Family Picnic Malahide Castle Sunday 7th November – book now

Book your seat on zoom workshop.

Monday 11th October 7.30pm, Challenging Behaviour Specialist John Curran will be joining us.

€3K Access to Angelman Grant awarded.

We are delighted to have been awarded €3K today December 16th from the RTE Comic relief grant fund in conjunction with Community Foundation. As part of our Access to Angelman project we will be working to host virtual meeting and meetups in the coming months. More details to follow.

Entitlements for families

Booklet for families explaining entitlements for families. Kindly reproduced here with permission from

2019 European Alliance Grants awarded


European Angelman  Alliance Announce 2019 Research Grant winners

ASA proudly announced the 3 recipients: Dr. Ype Elgersma (Netherlands), Dr. Ugo Mayor (Spain) and Dr. Ben Philpot (USA) –

Dr. Ype Elgersma, Professor of Molecular Nuroscience, Erasmus Centre, Rotterdam, postulates that UBE3A plays a major role in the regulation of gene expression and sets out to identify respective genes.

Dr. Ugo Mayor,, Ikerbasque Research Professor, Bilbao has a daring and novel approach to identify and validate the substrates and cofactors (including DUB enzymes) of UBE3A and to test the viability of targeting DUB enzymes as a therapeutic strategy for AS. That intrigued both scientific board as well as the international alliance of parent organizations (Angelman Syndrome Alliance – ASA).

Dr. Ben Philpot,, Associate Professor, University of North Carolina, finetunes his last discovery by looking at quantifying sleep spindles from overnight EEGs as an Angelman syndrome biomarker.

Speaking on behalf of the scientific advisory board,  Dr. Harald Sitte, : “The result of the 2018 call for research proposals has yielded a good combination of different research approaches which we hope to lead research on Angelman syndrome into a bright future. We congratulate the three awardees and look forward to follow their scientific work.”

The previous winners of the ASA Grants in 2014 and 2016 have been Dr. Geeske van Woerden, Dr. Ben Distel, Dr. Silvia Russo and Dr. Ben Philpot.

ASA is a global initiative of Angelman parent organizations.

Every country can have one representing AS parent-organisation participating in ASA. Our Scientific Advisory Board lends support and guidance to the members of the ASA parent organizations. Contact us if you wish to join or if you are interested to learn more about Angelman syndrome, ASA or the scientific challenges:

For further information  – Communication: Betty Willemsen (

Scientific Board: Harald Sitte (

Angelman Ireland  –

Angelman Syndrome Alliance research published

  • This study was funded in part by ASA through research grants to Ben Distel, Geeske van Woerden and Ype Elgersma. 

Location matters: recent study provides a new viewpoint on how loss of UBE3A causes Angelman syndrome  

Angelman syndrome (AS) is caused by mutations or deletions that result in the loss of functional UBE3A protein. However, despite many years of research, it remains unclear where in the cell UBE3A performs its function and how the loss of UBE3A causes AS. A collaboration of three research groups in The Netherlands (Ben Distel, Amsterdam UMC, Amsterdam), Steven Kushner and Ype Elgersma (both at Erasmus MC, Rotterdam) has now resulted in a remarkable new viewpoint: UBE3A has a critical role in the nucleus and loss of nuclear UBE3A causes Angelman Syndrome. The study is published in this month’s issue of Nature Neuroscience. 

Neurons form the computing core of our brain and communicate with each other through synaptic connections. Previous work of several research groups has established that the synapses of AS mouse models function suboptimal, and this deficit is likely underlying the severe neurodevelopmental delay. Since UBE3A is present in synapses, almost all research on UBE3A has focused on its role in the synapse, but its precise role remains elusive. However, UBE3A is also present in other places of the neuron, in particular it is highly abundant in the nucleus of neurons. The nucleus contains the DNA of the cell, and hence dictates the function of a cell. In the new study, the Dutch research team revealed precisely how UBE3A is able to get into the nucleus. They showed that UBE3A is able to bind to a protein called PSMD4, and that this binding is critical for bringing UBE3A into the nucleus. 

Since nuclear localization of UBE3A is highly controlled, the team reasoned that the nuclear localization might be important for AS pathophysiology. Hence, they investigated if UBE3A mutations found in AS patients disrupt the targeting of UBE3A to the nucleus. Indeed, they describe three AS-associated UBE3A mutations in which UBE3A is no longer present in the nucleus. 

To investigate this further, the team made use of the observation that the UBE3A protein comes in two different sizes (called isoforms). The authors showed that only the shorter form is present in the nucleus. The longer form of UBE3A is absent in nuclei and dispersed throughout the neuron (for instance in synapses). To further investigate the importance of the two UBE3A isoforms and their differential localization, the researchers generated two mouse models that either made the nuclear (short) UBE3A protein or the non-nuclear (long) UBE3A protein. Consistent with an important role of UBE3A in the nucleus the researches showed that mice which specifically lack nuclear UBE3A, highly resembled AS mice that lack UBE3A altogether. Not only did these mice show behavioral deficits, also the synapses of these mice were no longer functioning properly. In contrast, mice that lacked the non-nuclear (long) UBE3A appeared unaffected.  

