This presentation covers topics such as history, prevalence, genetics, diagnosis and treatment for Angelman Syndrome (AS). With more emphasis on the genetics, this presentation will explain how maternal 15q deletion and/or paternal disomy leads to the "puppet-like" features which are exclusive for AS. Hope you will get enough information from the slides about AS. (This is a presentation that was done with the help of my classmate Sindhu J. R., initially for her class presentation.)

1. ANGELMAN SYNDROME (AS)
Sindhu J. R.
RA1711014010118

2. What is Angelman Syndrome ?
• Angelman Syndrome is a complex genetic disorder that primarily affects the nervous system.
• AS can be hereditary or non-hereditary (sporadic or restricted to somatic cell lines)
• Angelman Syndrome also called as Happy Puppet Syndrome.
• Males and females are affected with equal frequency.
• Characteristic features include delayed development, intellectual disability, severe speech impairment,
ataxia, epilepsy, microcephaly, unusually fair skin with light-colored hair, scoliosis, ‘coarse’ facial features,
etc. Life expectancy: nearly normal.
• Children with AS typically have a happy, excitable behavior with frequent smiling, laughter and hand-
flapping movements. Hyperactivity, a short attention span and a fascination with water are common. Most
affected children also have sleeping difficulties and need less sleep than usual. With age, they become less
excitable and sleeping problems tend to improve.

3. HISTORY
1964: First observed by Dr. Harry Angelman on 3 handicapped children.
1965: Harry Angelman published his findings in a report entitled Puppet
Children.
1982: Name changed from ‘Happy Puppet’ to Angelman Syndrome by
Williams and Frias.
1987: Discovery of a genetic marker for AS - an absent genetic code on
maternal chromosome 15
1997: The cause of AS discovered by Dr. Joseph Wagstaff and Dr. Arthur
Beaudt – mutation or deletion in the UBE3A gene, specifically in maternal
chromosome 15.

4. 1998: Transgenic mice with absent maternal UBE3A created to illustrate motor and learning deficits in
addition to seizures.
2007: AS mouse model shows that neurological defects can be reversed by decreasing levels of alpha-
CaMKII inhibitory phosphorylation.
2010: Discovery of another gene mutation in TC4 gene in a small number of clinically diagnosed patients
with no identifiable genetic alteration in UBE3A.
2010: Protein named “Arc” identified as a target of AS gene product.
HISTORY

5. PREVALENCE
• AS affects 1 in 12,000 to 20,000 people, worldwide.
• Europe:
Denmark - 1:10,000
Sweden - 1:20,000
• Western Australia - 1:40,000
• The exact prevalence of AS has not been studied in India.

6. CLINICAL SYMPTOMS
• Developmental delays, first noted at around age 6 mo.
• Speech impairment
• Balance disorder (ataxia)
• Frequent smiling and laughter
• ‘Coarse’ facial features
• Recurrent seizures (epilepsy)
• Being restless, having short attention span, hyperactivity
• Microcephaly
• Scoliosis
• Unusually fair skin with light-colored hair

8. GENETIC CAUSES OF THE DISEASE
GENES ASSOCIATED WITH AS
1. UBE3A – ubiquitin protein ligase E3A gene (the main gene associated with AS)
2. OCA2 – oculocutaneous albinism II melanosomal transmembrane (P) protein-coding gene

9. GENETIC CAUSES OF THE DISEASE
• Many symptoms of AS result from the loss of function of a gene called ubiquitin protein ligase E3A
(UBE3A). Locus of UBE3A: 15q11.2
• UBE3A gene codes for UBE3A which are enzymes that target other proteins to be degraded within cells by
ubiquitination. Proteasomes recognize and digest these ubiquitin-tagged proteins. This process is essential
for the normal functioning of cells.
• In some people with AS, the loss of gene called oculocutaneous albinism II melanosomal transmembrane
protein (OCA2). Locus of OCA2: 15q12-q13.1
• OCA2 gene codes for a protein called P protein, which is located in melanocytes. Although the exact
function of P protein is unknown, it is essential for normal pigmentation and is likely involved in the
production of melanin. In melanocytes, P protein is involved in the transport of molecules in and out of
melanosomes (where melanin is synthesized), thus regulating melanosomal pH.

