of imprinted genes that are coordinately regulated by an imprinting center (PWS/AS-IC) that contains two functional elements, the PWS-SRO and the AS-SRO. A chromosome lacking the PWS-SRO has the maternal state of gene activity and epigenetic modification after either maternal or paternal transmission; a chromosome lacking the AS-SRO but containing the PWS-SRO has the paternal state of gene activity a...

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Deletion 22q13.3 syndrome.

Pain Physician — Thu, 03 Jul 2008 06:46:09 +0100

Authors: Phelan MC The deletion 22q13.3 syndrome (deletion 22q13 syndrome or Phelan-McDermid syndrome) is a chromosome microdeletion syndrome characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features. The deletion occurs with equal frequency in males and females and has been reported in mosaic and non-mosaic forms. Due to lack of clinical recognition and often insufficient laboratory testing, the syndrome is under-diagnosed and its true incidence remains unknown. Common physical traits include long eye lashes, large or unusual ears, relatively large hands, dysplastic toenails, full brow, dolicocephaly, full cheeks, bulbous nose, and pointed chin. Behavior is autistic-like with decrease...

No association between the ryanodine receptor 3 gene and autism in a Japanese population

Psychiatry and Clinical Neurosciences — Sat, 28 Jun 2008 04:00:00 +0100

Conclusions: The present study provides no positive evidence for the association between the RyR3 gene and autism in the Japanese population. (Source: Psychiatry and Clinical Neurosciences)

Abnormal myelination in Angelman syndrome.

European Journal of Paediatric Neurology — Sat, 21 Jun 2008 04:00:00 +0100

We report 9 patients with genetically proven Angelman syndrome, who were examined by magnetic resonance imaging (MRI) between the ages of 7.5 months and 5 years. MRI in the 5 patients examined during infancy revealed myelination delay and a deficit of white matter. Retarded and/or abnormal myelination in Angelman syndrome seems to be a common finding that may be diagnostically misleading. This is particularly important in the evaluation of infants with possible Angelman syndrome, who present with nonspecific clinical features and have not yet developed the characteristic behavioural, language, and movement abnormalities. PMID: 18573670 [PubMed - as supplied by publisher] (Source: European Journal of Paediatric Neurology)

15q13q14 deletions: Phenotypic characterization and molecular delineation by comparative genomic hybridization

American Journal of Medical Genetics Part A — Tue, 17 Jun 2008 04:00:00 +0100

We report on a detailed phenotypic characterization of two patients with novel de novo deletions involving 15q13q14, a chromosomal region immediately distal to the Prader-Willi/Angelman syndrome critical interval. Both cases were detected by the clinical array-based comparative genomic hybridization (array-CGH) and were precisely delineated through the high-density Agilent 244 K oligonucleotide array. The comparison of our patients with previously reported deletion cases involving the 15q13q14 region demonstrated a recurrent pattern of developmental anomalies including mild dysmorphic features, cleft palate/bifid uvula, congenital heart defects (PFO or ASD), developmental delay, and learning disabilities. The potential role of the genes within the deleted region in the pathogenesis of thes...

No association between the ryanodine receptor 3 gene and autism in a Japanese population

Psychiatry and Clinical Neurosciences — Thu, 12 Jun 2008 09:55:27 +0100

Psychiatry and Clinical Neurosciences, Volume 62, Issue 3, Page 341-344, June 2008. Aim: Autism is a neurodevelopmental disorder with a complex genetic etiology. Chromosome 15q11-q14 has been proposed to harbor a gene for autism susceptibility because deletion of the region leads to Prader-Willi syndrome or Angelman syndrome, having ... (Source: Psychiatry and Clinical Neurosciences)

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Creativity, psychosis, autism, and the social brain.

The Behavioral and Brain Sciences — Sun, 01 Jun 2008 04:00:00 +0100

Authors: Fitzgerald M, Hawi Z In the target article, Crespi & Badcock (C&B) propose a novel hypothesis based on observations that a large set of phenotypic traits exhibit diametrically opposite phenotypes in autism-spectrum versus psychotic-spectrum conditions. They propose that development of these conditions is mediated in part by alterations in "genomic imprinting." This hypothesis is based on the model of the Prader-Willi and Angelman syndromes. The authors have produced a masterful discussion of the differences between psychosis and autism. Of course, another article could be written on the similarities. PMID: 18578912 [PubMed - as supplied by publisher] (Source: The Behavioral and Brain Sciences)

Deletion 22q13.3 syndrome

BioMed Central — Tue, 27 May 2008 04:00:00 +0100

The deletion 22q13.3 syndrome (deletion 22q13 syndrome or Phelan-McDermid syndrome) is a chromosome microdeletion syndrome characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features. The deletion occurs with equal frequency in males and females and has been reported in mosaic and non-mosaic forms. Due to lack of clinical recognition and often insufficient laboratory testing, the syndrome is under-diagnosed and its true incidence remains unknown. Common physical traits include long eye lashes, large or unusual ears, relatively large hands, dysplastic toenails, full brow, dolicocephaly, full cheeks, bulbous nose, and pointed chin. Behavior is autistic-like with decreased perception of pain an...

