1. Scientific Overview of Angelman Syndrome and Its Social Implications Chelsea A Coburn, Melissa D Connell, Maureen P Kane, Jeff Min, and Xueying Wang University of Florida, Gainesville, FL 32611 Abstract Angelman Syndrome (AS) is a neuro-genetic disorder that occurs in 1 in 15,000 live births 10. 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 5. 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 10. Further scientific breakthroughs and increased social awareness is crucial in resolving controversial subjects of AS such as prenatal testing 8. Mendelian PHENOTYPE/CLINICAL CHARACTERISTICS 1,2 Significant developmental delay with cognitive impairment Overactive, exuberant, sociable, and happy demeanor Sleep abnormalities, and frequent laughter to minimal stimulus Presence of hypotonia in body trunk, and hypertonia in extremities Seizures in about 90% of patients, onset in first one to three years Large wide mouth/teeth, prominent pointy chin with flat midface Life span up to 70 years and behavioral problems improve with age Abnormalities in muscle tone lead to stiff and ataxic METHOD OF INHERITANCE Gene of interest: UBE3A gene on chromosome 15 Errors, failure to express, or the lack of maternal chromosome result in AS Recurrence in families: Male with silent mutant chromosome may pass it to his daughter, whose progeny have 50% chance of AS MECHANISM 4 90% of AS patients have little or no UBE3A gene expression due to a deletion of the 15q11 to the 15q13 region on the maternal chromosome 15. The gene UBE3A codes for an E3-ubiquitin protein ligase. The function of UBE3A is to tag proteins that need to be proteolysed by proteasomes. Ubiquitin proteolysis may be involved with synaptogenesis and long-term memory, thus deletion of the UBE3A gene may be detrimental to the brain’s maturation process. The rest 10-15 % of AS patients, suffer from a mutant UBE3A gene. The mutations include: Insufficient amount of DNA methylation to induce expression of UBE3A Inheritance of both chromosome 15’s from the father(Uniparental disomy). Uniparental disomy results from inheritance of both chromosomes from one parent, instead of one from each. It is possible that chromosome of both parents were present until the maternal chromosome was pushed out when cell division occurred; a cell is not feasible if there are three chromosome 15s present. Mutation of maternal chromosomes. Responsible for families with more than one AS patients. Japanese researchers believe there may be a link to mutants in the maternal chromosomes which turns off the gene expression Deletions of the 15q11 to 15q13 section of the chromosome 15 and a mutant chromosome which has a low amount of methylation have been known to cause the most brutal symptoms such as: poor communication abilities, more seizures, and microcephaly. Mechanism Summary 7 Molecular CLINICAL TESTING 5, 11 : GENETIC TESTING 8 : Step 1: Methylation Test: test for methylation pattern present in AS. Diagnosis is confirmed by positive results on 3 types of genetic causes. Step 2: FISH test: Test for deletion by chromosomal study to find small changes Step 3: RFLP analysis : Testing the lineage of chromosome 15. If only from one parent, then cause of AS is confirmed to be uniparental disomy. If from two parents, then the cause is imprinting. Step 4: Imprinting center mutation: precise changes on chromosome 15. Step 5: UNFE3A Screening: If methylation test is normal and AS is still suspected, the UNFE3A gene is screened for small changes. Changes are detected in 20% of AS patients and 80% of familial AS patients. Step 6: Consider other possibilities : If none of the above is positive, AS is unlikely, thought not impossible. Plan for new tests with neurologist 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 2 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 having a daughter with AS 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 handle the physical/hormonal changes of pregnancy 10 -Person with AS may not be fit for parenthood due to the need of assistance -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. 3 Reference 1.Butler MG. “Genomic imprinting disorders in humans: a mini-review.” J Assist Reprod Genet 21 Oct. 2009. 2.Carter MO, James HS Jr. “Imprinting Disorders and Assisted Reproductive Technology.” Seminars in Reproductive Medicine 27.5 (2009): 418-428. 3.Cassidy S, Schwartz S. “Prader-Willi and Angelman Syndromes: Disorders of Genomic Imprinting” Medicine 77.2 (1998): 140-151. 4.Dan B. “Angelman Syndrome: Current Understanding and Research Prospects.” Epilepsia 50.11 (2009): 2331– 2339. 5.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. 6.“Genetic Diagnostic Testing.” Angelman Syndrome Foundation. 29 Nov. 2009. 7.“Genetic Mechanisms that Cause AS.” Angelman Syndrome Foundation. 29 Nov. 2009. 8.James H, Clayton-Smith J. “Genetic Testing For Angelman Syndrome.” Angelman Syndrome. InternAnalysis. 29 Nov. 2009. 9.Lossie AC, Driscoll DJ. “Transmission of Angelman syndrome by an affected mother.” Genet Med 1.6 (1999): 262- 6. 10.“Stay Informed.” Angelman Syndrome Foundation. 29 Nov. 2009. 11.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. 12.Williams C A. “Neurological aspects of the Angelman syndrome.” Brain and Development, 27.2 (2005): 88-94. Discussion Syndrome 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 3. 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 future 4. Figure 1. Four mechanisms which lead to AS. 7 100% Frequent laughter/smile; happy demeanor; excitable personality, Uplifted hand-flapping/waving movements; hyper motor behavior Delayed development Movement/balance disorder, with tremors in limbs Lacking in verbal skills with stronger receptive communication 80% Disproportionate growth in head circumference Seizures Abnormal EEG patterns 10 20-80% Frequent drooling; protruding tongue Attraction to/fascination with water Increased sensitivity to heat Abnormal sleep wake cycles and diminished need for sleep Figure 2. Six steps of testing in diagnosing AS 6 Deletion of maternal UBE3A (68%) Mutation of maternal UBE3A(13%) Uniparental disomy (3%) Imprinting defect (6%)