10. GENETIC CAUSES OF THE DISEASE
GENETICS OF UBE3A GENE – GENOMIC IMPRINTING
• People normally inherit one copy of UBE3A gene from each parent.
• Both copies of this gene are active in many of the tissues, but in certain areas of the brain, only maternal
UBE3A is active. This parent-specific gene activation is caused by a phenomenon called genomic
imprinting.
• If the maternal UBE3A copy is lost because of chromosomal change or gene mutation, the person will have
no active copies of the gene in some parts of the brain.

11. GENETIC CAUSES OF THE DISEASE
GENETIC CAUSE – mainly due to MATERNAL CHROMOSOME 15 DELETION OR UNIPARENTAL DISOMY
• Several different genetic mechanisms can inactivate or delete the maternal copy of the UBE3A gene.
• Most cases of AS (~70%) occur due to deletion of segment 15q11.2-q13 in the maternal chromosome 15.
• ~11% of AS is caused by a mutation in the maternal UBE3A copy.
• A very small percentage (3-7%) of cases of AS is due to the inheritance of two copies of paternal chromosome
15. This phenomenon is called uniparental disomy (UPD), here, paternal UPD.
• Rarely, AS can also be caused due to translocation or mutation or other defect in the region of DNA that
controls activation of UBE3A gene. These genetic changes can abnormally inactivate UBE3A or other genes on
the maternal chromosome 15 (imprinting defects).
• The cause of ~10-15% of cases of AS is unknown. Changes involving other genes or chromosomes may be
responsible

12. GENETIC CAUSES OF THE DISEASE

13. GENETIC CAUSES OF THE DISEASE

14. GENETIC CAUSES OF THE DISEASE

15. GENETIC CAUSES OF THE DISEASE
INHERITANCE PATTERN OF AS
• Most cases of AS are non-inherited, particularly those caused by a deletion in the maternal chromosome 15 or
by paternal UPD.
• These genetic changes occur as random events during gametogenesis or in early embryonic development.
• Affected people typically have no familial history of AS.
• Rarely, a genetic change responsible for AS can be inherited. For example, it is possible for a mutation in the
UBE3A gene or in the nearby region of DNA that controls gene activation to be passed on from one generation
to the next.

16. DIAGNOSIS
• Physical examination , Articulation test
• Fluorescence in situ hybridization (FISH)
• Methylation-specific FISH, MS-MPLA (Methylation-specific Multiplex Ligation-dependent Probe Analysis)
• Deletion/duplication analysis, Imprinting analysis
• Detection of homozygosity, UPD study
• Exon sequencing

17. TREATMENT AND MANAGEMENT
• Routine management of feeding difficulties, constipation, gastroesophageal reflux and strabismus.
• Anti-epileptic medication to control seizures like topiramate, medication to treat obstructive sleep apnea like
modafinil, psychiatric medication like N-acetylcysteine (NAC).
• Physiotherapy, occupational therapy, speech therapy, etc.
• Surgical intervention for scoliosis and other chiropractic procedures.
• Evaluation of older children for obesity associated with excessive appetite.
• Avoid carbamezapine, vigabatrin and tigabine as they may exacerbate (worsen) seizures.

18. FAMOUS PEOPLE AFFECTED
James Farrell, son of actor Collin Farrell Dave Henderson, major League Baseball player

19. GROUPS WORKING ON THE DISEASE
• Angelman Syndrome Foundation
• FAST (Foundation for Angelman Syndrome Therapeutics)
• ASSERT (Angelman Syndrome Support Education and Research Trust), UK
• Canadian Angelman Syndrome Society