Anaesthesia for Angelman syndrome

Anaesthesia — Fri, 09 May 2008 08:22:08 +0100

We describe the administration of anaesthesia to a patient with Angelman syndrome, which is characterised by an abnormality of chromosome 15, where a subunit of the GABA receptor is coded. This has far-reaching anaesthetic implications as many ... (Source: Anaesthesia)

Sleep disturbance in adults with Angelman syndrome

Sleep and Biological Rhythms — Tue, 22 Apr 2008 00:59:34 +0100

Sleep and Biological Rhythms, Volume 6, Issue 2, Page 95-101, April 2008. Abstract Angelman syndrome is a neurodevelopmental disorder characterized by severe learning difficulties, epilepsy, and a typical behavioral phenotype. The diagnostic criteria state that 20–80% of individuals have decreased sleep need and abnormal sleep–... (Source: Sleep and Biological Rhythms)

Sleep disturbance in adults with Angelman syndrome

Sleep and Biological Rhythms — Tue, 22 Apr 2008 00:59:34 +0100

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Long-standing fever and Angelman syndrome: Report of two cases

Journal of Paediatrics and Child Health — Wed, 16 Apr 2008 01:22:46 +0100

Journal of Paediatrics and Child Health, Volume 44, Issue 5, Page 308-310, May 2008. Abstract: An 8-month-old girl and a 20-month-old boy who presented with motor and developmental delay and long-standing fever are presented. The patients were diagnosed as Angelman syndrome with fluorescence in situ hybridization (FISH) analysis. ... (Source: Journal of Paediatrics and Child Health)

Behavioural flexibility in individuals with Angelman syndrome, Down syndrome, non-specific intellectual disability and Autism spectrum disorder

Journal of Intellectual Disability Research — Wed, 02 Apr 2008 18:41:46 +0100

Journal of Intellectual Disability Research, Volume 0, Issue 0, Page ???, December 2004. Abstract Background Little is known about behavioural flexibility in children and adults with Angelman syndrome and whether people with this syndrome have more or less problems in being behaviourally flexible as compared with other people. Method ... (Source: Journal of Intellectual Disability Research)

In search of the psychosis gene in people with Prader-Willi syndrome

American Journal of Medical Genetics Part A — Thu, 06 Mar 2008 05:00:00 +0100

The two main causes of Prader-Willi syndrome (PWS) are a paternally derived deletion in the maternally imprinted 15q11-q13 region or UPD(15)mat. Both mechanisms result in a loss of the active paternal contribution to the region. The affective psychosis associated with PWS has been found to be mainly confined to the propositi with UPD(15)mat rather than to those with a deletion. This suggests that the psychosis may be related to the presence of two copies rather than a single copy of a gene or genes located in the distal half of the region which is paternally imprinted, but maternally active, and whose loss results in Angelman syndrome (AS). A large population-based study of PWS allowed the identification of 12 people with a 15q11-q13 deletion who had suffered psychotic episodes and four ad...

Vagal hypertonia and anesthesia in Angelman syndrome.

Paediatric Anaesthesia — Wed, 05 Mar 2008 21:50:34 +0100

Authors: Gardner JC, Turner CS, Ririe DG PMID: 18315655 [PubMed - in process] (Source: Paediatric Anaesthesia)

Beckwith Weidemann syndrome: A behavioral phenotype-genotype study

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics — Mon, 03 Mar 2008 05:00:00 +0100

Neurobehavioral defects have been reported in human imprinting disorders such as Prader-Willi syndrome and Angelman syndrome and imprinted genes are often implicated in neurodevelopment processes. Beckwith-Wiedemann syndrome (BWS) is a classical human imprinting disorder characterized by prenatal and postnatal overgrowth and variable developmental anomalies. As neurodevelopmental aspects of BWS have not previously been studied in detail, we undertook a questionnaire based neurobehavioral survey of 87 children with BWS. A greater than expected proportion of children demonstrated abnormal scores on measures of emotional and behavioral difficulties. In addition, 6.8% of children had been diagnosed with an autistic spectrum disorder (ASD). 4/6 BWS children with ASD had normal chromosomes and A...

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Angelman syndrome: clinical findings and follow-up data of 14 patients.

The Turkish Journal of Pediatrics — Sat, 01 Mar 2008 05:00:00 +0100

We report here on 14 patients with definite diagnosis of AS who displayed the characteristic clinical features of the syndrome and additional findings not previously reported, along with the follow-up data concerning neuromotor development and seizures. PMID: 18664077 [PubMed - in process] (Source: The Turkish Journal of Pediatrics)

Vagal hypertonia and anesthesia in Angelman syndrome

Pediatric Anesthesia — Fri, 29 Feb 2008 08:06:02 +0100

Pediatric Anesthesia, Volume 18, Issue 4, Page 348-349, April 2008. (Source: Pediatric Anesthesia)

Epigenetics and Assisted Reproductive Technologies: Human Imprinting Syndromes

Seminars in Reproductive Medicine — Thu, 28 Feb 2008 09:38:25 +0100

Semin Reprod Med 2008; 26: 143-152DOI: 10.1055/s-2008-1042953ABSTRACTWith the rise in use of assisted reproductive technologies (ARTs), there has been an increased awareness of potential genetic problems that may be initiated or propagated using these techniques. Several population studies have suggested a small but significantly increased risk of imprinting disorders like Angelman syndrome, Beckwith-Wiedemann syndrome, and possibly transient neonatal diabetes in children born through ARTs. Although the absolute risk appears to be very small, this association logically leads to the question of how ARTs affect gene imprinting. Studies investigating culture medias, timing of embryo transfer, intracytoplasmic sperm injection, and type of infertility have not yielded an association. There is e...

A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures

Nature Genetics — Sun, 17 Feb 2008 05:00:00 +0100

We report a recurrent microdeletion syndrome causing mental retardation, epilepsy and variable facial and digital dysmorphisms. We describe nine affected individuals, including six probands: two with de novo deletions, two who inherited the deletion from an affected parent and two with unknown inheritance. The proximal breakpoint of the largest deletion is contiguous with breakpoint 3 (BP3) of the Prader-Willi and Angelman syndrome region, extending 3.95 Mb distally to BP5. A smaller 1.5-Mb deletion has a proximal breakpoint within the larger deletion (BP4) and shares the same distal BP5. This recurrent 1.5-Mb deletion contains six genes, including a candidate gene for epilepsy (CHRNA7) that is probably responsible for the observed seizure phenotype. The BP4–BP5 region undergoes freq...

