What is Angelman Syndrome?

Angelman Syndrome (AS) is a rare neurogenetic disorder that affects approximately one in 15,000 people – about 500,000 individuals worldwide. Children and adults with Angelman syndrome typically have balance issues, motor impairment and debilitating seizures. Some individuals never walk. Most do not speak. Disrupted sleep cycles also can be a serious challenge to the individual and caretakers.

Individuals with Angelman syndrome require continuous care and are unable to live independently, and they have a normal life expectancy. Foundation for Angelman Syndrome Therapeutics (FAST) is the charity organisation that was founded in 2008 in the USA with a mission to cure Angelman syndrome. Today, with operations also in Australia, Canada, France, Italy, Poland, Spain and here in the UK, FAST has become the largest non-governmental funder of AS research.

Angelman Syndrome is caused by a disruption in the UBE3A gene on chromosome 15, a gene essential for brain function. In most cells, both the maternal and paternal copies of the UBE3A gene are active. However, in neurons within the brain, the paternal copy is naturally silenced, leaving the maternal copy responsible for producing the UBE3A protein. When the maternal gene is missing or not functioning properly, it results in the symptoms characteristic of Angelman Syndrome.

Several genetic mechanisms can result in the loss of function of the maternal UBE3A gene:

Deletion: The most common cause, where a segment of the maternal chromosome 15, including the UBE3A gene, is missing.
UBE3A Mutation: Changes or mutations in the maternal UBE3A gene that render it nonfunctional.
Uniparental Disomy (UPD): Both copies of chromosome 15 are inherited from the father, resulting in no active UBE3A gene in neurons.
Imprinting Center Defect (ICD): Defects in the imprinting centre on chromosome 15 lead to the silencing of the maternal UBE3A gene.

These genetic changes disrupt the production of the UBE3A protein in the brain, leading to the developmental, motor, and communication challenges associated with Angelman Syndrome. By understanding these mechanisms, researchers are working to develop therapies that target and restore UBE3A function, offering hope for individuals and families affected by this condition.

Angelman Syndrome is characterised by a unique set of symptoms that affect development, motor skills, and behaviour. While the severity of these symptoms can vary, they often include:

Developmental Delays: Significant delays in reaching milestones such as sitting, walking, or speaking, often noticeable within the first year of life.
Speech Impairments: Most individuals have little to no speech, relying on gestures, vocalisations, or alternative communication methods.
Movement and Balance Issues: Ataxia (impaired coordination), tremors, and difficulty with balance are common, with some individuals unable to walk independently.
Seizures: Epileptic seizures affect the majority of individuals, typically beginning between ages 2 and 3.
Sleep Disorders: Disrupted sleep patterns, including difficulty falling or staying asleep, often impact both individuals and their caregivers.
Behavioural Traits: Frequent laughter, smiling, and an excitable personality are hallmark features, alongside a fascination with water and a tendency to hyperactivity.

Additional physical traits may include a flattened back of the head, light hair and skin (in some genetic subtypes), and an unusually wide mouth with widely spaced teeth. Understanding these symptoms is essential for early diagnosis, effective management, and targeted interventions to improve the quality of life for those living with Angelman Syndrome.

This interactive repository serves as a dynamic, visual tool for exploring AS literature. Developed to assist researchers, clinicians, and stakeholders, it organises publications, studies, and reviews in an accessible network, where relationships among clinical presentation, genotype, model of study, and FAST pillar become immediately clear.

Key Features:
Visual Mapping: Our Kumu repository organises literature through visual maps, making it easy to identify connections between articles, authors, and topics.

Filter and Focus Options: Filter content by age, FAST pillar, organism of study, genotype, phenotype, study type, or specific keywords to dive into particular areas of interest.

Collaborative Potential: The repository encourages a collaborative environment, making it easy to share insights and discuss new ideas with colleagues or identify gaps in the research where research is critical.

Coming soon: As this is an evolving repository, newly published work will be added when available. We are excited to be adding additional categorization groups including 1. Therapeutic modality, 2. Natural History Study, 3. Drug delivery, 4. Biomarkers and endpoints, 5. Clinical assessments (EEG, sleep, seizure, ORCA, Bayley, Vineland, etc.), 6. Economic burden, 7. Newborn screening, 8. Model genotype, 9. Age of model, and 10. Keystone publications that established a proof of concept for therapeutic approach.

Whether you’re delving into emerging research trends, reviewing foundational studies, or exploring a niche within AS, this repository aims to facilitate deeper understanding and inspire impactful discoveries. Dive in, explore the FAST literature repository, and let it serve as a guide for your next research endeavors.

Managing Angelman Syndrome requires a comprehensive, multidisciplinary approach to address the diverse needs of individuals affected by the condition. While there is currently no cure, the following standards of care help improve quality of life and manage symptoms effectively:

Medical Management

Regular monitoring and treatment for seizures, gastrointestinal issues, and sleep disturbances. Anti-epileptic medications are often prescribed for seizure control, while melatonin or other interventions may assist with sleep regulation.

Physiotherapy

ailored exercises to improve motor skills, balance, and coordination, helping individuals achieve their highest level of mobility.

Speech and Communication Therapy

Focus on alternative and augmentative communication (AAC) methods, such as picture boards, sign language, or communication devices, to aid non-verbal individuals in expressing themselves.

Occupational Therapy

Activities to enhance fine motor skills, independence in daily tasks, and sensory integration, often customised to the individual’s developmental stage.

Behavioural and Educational Support:

Strategies to address hyperactivity, attention challenges, and behavioural traits, while fostering learning through specialised education plans.