The authors indicate that these findings change the current view of how UBE3A causes AS. The team suggests that future studies should elucidate the precise role of UBE3A in the nucleus and how this role relates to the pathophysiology of AS. This knowledge is important to develop new treatments. 

This study was funded in part by ASA through research grants to Ben Distel, Geeske van Woerden and Ype Elgersma. 

Full text available at: 

Avagliano-Trezza et al., Loss of nuclear UBE3A causes electrophysiological and behavioral deficits in mice and is associated with Angelman syndrome, Nature Neuroscience, doi: 10.1038/s41593-019-0425-0. 

Mick Falvin to perform at fundrasier – Naomh Malachi GFC club Saturday 15th June.

The family of Shane Gorman are hosting an evening of music with the fantastic Mick Flavin – 16th June. Tickets $10 with all proceeds kindly being donated to ASI. For details and if you can support or donate prizes contact Seamus – 086 325 6906 or email ASI at

IAD 2019

Dublin family meet up details : Sunday 17th Marley park playground 1pm.

Belfast ASI/ASSERT Sunday 17th Kids Together, Stewartstown Road Belfast 12.30-3.30.

For more details email

2019 Call to research Grant ASI


Call for Applications for Research Grants into Angelman Syndrome

Deadline 4th January 2019

Angelman Syndrome is a rare neurogenetic disorder, resulting from the loss of function of a single gene, UBE3A, which encodes for the ubiquitin ligase E6-AP. It is characterised by severe intellectual disability, lack of speech, motor coordination deficits, sleep disturbance and an unusually happy demeanour.

The international Angelman Syndrome Alliance (ASA) is an initiative of parent support organisations from 15 countries (including Ireland, UK, Belgium, Netherlands, Germany, Austria, France, Italy, Portugal, Japan, Israel, and Spain) who have pooled resources and funds in order to advance research into the syndrome.

The ASA is now inviting applications from researchers from any country for grants of up to €175,000 (total grant fund €350,000). Proposals covering preclinical (basic) research as well as translational research are welcomed, however applications for behavioural therapies are not eligible at this point.

The duration of the grant is flexible up to a maximum of 4 years. After 50% completion of the anticipated duration, an evaluation of the project’s progress will be expected. This will be in the form of both a detailed written scientific report for the Scientific Advisory Board (SAB) and an update in more general layman’s terms to share with the parent organisations who fund the grant.

This is a two-stage application process. In the first instance, a short initial application should be submitted via the ASA website ( by 12:00 noon on 4th January 2019 and should include the following:

  1. A cover letter, including the title of the proposal and the name of the principal investigator.
  2. A two-page summary of the proposed research including paragraphs on the hypothesis, background, research plan, principal methodology, and the significance of the proposed research. An overview of the budget must also be included (indirect costs cannot be applied for).
  3. The Curriculum vitae of the applicant.

All applications should be written in English, in Times New Roman, 10 point, 1.5 spaced on A4 paper.

From 14th January 2019, detailed applications will be invited for proposals passing stage 1, to be submitted by 12:00 noon on or before 11th March 2019. Successful applicants will be informed by 22nd July 2019 and will be invited to give the ASA-AWARD LECTURE at the next biennial ASA scientific conference in autumn 2020.

Proposals involving laboratory animal testing must be approved by the respective institutional review boards before funding can be released.  Research applications from outside the EU, must still conform to ethical guidelines and laws within the EU.

à Questions about the grant process should be directed to the ASA Board at: Manuel Duarte –

à Questions about research on Angelman Syndrome should be directed to the Scientific Advisory Board at: Harald Sitte –


Research updates and summary Germany 2018

See below  the latest summary of Alliance Funded research presented in Germany October 2018. Thanks to Annette Kent who has summarised it in a family friendly version.


Summary report from the 6th International Scientific Conference, Hamburg, Germany by Annette Kent Bsc PhD, on behalf of Angelman Syndrome Ireland

Molecular mechanisms underlying Angelman Syndrome (AS) and investigating treatment options 

Rosella Avagliano Trezza, Centre for Neurodevelopmental Disorders, Dept of Neurosciences, Erasmus MC, Netherlands

This work aimed to understand the key proteins in the cytoplasm and nucleus of the cell, exploring the circumstances under which the various forms of Ube3a move or are retained in either location.  This work showed that 80% of the ube3a is the short form and 20% is the long form.