A new case of mosaicism for invdup(15) duplicated for Prader-Willi/Angelman syndrome critical region (PWACR) in an adult healthy man.

European Journal of Medical Genetics — Wed, 13 Feb 2008 05:00:00 +0100

We report on a healthy adult male carrying an sSMC(15) with two copies of PWACR in 20-50% of cells from different tissues. Molecular analyses showed the sSMC(15) as resulting from a PWACR-duplicated region spanning 8Mb which is larger than those in the only two other healthy PWACR-duplicated sSMC(15) carriers previously reported. Mosaicism level and mosaic cell line rate variation among different tissues observed in our case support mosaicism in critical tissues as of relevance for sSMC(15) phenotype-genotype correlations. PMID: 18378203 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)

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Methylation-Specific Multiplex Ligation-Dependent Probe Amplification Analysis of Subjects with Chromosome 15 Abnormalities

Genetic Testing — Tue, 15 Jan 2008 12:29:21 +0100

Genetic Testing Dec 2007, Vol. 11, No. 4: 467-476. Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurodevelopmental disorders caused by loss of expression of imprinted genes from the 15q11-q13 region. They arise from similar defects in the region but differ in parent of origin. There are two ... (Source: Genetic Testing)

Multiple forms of atypical rearrangements generating supernumerary derivative chromosome 15

BMC Genetics - Latest articles — Fri, 04 Jan 2008 05:00:00 +0100

Conclusions: Involvement of atypical BP in the generation of idic(15) chromosomes can lead to considerable structural heterogeneity. (Source: BMC Genetics - Latest articles)

Clinical studies and analysis of the rett syndrome gene (mecp2) in children with mental retardation in the greek population

PEDIATRICS — Wed, 02 Jan 2008 05:00:00 +0100

CONCLUSIONS: MECP2 gene analysis provides an appropriate diagnostic tool for RS and contributes additional information for research into MR. (Source: PEDIATRICS)

Dental treatment of children with Angelman syndrome: a case report.

Special Care in Dentistry — Tue, 01 Jan 2008 05:00:00 +0100

Authors: Murakami C, Nahás Pires Corrêa MS, Nahás Pires Corrêa F, Nahás Pires Corrêa JP Angelman syndrome (AS) is a rare genetic neurological disorder. The main clinical characteristics of this syndrome are delayed neuropsychological development, intellectual disability, speech impairment, movement or balance disorder, and a behavioural uniqueness. The syndrome has oral manifestations such as diastemas, tongue thrusting, sucking/swallowing disorder, mandibular prognathism, a wide mouth, frequent drooling, and excessive chewing behaviour. The dental literature on the syndrome is scarce. The purpose of paper is to describe the interesting aspects of the dental treatment of a child with AS. PMID: 18271768 [PubMed - indexed for MEDLINE] (Source: Special Ca...

Angelman syndrome

MayoClinic.com Full Feed — Tue, 18 Dec 2007 06:00:00 +0100

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

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A ligation assay for multiplex analysis of CpG methylation using bisulfite-treated DNA

Nucleic Acids Research — Tue, 18 Dec 2007 05:00:00 +0100

In this report, we describe an approach to simultaneous analysis of multiple CpG islands, where methylation-specific oligonucleotide probes are joined by ligation and subsequently amplified by polymerase chain reaction (PCR) when hybridized in juxtaposition on bisulfite-treated DNA. Specificity of the ligation reaction is achieved by (i) using probes containing CpGpCpG (for methylated sequences) or CpApCpA (for unmethylated sequences) at the 3' ends, (ii) including three or more probes for each target, and (iii) using a thermostable DNA ligase. The external probes carry universal tails to allow amplification of multiple ligation products using a common primer pair. As proof-of-principle applications, we established duplex assays to examine the FMR1 promoter in individuals with fragile-X sy...

Prenatal testing for uniparental disomy: indications and clinical relevance

Ultrasound in Obstetrics and Gynecology — Wed, 05 Dec 2007 05:00:00 +0100

This review aims to provide a rational and ethical basis for prenatal testing for uniparental disomy (UPD) in cases with abnormal ultrasound findings or numeric and/or structural chromosomal aberrations in chorionic villous or amniotic fluid samples. The clinical phenotypes of the genomic imprinting-associated paternal UPD 6 (transient neonatal diabetes mellitus), maternal UPD 7 (Silver-Russell syndrome), paternal UPD 11p (Beckwith-Wiedemann syndrome), maternal UPD 14 (precocious puberty, short stature and highly variable developmental delay), paternal UPD 14 (polyhydramnios and a bell-shaped thorax), maternal UPD 15 (Prader-Willi syndrome), paternal UPD 15 (Angelman syndrome), maternal UPD 16 and UPD 20, as well as the diagnostic options, are summarized. In addition, the clinical impact o...

Bone mineral density in angelman syndrome.

