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Figure 2. Six steps of testing in diagnosing AS 6Scientific Overview of Angelman Syndrome and Its Social Implications Chelsea A Coburn, Melissa D Connell, Maureen P Kane, Jeff Min, and Xueying WangUniversity of Florida, Gainesville, FL 32611

Abstract

Angelman Syndrome (AS) is a neuro-genetic disorder that occurs in 1 in 15,000 live births. Since the initial diagnose by Dr. Harry Angelman in 1965, scientific advancements enable in depth analysis of the disorder at the molecular level. The cause of AS includes uniparental disomy, imprinting defect, and deletion or mutation of the maternal UBE3A gene on chromosome 15. Clinical and genetic tests are possible using the distinctive behavior markers displayed by AS patients collectively with sophisticated technology. There are no known cures for AS, and patients generally require life-long care; however many symptoms can be controlled by medication. Further scientific breakthroughs and increased social awareness is crucial in resolving controversial subjects of AS such as prenatal testing. Mendelian

PHENOTYPE/CLINICAL CHARACTERISTICS 1,2Significant developmental delay with cognitive impairmentOveractive, exuberant, sociable, and happy demeanorSleep abnormalities, and frequent laughter to minimal stimulusPresence of hypotonia in body trunk, and hypertonia in extremitiesSeizures in about 90% of patients, onset in first one to three yearsLarge wide mouth/teeth, prominent pointy chin with flat midfaceLife span up to 70 years and behavioral problems improve with ageAbnormalities in muscle tone lead to stiff and ataxic

METHOD OF INHERITANCEGene of interest: UBE3A gene on chromosome 15Lack of maternal chromosome, errors in maternal chromosome, or failure to express result in ASRecurrence in families: Male with silent mutant chromosome may pass it to his daughter, whose progeny have 50% chance of AS

MECHANISM

Deletion of maternal UBE3A gene (68%)Mutation of maternal UBE3A gene (13%)Uniparental disomy (3%)both chromosomes inherited from same parent as result of nondisjunctionImprinting defect (6%)Deletion/abnormality in imprinting center may cause failure to activate or silence the appropriate genesMolecular

CLINICAL TESTING 5:100%:Frequent laughter/smile; happy demeanor; excitable personality, Uplifted hand-flapping/waving movements; hyper motor behaviorDelayed developmentMovement/balance disorder, with tremors in limbsLacking in verbal skills with stronger receptive communication80%Disproportionate growth in head circumferenceSeizuresAbnormal EEG patterns 1020-80%Frequent drooling; protruding tongueAttraction to/fascination with waterIncreased sensitivity to heatAbnormal sleep wake cycles and diminished need for sleep

GENETIC TESTING 8:

Step 1: Methylation Test : Methylation pattern consistent of AS. If positive (abnormal), diagnosis is confirmed by testing for the 3 types of genetic causes.Step 2: FISH test: Tests for deletion. A chromosomal analysis which can detect small abnormalities.Step 3: RFLP analysis : Testing the lineage of chromosome 15. If found to only come from one parent, then cause of AS is confirmed to be uniparental disomy. If came from 2 parents, then the cause is imprinting.Step 4: Search for imprinting center mutations: Must test for precise change on chromosome 15. Step 5: UNFE3A Screening: If methylation test is normal and AS is still suspected due to clinical analysis, the UNFE3A gene is screened and small changes are searched for. Changes are detected in 20% AS patients (80% familial AS).Step 6: Consider other possibilities : If none of the above is found positive, AS is unlikely, thought not impossible. A new plan with neurologist is made, and/or wait for new tests. Ethical Legal Social Issues (ELSI):

Is there a cure for AS? NO, but medication can control symptoms of seizures, behavioral/sleep issues

Is there an increased risk of AS when using assisted reproductive technology? YES, some reports show increased chance of imprinting disorders in children conceived using assisted reproductive technology (ART). It is believed that maternal allele is more likely to be effected than paternal because of altered methylation of the female gamete. However, there is not enough of a risk or evidence to cease use of this technology

Can people with AS develop to be healthy reproducing adults? YES, mutation of chromosome 15 does not affect the reproduction system

Is it possible for an AS person to have children with AS? YES, there is one reported case of a women with AS passing it on to her daughter 9

What would happen if a woman with AS has a child? This is decision that needed to be made on a patient to patient basis Women with AS may not easily handle the physical/hormonal changes of pregnancy-A person with AS may not be fit for parenthood due to the need of assistance or support-Adoption is an option that could be considered if a child is conceived

Can prenatal testing be done to accurately determine if child will develop AS?YES, identification of the mutation or maternal methylation pattern in a fetus is possible. It can be used with successive pregnancies after having a child with AS. However, the ethical issue lies with the decision of what to do when parents are told they will have a child with AS. If parents consider termination options, then they have to deal with legal and moral issues of abortion. Reference

Butler MG. Genomic imprinting disorders in humans: a mini-review. J Assist Reprod Genet 21 Oct. 2009.Carter MO, James HS Jr. Imprinting Disorders and Assisted Reproductive Technology. Seminars in Reproductive Medicine 27.5 (2009): 418-428.Clayton-Smith J, Laan L. Angelman syndrome: a review of the clinical and genetic aspects. J Med Genet. 2003 Feb; 40(2):87-95.Dan B. Angelman Syndrome: Current Understanding and Research Prospects. Epilepsia 50.11 (2009): 23312339.Dittrich B, Robinson WP, Knoblauch H, et al. Molecular diagnosis of the Prader-Willi and Angelman syndromes by detection of parent-of-origin specific DNA methylation in 15q11-13. Human Genetics 90.3 (1992): 313-315.Genetic Diagnostic Testing. Angelman Syndrome Foundation. 29 Nov. 2009. < http://www.angelman.org/stay-informed/facts-about-angelman-syndrome---7th-edition/genetics-of-as/genetic-diagnostic-testing/>Genetic Mechanisms that Cause AS. Angelman Syndrome Foundation. 29 Nov. 2009. James H, Clayton-Smith J. Genetic Testing For Angelman Syndrome. Angelman Syndrome. InternAnalysis. 29 Nov. 2009. < http://www.armyofangels.org/angeltest.htm>Williams CA, Beaudet AL, Clayton-Smith J, et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A 140.5 (2006): 413-8.Williams C A. Neurological aspects of the Angelman syndrome. Brain and Development, 27.2 (2005): 88-94.

DiscussionSyndrome is gaining world wide attention through representation from parents of the patients. The increasing awareness and the establishment of support groups for care takers widens the social circle for individuals with AS. However, many individuals are falsely diagnosed with cerebral palsy or autism. Future studies will allow scientists and doctors to gain a deeper understanding of the molecular mechanisms of the disease, and consequently decrease the number of misdiagnosis. It is expected that further research in the field of gene therapy will lead to a possible cure for AS in the future3,4.

Figure 1. Four mechanisms which lead to AS. 71