Removing the AZUL domain changed the location of the short form from nucleus to the cytoplasm and it is thought that the AZUL domain is necessary but not sufficient for Ube3a nuclear localization.

Doing experiments using leptomycin (inhibitor of movement from the nucleus) showed that the short form starts and stays nuclear however the short form without the Azul domain stays in the cytoplasm.

*AZUL domain is a specific location on Uba3e gene.

*Individual cells are comprised of a nucleus (the part of the cell that contains the genetic material) and the cytoplasm.  The cytoplasm describes all the material in the cells outside of the nucleus.

A behavioural test battery for mouse models for AS: a powerful tool for testing drugs and novel Ube3a mutants:

Monica Sonzogoni, Centre for Neurodevelopmental Disorders, Dept of Neurosciences, Erasmus MC, Netherlands

This group previously described the characteristics/phenotypes of AS, and their work now focused on testing the robustness of these characteristics using a battery of behaviour tests.  It was pointed out that there are important clinical questions to focus on including: information on meaningful outcome measures, assessment of the characteristics and various interventions.

A conclusion from this work was that the AS mouse model can be used to assess the majority of the shared AS characteristics except the absence of speech, providing confirmation that AS characteristics can be identified, can be put into a mouse model and can be used for drug testing.

Cellular phenotypes of human AS iPSC derived neurons

Stormy Chamberlain, Dept of Genetics and Genome Sciences, UConn Health, USA

This work focused on stem cell derived human neurons and characterisation of neurons generated from people with AS.  It aimed to understand neuronal maturation and seeing whether specific phenotypes could be made from human AS neurons. One of the key reasons for doing this work was to help develop future therapies.

The generated neurons facilitated various studies, used to assess whether specific mutations/changes in Ube3a are likely to cause AS and whether therapeutic approaches can successfully restore neuronal function.

*iPSC – induced Pluripotent Stem cell culture are those generated from adult cells.  Pluripotent stem cell are master cells. They can potentially produce any cell or tissue the body needs to repair itself. This “master” property is called pluripotency.

*Phenotype is the set of observable characteristics of an individual resulting from the interactions of its genes or genotype with the environment.



Potential therapeutic approach for synaptic deficit in AS – the JNK inhibitor peptide (human in vitro model)

Tiziano Borsello, IRCCS Cytogenetics and Molecular Genetics Lab, Istito Auxologico Italiano, Milano, Italy

This work focused on the role of JNK at the nerve synapse.  It is known that Ube3a loss impairs synaptic transmission but the mechanism involved needs to be further understood.  Early data from this work shows that differences exist between samples from people with AS and controls (i.e. non-AS).   JNK plays a significant role and works by controlling a number of cellular processes including proliferation, embryonic development and apoptosis. It is thought that differences observed in AS group between the males and females may be due to hormonal differences.

*Apoptosis is the death of cells as a normal and controlled part of development and growth.

*JNK, c-jun N terminal kinase, a group of enzymes which play an important an important role in the regulation of neuronal functions. *

*Synapses is a structure that allows a nerve cell to pass an electrical or chemical signal to another nerve.

AS treatment opportunities and clinical biomarkers

Ben Philpot, University of North Carolina, USA

This work focused on ‘Epiloptogenesis’ which is the serialisation of seizures i.e. the gradual process of becoming more susceptible to seizures.  Using mice, they showed that the loss of Ube3a from GABAergic neurons (inhibitory neurons) increased seizure sensitivity which was not observed in glutamerigic neurons (excitatory neurons).

Tests carried out using mice showed similar susceptibility in early stages of the experiments, with larger differences observed in the later stages in the normal vs the AS mice (greater susceptibility in AS neurons).  They also used a hyperthermia induced seizure model where it was observed that seizures occur at much lower temperatures in the AS mice than in normal mice.

A very interesting piece of work gave the results of deleting ube3a in excitatory and inhibitory neurons followed by their reinstatement, helping to understand the reversibility of the epiloptogenesis. Reinstatement of ube3a reduced susceptibility in juvenile mice which was not seen in adult AS.



GABA mediated inhibitory dysfunction and its pathophysiological contribution in AS

 Kiyoshi Egawa, Pediatric Dept., Hokkaido University Graduate School of Medicine, Japan

Analysis of the somatosensory evoked response using magnetoencephalography was performed and shown to be modified by GABAa receptor agonists. The total amount of GABAa receptor is not decreased in people AS. Tonic inhibition is different in different parts of the brain and maybe due to the GAT1 (GABA transporter 1).  Dysregulation of tonic inhibition is a potential target for developing pharmacological strategy for AS.

*Tonic inhibition is a constant, long-lasting inhibition which is in contrast with phasic inhibition describing short intermittent bursts of inhibition.  Recently, gain, rather than loss, of tonic inhibition has been shown to underlie the pathophysiology of epilepsy.