Pediatric Neurology — Sat, 01 Dec 2007 05:00:00 +0100

In conclusion, our study revealed osteopenia in almost half the children and young patients with Angelman syndrome. Dual-energy X-ray absorptiometry should be performed in all patients with Angelman syndrome, particularly if they are treated with antiepileptic drugs. PMID: 18021922 [PubMed - indexed for MEDLINE] (Source: Pediatric Neurology)

A survey of assisted reproductive technology births and imprinting disorders

Human Reproduction — Mon, 19 Nov 2007 05:00:00 +0100

CONCLUSIONS Although previous studies have suggested an increased relative risk of BWS and AS after ART, our findings suggest that the absolute risk of imprinting disorders in children conceived by ART is small (<1%). Precise risk estimates of risk are difficult to define because of the rarity of the conditions and incomplete response rates to the questionnaire and clinical examination invitations. Hence further investigations are indicated to (i) refine the absolute and relative risks of imprinting disorders after ART and (ii) ensure that changes in ART protocols are not associated with increased frequencies of epigenetic changes and imprinting disorders in children born after ART. (Source: Human Reproduction)

Utility of microsatellite analysis in evaluation of pregnancies with placental mesenchymal dysplasia

Prenatal Diagnosis — Mon, 12 Nov 2007 05:00:00 +0100

We present a case report in which several molecular analyses of amniocytes and products of conception were used in combination with cytogenetic and ultrasound studies to evaluate a pregnancy with a clinical suspicion of PMD. A combination of Southern blotting analysis, methylation-sensitive polymerase chain reaction (PCR) and multiplex ligation-dependent probe amplification (MLPA) was utilized to evaluate methylation patterns in the Beckwith-Wiedemann syndrome (BWS) and Prader-Willi/Angelman syndrome (PW/AS) critical regions. A series of microsatellite markers were used to evaluate the possibility of an androgenetic cell line.Methylation studies performed for the BWS and PW/AS critical regions were abnormal and consistent with a molecular diagnosis of BWS and Angelman syndrome. Further stu...

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Atypical Angelman syndrome with macrocephaly due to a familial imprinting center deletion

American Journal of Medical Genetics Part A — Thu, 01 Nov 2007 04:00:00 +0100

We report on a familial imprinting center deletion and the importance of considering the mild and atypical Angelman syndrome phenotypes within the differential diagnosis of intellectual handicap, particularly in clarifying the genetic risk to other family members. © 2007 Wiley-Liss, Inc. (Source: American Journal of Medical Genetics Part A)

[Technical Briefs] Methylation-Sensitive High-Resolution Melting-Curve Analysis of the SNRPN Gene as a Diagnostic Screen for Prader-Willi and Angelman Syndromes

Clinical Chemistry — Mon, 22 Oct 2007 04:00:00 +0100

Conclusions: MS-HRM is a simple, rapid, and robust method for screening methylation differences at the SNRPN locus and could be used as a diagnostic screen for PWS and AS. (Source: Clinical Chemistry)

Angelman Syndrome

MedicineNet Kids Health General — Tue, 16 Oct 2007 07:00:00 +0100

Title: Angelman SyndromeCategory: Diseases and ConditionsCreated: 10/16/2007Last Editorial Review: 10/16/2007 (Source: MedicineNet Kids Health General)

New insight into the role of the beta3 subunit of the GABAA-R in development, behavior, body weight regulation, and anesthesia revealed by conditional gene knockout

BMC Neuroscience - Latest articles — Wed, 10 Oct 2007 04:00:00 +0100

Conclusions: Conditional inactivation of the beta3 gene revealed novel insight into the function of this GABAA-R subunit. The floxed beta3 knockout mice described here will be very useful for conditional knockout studies to further investigate the role of the beta3 subunit in development, ethanol and anesthetic action, normal physiology, and pathophysiologic processes. (Source: BMC Neuroscience - Latest articles)

Albinism and developmental delay: the need to test for 15q11-q13 deletion.

Pediatric Neurology — Mon, 01 Oct 2007 04:00:00 +0100

We report on a 17-month-old African girl with cutaneous and ophthalmologic features of oculocutaneous albinism type 2 as well as microcephaly, absent speech, and tremulous movements. Mutations of the P gene within the Angelman/Prader-Willi syndrome critical region at 15q11-q13 cause oculocutaneous albinism type 2. Comorbid oculocutaneous albinism and Angelman syndrome were suspected and confirmed by cytogenetics. Phenotypic features of Angelman syndrome or Prader-Willi syndrome in a patient with albinism should prompt further investigation. PMID: 17903679 [PubMed - indexed for MEDLINE] (Source: Pediatric Neurology)

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Angelman Syndrome Revisited.

The Neurologist — Wed, 12 Sep 2007 00:55:35 +0100

Page: 305DOI: 10.1097/01.nrl.0000253067.32759.aaAuthors: Paprocka, Justyna MD *; Jamroz, Ewa PhD *; Szwed-Bialozyt, Barbara PhD *; Jezela-Stanek, Aleksandra MD +; Kopyta, Ilona PhD *; Marszal, Elzbieta * (Source: The Neurologist)

Are there distinctive sleep problems in Angelman syndrome?

Sleep Medicine — Thu, 30 Aug 2007 04:00:00 +0100

Authors: Pelc K, Cheron G, Boyd SG, Dan B Angelman syndrome is a neurogenetic condition characterized by developmental delay, absence of speech, motor impairment, epilepsy and a peculiar behavioral phenotype that includes sleep problems. It is caused by lack of expression of the UBE3A gene on the maternal chromosome 15q11-q13. Although part of the diagnostic description, 'sleep problems' are not well characterized. A pattern emerges from the available reports. It includes reduced total sleep time, increased sleep onset latency, disrupted sleep architecture with frequent nocturnal awakenings, reduced rapid eye movement (REM) sleep and periodic leg movements. Poor sleep does not significantly interfere with daytime alertness and sleep problems commonly diminish by late childhood, with co...

