Angelman SyndromeIts history, causes, symptoms, treatment,

diagnosis, and controversies

by Gina ElbertFebruary 2013

History1965: Dr. Harry Angelman described three “Puppet Children”

Named them after the painting by Giovanni Francesco CarotoDescribed common symptoms:

Stiff, jerky gaitAbsent speechExcessive laughterSeizures

Eventually, renamed Angelman Syndrome (A.S.)Progress was made in identifying chromosomal causes in 1980s

How does Angelman Syndrome affect those who have it?Developmental DelayAtaxia, or problems with muscle coordinationUnique behavior: frequent laughter/smiling, apparent happy demeanor, excitable, hand-waving movementsSevere speech impairmentMost (80% and above) have seizures, disproportionate growth of the head, and abnormal EEG readingsSome (20-80%) have tongue problems, drooling, wide mouths, increased sensitivity to heat, abnormal sleep cycles, and many other symptomsLife expectancies are normal

What are the symptoms?

How does Angelman Syndrome affect the patients’ families?Patients require lifelong careMedical bills can be very highNot all students are capable of being educated in a general classroom; many need a resource room or a special schoolMost need an aide at school and different types of therapy

What are the symptoms?

All possible mechanisms are related to maternal chromosome 15 in the child, in gene UBE3AIn all paternal sperm, UBE3A is turned off, so that the active UBE3A gene in the offspring is on the maternal chromosomeThe possible problems are:

Deletion of UBE3A (70% frequency) UBE3A is turned off (its imprinting center does not work) (3-5% frequency)A mutation in UBE3A (5-10% frequency)The child inherits two paternal chromosomes instead of one paternal and one maternal chromosome (2-3% frequency)Often, the cause is unknown (10-15% frequency)

What causes the disease?

What causes the disease?

People with different genetic causes tend to have certain symptoms more than others

For example, those with a deleted UBE3A gene tend to have more seizures, hypopigmentation (skin, hair, and eyes), abnormal head sizes, motor difficulties, and language impairment

The gene UBE3A is responsible for the ubiquitin-proteasome pathway, a process closely related to brain function that can impair it if it works incorrectly.

This pathway helps degrade proteinsE6-AP (coded for by UBE3A) is involved in transferring ubiquitin to the target protein

What causes the disease?

There is no cure, because Angelman Syndrome is geneticTo help alleviate symptoms, there are several options:

Medications to prevent seizuresPhysical therapy to treat motor problemsCommunication therapy to help verbal problems and teach alternative forms of communicationBehavioral therapy to ease hyperactivity and attention problems

How can it be treated?

Blood Test for DNA Methylation

How is it identified or diagnosed?

If normal results, then test UBE3A for mutation.

If abnormal results, then FISH or CGH study (for deletion) and/or DNA marker analysis (for duplicated paternal chromosome).

If both are normal, then an imprinting defect is assumed.

If results are normal, then A.S. is unlikely, but there is about a 10% chance that it is the problem.

The child will only have A.S. if they inherit an inactive or mutated gene from their mother

If they inherit a mutant gene from their father, they will not have the disease, because the UBE3A gene is turned off on the paternal chromosome

Sample pedigree:

Inheritance of Angelman Syndrome

However, most people get A.S. from a spontaneous mutation or deletion, not by inheritanceThe below diagram explains the percent chance of offspring inheriting A.S. in four scenarios:

Inheritance of Angelman Syndrome

Most ethical problems related to A.S. are also related to other neurological disorders; there are little or no ethical problems that relate only to A.S.How ethical are the clinical trials?

Problems can arise when a drug is found to help the experimental group, as then it is unfair to withhold it from the control groupIf the experimental group is harmed by the drug, then it is unethical to continue the studyTo what extent should trial data be available to parents and patients?

What are the bioethical considerations?

Calculator, Stephen, et al. “Facts about Angelman Syndrome.” Angelman Syndrome Foundation. 7th Edition. Online. 1 January, 2009. 21 February, 2013. <http://www.angelman.org/_angelman/assets/File/facts%20about%20as%202009%203-19-10.pdf>

Caroto, Giovanni Francesco. Boy with a Puppet. 16th Century. Museo di Castelvecchio, Verona.

“Ethical Considerations in Rare Disease Research.” Angelman Syndrome Foundation. Online. 2012. 21 February, 2013. <http://www.angelman.org/2012-dinner-debate/>

Mayo Clinic staff. “Angelman Syndrome.” Mayo Clinic. Online. 17 January, 2012. 21 February, 2013. <http://www.mayoclinic.com/health/angelman-syndrome/DS01048>

Unknown. “Angelman Syndrome.” Genetics Home Reference. Online. 18 February, 2013. 21 February, 2013. <http://ghr.nlm.nih.gov/condition/angelman-syndrome>

Unknown. Untitled. 2013. Angelman Syndrome Foundation. Online. 21 February, 2013. <http://www.angelman.org/_angelman/cache/file/6E38350F-2EB3-4D38-8B845338F9516A68.jpg>

Unknown. Untitled. June 2008. The Tuscon Citizen. Online. 21 February, 2013. <http://tucsoncitizen.com/morgue/files/2008/06/l87035-1.jpg>

Bibliography