Nutritional and Gastrointestinal Care

Regular assessments to address feeding difficulties, reflux, or constipation, with nutritional plans tailored to meet individual needs.

Sleep Interventions

Creating structured bedtime routines and, where necessary, using medications or therapies to improve sleep patterns.

Collaborating with healthcare professionals, therapists, educators, and families ensures a holistic care approach. Early intervention and consistent support are key to helping individuals with Angelman Syndrome lead fulfilling lives.

The world of Angelman Syndrome can involve complex medical and scientific language. This glossary is here to help you make sense of key terms and concepts, empowering you with the knowledge to better understand the condition, its management, and ongoing research. Explore the definitions below to deepen your understanding and navigate this journey with confidence.

Adeno-Associated Virus - Gene Therapy (AAV-GT)

An in-vivo therapeutic approach that delivers a functional copy of the UBE3A gene directly into brain cells (neurons) using a viral vector known as Adeno-Associated Virus.

Allele

One of two or more versions of a gene located at a specific position on a chromosome.

Antisense Oligonucleotides (ASO)

Modified RNA or DNA molecules designed to bind to the UBE3A antisense transcript (UBE3A-ATS), inhibiting its function and thereby allowing expression of the paternal UBE3A gene.

Artificial Transcription Factors/Zinc Fingers (ATF-ZF)

Custom-designed regulatory proteins that target and inhibit the UBE3A-ATS, enabling activation of the paternal UBE3A gene in neurons.

Biomarker

A measurable biological indicator, such as EEG delta power or UBE3A protein levels in cerebrospinal fluid, used to assess the presence or progression of a disease.

Brain-Derived Neurotrophic Factor (BDNF)

A protein essential for learning and memory; found to be deficient in individuals with Angelman Syndrome, making it a potential target for therapeutic intervention.

Central Nervous System (CNS)

Comprises the brain and spinal cord, serving as the primary control center for the body.

Clinical Trial

A research study conducted to evaluate the efficacy and safety of medical interventions in humans.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)

A gene-editing technology that uses a guide RNA to direct an enzyme to a specific DNA or RNA sequence, enabling targeted modifications such as activating the paternal UBE3A gene.

Delivery

The method by which a therapeutic agent is administered to the central nervous system, including routes like intracerebral, spinal, or intravenous, and the carriers used, such as viral vectors or stem cells.

DNA (Deoxyribonucleic Acid)

The molecule that carries genetic instructions for the development, functioning, growth, and reproduction of all known organisms.

Downstream Targets

Symptomatic therapeutic strategies focusing on molecular pathways and proteins affected by the absence of functional UBE3A protein.

Dystonia

A movement disorder characterised by involuntary muscle contractions, leading to repetitive movements or abnormal postures.

E3 Ubiquitin Protein-Ligase Gene (UBE3A) Mouse

The gene encoding the UBE3A protein in rodent models, used to study the function and regulation of this protein.

E3 Ubiquitin Protein-Ligase Mouse Protein (UBE3A) Mouse

The protein produced by the UBE3A gene in rodents, serving functions analogous to the human UBE3A protein.

Electroencephalogram (EEG)

A test that detects electrical activity in the brain using small electrodes attached to the scalp, often used to identify abnormalities such as seizures.

Electrophysiology

The study of the electrical properties of biological cells and tissues, crucial for understanding neuronal function and dysfunction.

Exon

A segment of a DNA or RNA molecule containing information coding for a protein or peptide sequence.

Gene Therapy

A technique that modifies a person’s genes to treat or cure disease, including approaches like AAV-GT.

Genotype

The genetic constitution of an individual organism, often influencing specific traits or conditions.

Haploinsufficiency

A condition in which a single functional copy of a gene does not produce enough of a gene product (typically a protein) to bring about a normal condition, leading to an abnormal state.

In-Vivo

Research or treatment conducted within a living organism.

In-Vitro

Research or treatment conducted outside of a living organism, typically in a laboratory setting.

Intracerebroventricular (ICV)

Administration of substances directly into the brain’s ventricular system.

Intrathecal (IT)

Administration of substances into the spinal canal, specifically into the cerebrospinal fluid.

Knockout Mouse

A genetically engineered mouse in which one or more genes have been turned off through a targeted mutation, used to study gene function.

Messenger RNA (mRNA)

A type of RNA that conveys genetic information from DNA to the ribosome, where proteins are synthesised.

Methylation

A chemical modification of DNA that can regulate gene expression without altering the DNA sequence.

Neurogenetic Disorder

A disorder caused by abnormalities in the genes that affect the nervous system.

Neurons

Nerve cells that transmit information through electrical and chemical signals.

Phenotype

The set of observable characteristics resulting from the interaction of an individual’s genotype with the environment.

Promoter

A region of DNA that initiates transcription of a particular gene.

Protein

Large, complex molecules that play many critical roles in the body, made up of one or more chains of amino acids.

RNA (Ribonucleic Acid)

A nucleic acid present in all living cells, acting as a messenger carrying instructions from DNA for controlling the synthesis of proteins.

Seizure

A sudden, uncontrolled electrical disturbance in the brain, causing changes in behavior, movements, feelings, or consciousness.

Symptomatic Therapy

Treatment aimed at alleviating the symptoms of a disease rather than addressing its cause.

Transcription

The process of copying a segment of DNA into RNA.

Translation

The process by which a protein is synthesized from the mRNA sequence.

UBE3A Antisense Transcript (UBE3A-ATS)

A naturally occurring RNA molecule that silences the paternal copy of the UBE3A gene in neurons.

An Introduction to Angelman Syndrome

Prof Art Beaudet

There are many disorders that will not be cured or treated in our lifetime, but Angelman Syndrome will not be one of them. at FAST UK