Infertility, assisted reproduction technologies and imprinting disturbances: a Dutch study

Human Reproduction — Fri, 17 Aug 2007 04:00:00 +0100

BACKGROUND Evaluation of relationships between assisted reproduction technologies (ART), fertility problems and disorders caused by disturbed genetic imprinting such as Angelman syndrome (AS) and Beckwith–Wiedemann syndrome (BWS). METHODS A nation-wide questionnaire survey was performed regarding ART in families with a child with AS, BWS or Prader–Willi syndrome (PWS) including questions on fertility. Molecular data on the genetic disorder in affected children were gathered. RESULTS Of the 220 affected children in this study, 14 (6.4%) were born following any form of ART compared with 83 818 (2.1%) in the Dutch population. Of AS, PWS or BWS children 15 (6.8%) were born after a fertility problem (Time To Pregnancy > 12 months, no forms of ART) compared to 141,340 (3.5%) in ...

Paternal uniparental isodisomy for chromosome 14 with mosaicism for a supernumerary marker chromosome 14

American Journal of Medical Genetics Part A — Mon, 13 Aug 2007 04:00:00 +0100

Uniparental disomy (UPD) describes the inheritance of two homologous chromosomes from a single parent. Disease phenotypes associated with UPD and chromosomal imprinting, rather than with mutations, include Beckwith-Wiedemann syndrome (paternal UPD11p), Angelman syndrome (paternal UPD15), Prader-Willi syndrome (maternal UPD15), and transient neonatal diabetes (paternal UPD6). Here we report on the first case of paternal uniparental isodisomy of chromosome 14 with a mosaicism for a supernumerary marker chromosome 14. The patient demonstrated a small thorax with a 'coat hanger' shape of the ribs, kyphoscoliosis, hypoplasia of the maxilla and mandible, a broad nasal bridge with anteverted nares, contractures of the wrists with ulnar deviation bilaterally, diastasis recti, and marked muscle hyp...

Highest accuracy of combined consensus clinical criteria and SNRPN gene molecular markers in diagnosis of Prader-Willi syndrome in Thai patients

Clinical Chemistry and Laboratory Medicine — Thu, 09 Aug 2007 04:00:00 +0100

Conclusions: We demonstrate here the high power of combining clinical findings, FISH and MSP in definitive diagnosis of PWS and in distinguishing between the two major different types of molecular mechanisms. No false positives or false negatives were observed in our analysis. Clin Chem Lab Med 2007;45:972–80. (Source: Clinical Chemistry and Laboratory Medicine)

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Lamotrigine Effect on GABA Transmission in Angelman Syndrome?

Epilepsia — Tue, 07 Aug 2007 14:42:45 +0100

Epilepsia Volume 48, Issue 8, Page 1634-1634, Aug 2007. (Source: Epilepsia)

Prevalence of Angelman syndrome amongst referrals with epilepsy and developmental delay

American Journal of Medical Genetics Part A — Fri, 03 Aug 2007 04:00:00 +0100

No Abstract. (Source: American Journal of Medical Genetics Part A)

Visualization of uniparental inheritance, Mendelian inconsistencies, deletions, and parent of origin effects in single nucleotide polymorphism trio data with SNPtrio

Human Mutation — Sat, 28 Jul 2007 04:00:00 +0100

A variety of alterations occur in chromosomal DNA, many of which can be detected using high density single nucleotide polymorphism (SNP) microarrays. These include deletions and duplications (assessed by observing changes in copy number) and regions of homozygosity. The analysis of SNP data from trios can provide an additional category of information about the nature and origin of inheritance patterns, including uniparental disomy (UPD), loss of transmitted allele (LTA), and nonparental relationship. The main purpose of SNPtrio is to locate regions of uniparental inheritance (UPI) and Mendelian inconsistency (MI), identify the type (paternal vs. maternal, iso- vs. hetero-), and assess the associated statistical probability of occurrence by chance. SNPtrio's schema permits the identificatio...

Rett syndrome.

Child and Adolescent Psychiatric Clinics of North America — Sun, 17 Jun 2007 04:46:14 +0100

Authors: Ben Zeev Ghidoni B Rett syndrome (RS) is an X-linked neurodevelopmental disorder and the second most common cause of genetic mental retardation in females. Different mutations in MECP2 are found in up to 95% of typical cases of RS. This mainly neuronal expressed gene functions as a major transcription repressor. Extensive studies on girls who have RS and mouse models are aimed at finding main gene targets for MeCP2 protein and defining neuropathologic changes caused by its defects. Studies comparing autistic features in RS with idiopathic autism and mentally retarded patients are presented. Decreased dendritic arborization is common to RS and autism, leading to further research on similarities in pathogenesis, including MeCP2 protein levels in autistic brains and MeCP2 effects...

Detailed analysis of 15q11-q14 sequence corrects errors and gaps in the public access sequence to fully reveal large segmental duplications at breakpoints for Prader-Willi, Angelman and inv dup(15) syndromes

Genome Biology — Fri, 15 Jun 2007 04:00:00 +0100

Conclusions: We have produced a segmental map of 15q11-q14 that reveals several large direct and inverted repeats that are incompletely and inaccurately represented on the current human genome sequence. Some of these repeats are clearly responsible for deletions and duplications in known genomic disorders, while some may increase susceptibility to other disorders. (Source: Genome Biology)

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Identification of novel deletions of 15q11q13 in Angelman syndrome by array-CGH: molecular characterization and genotype–phenotype correlations

European Journal of Human Genetics — Wed, 23 May 2007 04:00:00 +0100

Identification of novel deletions of 15q11q13 in Angelman syndrome by array-CGH: molecular characterization and genotype–phenotype correlations European Journal of Human Genetics advance online publication, May 23, 2007. doi:10.1038/sj.ejhg.5201859 Authors: Trilochan Sahoo, Carlos A Bacino, Jennifer R German, Chad A Shaw, Lynne M Bird, Virginia Kimonis, Irinia Anselm, Susan Waisbren, Arthur L Beaudet & Sarika U Peters (Source: European Journal of Human Genetics)