*Somatosensory is a part of the sensory nervous system which is made up a sensory neurons and pathways.

Cannabidiol extract as a new approach in the anticonvulsive treatment of the Angelman Syndrome – based on neurotransmitter profile, particularly in consideration of GABA and glutamate

Christel KannegieBer-Leitner, Research Group Angelman e.V., Germany

This presentation focused on the use cannabidiol extract (CBD) in AS a potential new approach.  Details of experience with a young man, the son of Christel, with AS and NCSE (Non-Convulsive Status Epilepticus) who had immediate freedom from seizures for 8 months after treatment with CBD.

A stronger glutamate was found in Magnesium (Osborn et al., The Journal of Clinical Pharmacology, 2016, 56(3) 260-265).  The experience was that irregular use of Magnesium could be useful.  However, questions remain on both these approaches and research is needed to understand long- and short-term side and also the role that genetics may play.

Imprinting defects and differential diagnosis

Bernhard Horsthemke, Jasmin Beygo and Karin Buiting Universitatsklinikum, Essen, Germany

This presentation focused on the imprinting defects and differential diagnoses within the family of AS syndromes.

Adeno Associated Virus Mediated Ube3a gene or protein replacement strategies

Ed Weber, Molecular Pharmacology and Physiology, CSO Byrd Alzheimer’s Institute, USA and also for AGILIS Biotherapeutics, USA

This talk focused on a gene therapy shown to restore learning and memory in a mouse model. This group previously showed a recovery in spatial and associated memory defects as well as the underlying alteration in hippocampal synaptic plasticity following the use of “Adeno Associated Virus” also known as AAV to deliver either the ube3a protein or gene.

This work is advancing and the current focus is on bioavailability. The phase I clinical trial protocol is being worked on however it needs good outcome measures but plans to be active for late 2020.

*Bioavailability is the proportion of a drug or other substance which enters the circulation when given to an individual and able to have effect.

Potential therapeutic approach for synaptic deficit in AS: the JUNK peptide (mouse model in vivo)

Silvia Russo, Neuronal Death and Neuroprotection Lab, Dept of Pharmacological and Biomolecular Sciences, CEND, Milano, Italy

Potential therapeutic approach for synaptic deficit in AS with the aim of creating a patient specific model to detect biomarkers (morphological biochemical ad functional biomarkers).

Natural history study efforts in the AS and the scientific rationale for therapy with antisense oligonucleotides

Rebecca Crean, Director, Clinical Development, IONIS, USA

IONIS are working on anitsense oligonucleotide (ASO) therapy as a platform and focused on AS to unsilence a protein. IONIS are working on a large number of ASOs for activity in multiple tissues.  ASOs do not cross the blood brain brain so administration is via bolus intra-thecal injections. In AS paternal ube3a is silenced, using an ASO this could be unsilenced and therefore could be a novel approach to treat AS.

Foundational science needs to enable feasible efficient drug development and assist in the understanding the impact on the individual patient measures including patient reported outcomes will be very important.

IONIS is focused on developing natural history studies which will facilitate drug development.  Natural history studies are studies on individuals over time who have or are at risk of developing a specific medical condition. They allow door greater understanding of the disease and help guide clinical trials.  The main gaps in knowledge are longitudinal changes, biomarkers, correlation between ube3a levels and clinical features.  A number of international registries exist which assist including the following,, AS registry, China Angelman registry, and Angelman Biomarkers and Outcomes Measures (ABOM).

*Anti-sense oligonucleotides are short, synthetic, single-stranded DNA (that can alter protein production.

*Intra-thecal is a route of administration for drugs via an injection into spinal cord

OVID Therapeutics: Update on the AS STARS: Topline results from a phase 2 adults and adolescent AS clinical trial.  A randomised, double blind, safety and efficacy study of Gaboxadol (OV101)

Amit Rakhit, Chief Medical and Portfolio Officer, OVID Therapeutics, USA.

This presentation focused on the development work that OVID are focused on in particular the STARS clinical trial using OV101.   OV101 is a selective GABAa receptor agonists which was tested in this phase II study in 3 groups I.e. placebo, once daily dosing and twice daily dosing (10mg, 15mg).

A total of 88 peope with AS were recruited to the study and assessments completed included were adverse events, global symptoms, behaviour scales and sleep diaries.

The primary endpoint of the study was met in that the agent was safe and tolerable as measured by the adverse events.  Some exploratory end points were assessed at 12 weeks with global functioning AS assessed by a Clinician Global Impression-improvement (CGI-I) was statistically different between placebo and the treatment groups, with a 27.4% difference being reported.

It is recognised in their studies that behaviour scales need to be altered to consider non-verbal nature of AS.  Additional data is presented in 2 weeks at the international conference for American Academy of Child and Adolescent Psychiatry.