A targeted deletion upstream of Snrpn does not result in an imprinting defect

Mammalian Genome — Sat, 19 May 2007 07:31:11 +0100

Abstract Prader-Willi syndrome (PWS) and Angelman syndrome (AS) result from the disturbance of imprinted gene expression within human chromosome 15q11–q13. Some cases of PWS and AS are caused by microdeletions near the SNRPN gene that disrupt a regulatory element termed the imprinting center (IC). The IC has two functional components; an element at the promoter of SNRPN involved in PWS (PWS-IC) and an element 35 kilobases (kb) upstream of SNRPN involved in AS (AS-IC). To further understand the function of the IC, we sought to create a mouse model for AS-IC mutations. We have generated two deletions at a location analogous to that of the human AS-IC. Neither deletion produced an imprinting defect as indicated by DNA methylation and gene expression analyses. These results in...

C15orf2 and a novel noncoding transcript from the Prader-Willi/Angelman syndrome region show monoallelic expression in fetal brain.

Genomics — Tue, 01 May 2007 04:00:00 +0100

Authors: Buiting K, Nazlican H, Galetzka D, Wawrzik M, Groβ S, Horsthemke B The Prader-Willi syndrome (PWS) region contains several genes transcribed from the paternal chromosome only. We have previously identified a testis-specific gene, C15orf2, which maps between NDN and SNURF-SNRPN and is expressed from both alleles. Here we report on two novel genes (prader-willi region non-protein-coding RNA 1 and 2) located between NDN and C15orf2. By database search we found five partially duplicated copies, of which only one of each appears to be active. PWRN2 is expressed only in testis and is biallelic. PWRN1 is biallelically expressed in testis and kidney, but monoallelically in fetal brain. Methylation analysis of a CpG island 15 kb upstream of exon 1 showed absence of methylation in sper...

Evaluation of autism traits in Angelman syndrome: a resource to unfold autism genes

Neurogenetics — Fri, 06 Apr 2007 06:48:01 +0100

Abstract Linkage and cytogenetics studies have found the Angelman syndrome (AS) chromosomal region to be of relevance to autism disorder (AD) or autism spectrum disorder (ASD). Autism is considered part of the behavioural phenotype in AS based on formal autism assessments (autism diagnostic interview—revised [ADI-R] and autism diagnostic observation schedule [ADOS]), which have mainly addressed the deleted AS group. We explored 23 AS patients including all genetic subtypes and made a co-morbid diagnosis of AD/ASD in 14/23 (61%), which does not include 4 cases classified within the broader autism spectrum disorder (bASD). Deletions accounted for the main fraction (35%), ubiquitin-protein ligase E3A (UBE3A) mutation represented 13%, imprinting defects and uniparental disom...

Cryptic duplication of 12q24.33 [rarr] qter in a child with Angelman syndrome - simultaneous occurrence of two unrelated cytogenetic events

American Journal of Medical Genetics Part A — Thu, 29 Mar 2007 04:00:00 +0100

We present a case of Angelman Syndrome (AS) deletion and 12q duplication in a child with a history of developmental delay, microcephaly, cerebral palsy, and seizures. Traditional cytogenetic studies showed a normal 46,XY karyotype. Fluorescence in situ hybridization (FISH) using probe D15S10 (AS region/15q11.2) revealed a deletion. In addition, we serendipitously detected 12q24.3 duplication by FISH with 12q subtelomere probe. He inherited this duplication from the mother who presented with a balanced translocation karyotype 46,XX,add(12)(q24.3).ish t(12;13)(q24.3;p11.2)(12qtel-;12qtel+,D13Z1/D21Z1+,RB1+). Array comparative genomic hybridization (array-CGH) revealed a duplication of three bacterial artificial chromosome (BAC) clones (RP11-46H11, RP11-386I8, and RP11-309H3) covering about 4...

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Haploinsufficiency of TCF4 Causes Syndromal Mental Retardation with Intermittent Hyperventilation (Pitt-Hopkins Syndrome)

Am J Hum Genet Latest Articles — Fri, 23 Mar 2007 05:00:00 +0100

Pitt-Hopkins syndrome is a rarely reported syndrome of so-far-unknown etiology characterized by mental retardation, wide mouth, and intermittent hyperventilation. By molecular karyotyping with GeneChip Human Mapping 100K SNP arrays, we detected a 1.2-Mb deletion on 18q21.2 in one patient. Sequencing of the TCF4 transcription factor gene, which is contained in the deletion region, in 30 patients with significant phenotypic overlap revealed heterozygous stop, splice, and missense mutations in five further patients with severe mental retardation and remarkable facial resemblance. Thus, we establish the Pitt-Hopkins syndrome as a distinct but probably heterogeneous entity caused by autosomal dominant de novo mutations in TCF4. Because of its phenotypic overlap, Pitt-Hopkins syndrome evolves as...

[Membrane Transport, Structure, Function, and Biogenesis] NIPA1(SPG6), the Basis for Autosomal Dominant Form of Hereditary Spastic Paraplegia, Encodes a Functional Mg2+ Transporter

Journal of Biological Chemistry — Fri, 09 Mar 2007 05:00:00 +0100

Mutations in the NIPA1(SPG6) gene, named for "nonimprinted in Prader-Willi/Angelman" has been implicated in one form of autosomal dominant hereditary spastic paraplegia (HSP), a neurodegenerative disorder characterized by progressive lower limb spasticity and weakness. However, the function of NIPA1 is unknown. Here, we show that reduced magnesium concentration enhances expression of NIPA1 suggesting a role in cellular magnesium metabolism. Indeed NIPA1 mediates Mg2+ uptake that is electrogenic, voltage-dependent, and saturable with a Michaelis constant of 0.69 ± 0.21 mm when expressed in Xenopus oocytes. Subcellular localization with immunofluorescence showed that endogenous NIPA1 protein associates with early endosomes and the cell surface in a variety of neuronal and epithelial c...

Unraveling the mechanisms of Angelman Syndrome

Nature Neuroscience — Sat, 03 Mar 2007 03:10:02 +0100

(Source: Nature Neuroscience)

Genomic imprinting and the expression of affect in Angelman syndrome: What's in the smile?

Journal of Child Psychology and Psychiatry — Thu, 22 Feb 2007 14:00:37 +0100

Journal of Child Psychology and Psychiatry Volume 0, Issue 0, Page ???-???. (Source: Journal of Child Psychology and Psychiatry)

Angelman Syndrome Deficits Rescued In Mice

Health News from Medical News Today — Wed, 14 Feb 2007 15:00:00 +0100

Children with Angelman syndrome are often seen laughing and smiling, but this cheerful demeanor masks serious neurological problems - mental retardation, movement problems and seizures.New research in mice, however, suggests that many of these deficits could be alleviated.Edwin Weeber, Ph.D. [click link for full article] (Source: Health News from Medical News Today)

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Angelman Syndrome Deficits Rescued In Mice

Pediatrics News From Medical News Today — Wed, 14 Feb 2007 15:00:00 +0100

Newsdesk: Genetic Engineering Cures Mice Of Brain Disorder

CounsellingResource.com News and Features — Mon, 12 Feb 2007 12:05:04 +0100

Author: NewsEditor Subject: Genetic Engineering Cures Mice Of Brain Disorder Posted: Mon 12 Feb 2007 1:05 pm (GMT 1) Researchers at Vanderbilt University Medical Center and Erasmus Medical Center show that preventing the inhibition of CaMKII reverses the neurological deficits in a mouse model of Angelman syndrome, a rare disorder that causes mental retardation,...view forum post_________________News Editor, CounsellingResource.com Also see our Daily Mental Health News Page (Source: CounsellingResource.com News and Features)

Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of αCaMKII inhibitory phosphorylation

Nature Neuroscience — Sun, 28 Jan 2007 05:00:00 +0100

Angelman syndrome (AS) is a severe neurological disorder characterized by mental retardation, motor dysfunction and epilepsy. We show that the molecular and cellular deficits of an AS mouse model can be rescued by introducing an additional mutation at the inhibitory phosphorylation site of αCaMKII. Moreover, these double mutants no longer show the behavioral deficits seen in AS mice, suggesting that these deficits are the direct result of increased inhibitory phosphorylation of αCaMKII. (Source: Nature Neuroscience)

Imprinting center analysis in Prader-Willi and Angelman syndrome patients with typical and atypical phenotypes.

European Journal of Medical Genetics — Mon, 01 Jan 2007 05:00:00 +0100

Authors: Camprubí C, Coll MD, Villatoro S, Gabau E, Kamli A, Martínez MJ, Poyatos D, Guitart M Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic disorders caused by a deficiency of imprinted gene expression from the paternal or maternal chromosome 15, respectively. This deficiency is due to the deletion of the 15q11-q13 region, parental uniparental disomy of the chromosome 15, or imprinting defect (ID). Mutation of the UBE3A gene causes approximately 10% of AS cases. In this present study, we describe the molecular analysis and phenotypes of two PWS patients and four AS patients with ID. One of the PWS patients has a non-familial imprinting center (IC) deletion and displayed a severe phenotype with an atypical PWS appearance, hyperactivity and psychiatric vulnerabili...

MLPA analysis for a panel of syndromes with mental retardation reveals imbalances in 5.8% of patients with mental retardation and dysmorphic features, including duplications of the Sotos syndrome and Williams-Beuren syndrome regions.

European Journal of Medical Genetics — Mon, 01 Jan 2007 05:00:00 +0100

Authors: Kirchhoff M, Bisgaard AM, Bryndorf T, Gerdes T MLPA analysis for a panel of syndromes with mental retardation (MRS-MLPA) was used for investigation of 258 mentally retarded and dysmorphic patients with normal conventional karyotypes (P064 probe set, MRC-Holland, for detection of (micro)deletions associated with 1p36-deletion, Sotos, Williams-Beuren, Prader-Willi, Angelman, Miller-Dieker, Smith-Magenis, and 22q11-deletion syndromes). Patients were initially referred for HR-CGH analysis and MRS-MLPA was performed retrospectively. MRS-MLPA analysis revealed imbalances in 15/258 patients (5.8%). Ten deletions were identified, including deletions of 1p36, 5q35 (Sotos syndrome), 7q11 (Williams-Beuren syndrome), 17p11 (Smith-Magenis syndrome), 15q11 (Angelman syndrome) and 22q11. Dup...

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Subtelomeric trisomy 21q: a new benign chromosomal variant.

European Journal of Medical Genetics — Mon, 01 Jan 2007 05:00:00 +0100

This report shows that new, previously unknown, benign subtelomeric variants may complicate the correct clinical diagnosis. PMID: 17055792 [PubMed - indexed for MEDLINE] (Source: European Journal of Medical Genetics)

Imprinting in human disease with special reference to transient neonatal diabetes and Beckwith-Wiedemann syndrome.

Endocrine Development — Mon, 01 Jan 2007 05:00:00 +0100

Authors: Temple IK There are at least 6 well-studied imprinting domains on human autosomes. Each domain is under the regulatory control of an 'imprinting centre' that harbours a differentially methylated region. A number of molecular mechanisms result in differential silencing of some genes within these domains and gene expression is tightly regulated in normal individuals. However, this makes them vulnerable to naturally occurring genetic and epigenetic aberrations. Nine recognisable developmental syndromes have been described due to abnormalities within these 6 domains: transient neonatal diabetes (TND; at 6q24); Beckwith- Wiedemann syndrome (BWS) and Silver-Russell syndrome (at 11p15.5; 2 imprinted domains); maternal and paternal uniparental disomy syndromes (at 14q32); Angelman and...

Characterization of a 5.3 Mb deletion in 15q14 by comparative genomic hybridization using a whole genome "tiling path" BAC array in a girl with heart defect, cleft palate, and developmental delay

American Journal of Medical Genetics Part A — Tue, 12 Dec 2006 07:00:00 +0100

We describe the successful application of a submegabase resolution whole genome "tiling path" BAC array to confirm and characterize a de novo interstitial deletion of chromosome 15. The deletion has a size of 5.3 Mb and is located within chromosome band 15q14, distal to the Prader-Willi/Angelman region. The affected girl had a heart defect, cleft palate, recurrent infections, and developmental delay. In contrast to GTG banding, array CGH determined the exact number of deleted genes and thus allowed the identification of candidate genes for cleft palate (GREM1, CX36, MEIS2), congenital heart defect (ACTC, GREM1, CX36, MEIS2), and mental retardation (ARHGAP11A, CHRNA7, CHRM5). © 2006 Wiley-Liss, Inc. (Source: American Journal of Medical Genetics Part A)

Angelman syndrome caused by an identical familial 1,487-kb deletion

American Journal of Medical Genetics Part A — Wed, 06 Dec 2006 07:00:00 +0100

No Abstract. (Source: American Journal of Medical Genetics Part A)

[Original articles] The epigenetic imprinting defect of patients with Beckwith--Wiedemann syndrome born after assisted reproductive technology is not restricted to the 11p15 region

Journal of Medical Genetics — Fri, 01 Dec 2006 07:00:00 +0100

Conclusions: Some patients with BWS show abnormal methylation at loci other than the 11p15 region, and the involvement of other loci is not restricted to patients with BWS born after ART was used. Moreover, the mosaic distribution of epimutations suggests that imprinting is lost after fertilisation owing to a failure to maintain methylation marks during pre-implantation development. (Source: Journal of Medical Genetics)

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Childhood autism and associated comorbidities.

Brain & Development — Fri, 03 Nov 2006 07:00:00 +0100

Authors: Zafeiriou DI, Ververi A, Vargiami E Autism is a heterogeneous neurodevelopmental disorder with a variety of different etiologies, but with a heritability estimate of more than 90%. Although the strong correlation between autism and genetic factors has been long established, the exact genetic background of autism is still unclear. This review refers to all the genetic syndromes that have been described in children with pervasive developmental disorders (tuberous sclerosis, fragile X, Down, neurofibromatosis, Angelman, Prader-Willi, Gilles de la Tourette, Williams, etc.). Issues covered include prevalence and main characteristics of each syndrome, as well as the possible base of its association with autism in terms of contribution to the current knowledge on the etiology and gen...

Detection of a deletion of exons 8-16 of the UBE3A gene in familial Angelman syndrome using a semi-quantitative dosage PCR based assay.

European Journal of Medical Genetics — Wed, 01 Nov 2006 05:00:00 +0100

We report here the development of a semi-quantitative dosage PCR technique used to identify sub-microscopic deletions involving UBE3A. Using this method we analysed a panel of 26 patients from 24 families, all fulfilling the clinical criteria for AS. We identified a deletion of UBE3A exons 8-16 in a sibling pair. Analysis of parental samples revealed the same deletion in their phenotypically normal mother. This is an inexpensive and valuable method for detecting UBE3A deletions in a small but important proportion of AS cases of unidentifiable cause. PMID: 16740422 [PubMed - indexed for MEDLINE] (Source: European Journal of Medical Genetics)

Effects of social stimuli on laughing and smiling in young children with Angelman syndrome.

American Journal of Mental Retardation : AJMR — Wed, 01 Nov 2006 05:00:00 +0100

Authors: Richman DM, Gernat E, Teichman H The effects of social stimuli present and absent on laughing and smiling in 2 young children with Angelman syndrome were assessed via a multielement design. Results indicated that laughing and smiling for either child was unaffected by the social stimuli assessed in the social interaction condition. Results are discussed in terms of the effects of biological variables and environmental stimuli on children with specific genetic disorders across the lifespan. PMID: 17029501 [PubMed - indexed for MEDLINE] (Source: American Journal of Mental Retardation : AJMR)

[Research Papers] Deficiency of Rbbp1/Arid4a and Rbbp1l1/Arid4b alters epigenetic modifications and suppresses an imprinting defect in the PWS/AS domain

Genes and Development — Mon, 16 Oct 2006 06:00:00 +0100

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are caused by deficiency of imprinted gene expression from paternal or maternal chromosome 15q11–q13, respectively. Genomic imprinting of the PWS/AS domain is regulated through a bipartite cis-acting imprinting center (PWS-IC/AS-IC) within and upstream of the SNRPN promoter. Here, we show that two Rb-binding protein-related genes, Rbbp1/Arid4a and Rbbp1l1/Arid4b, are involved in the regulation of imprinting of the IC. We recovered these two genes from gene trap mutagenesis selecting for altered expression of an Snrpn-EGFP fusion gene strategy. RBBP1/ARID4A is an Rb-binding protein. RBBP1/ARID4A interacts with RBBP1L1/ARID4B and with the Snrpn promoter, implying that both are part of a protein complex. To further elucidate their r...