Angelman Syndrome Essay
Diarmuid Sugrue
Angelman Syndrome
SYMPTOMS
Angelman Syndrome is a neuro-genetic disorder involving the chromosomal region 15q, between positions 11-13. The symptoms primarily include intellectual development retardation, epilepsy, speech impairment, ataxia, and persistent laughing or smiling.
CAUSATIVE MUTATIONS
A healthy individual receives 2 copies of the 15 chromosome, one maternal and one paternal.
The chromosomal region 15q11-13 (base pairs 23,133,488-23,235,220), contains the gene UBE3A. However in brain, UBE3A is expressed differently due to epigenetic imprinting, the mechanism for which is DNA methylation. The maternal allele is expressed and the paternal imprinted. Therefore any defect in the maternal allele, caused …show more content…
by micro-deletion, paternal disomy, translocation, or single gene mutation, can cause AS. The most common cause is a 4Mb maternal deletion on the chromosome, inhibiting UBE3A expression.
CONSEQUENCES OF MUTATIONS
UBE3A codes for E6-AP, ubiquitin protein ligase.
Mutations in UBE3A result in truncated and denatured E6-AP production in the brain. This causes the failure to tag proteins for degradation with ubiquitin, and therefore the failure of proteasomes to recognize and digest them. This particularly affects the hippocampus and cerebellum, where the maternal allele is almost completely exclusive. This in turn causes the characteristic physiological symptoms of the disease, including difficulty converting short to long term memory (hippocampus), motor, language, and attention span difficulties (cerebellum). Gene mutations correlate to the least affected patients, and chromosomal deletion to the most …show more content…
affected.
TREATMENT/PROGNOSIS
There is currently no cure, and severity varies greatly. Melatonin and anticonvulsants can control sleep and epilepsy respectively. However hyperactivity and seizures tend to decrease with age. Physical, occupational and communication therapies improve prognosis. Patients tend to develop strong non-verbal methods of communication, and their ability to understand is much greater than their ability to express. Although EEG’s remain abnormal, AS is not degenerative, and they tend to be less acute over time. Life expectancy is near average.
WORD COUNT: 294
REFERENCES
Charles A.
Williams, M.D, Sarika U. Peters, Ph.D. Stephen N. Calculator, Ph.D. “Facts about Angelman syndrome 7th Edition January 1, 2009”. Angelman syndrome Foundation inc.
Magenis, RE; Brown MG, Lacy DA, Budden S, LaFranchi S. (1987). "Is Angelman syndrome an alternate result of del(15)(q11q13)?". Am J Med Genet. 28 (4): 829–38.
Sadler, T.W. “Langman’s Medical Embroyology 8th Ed.” Lippincott Williams 2000, 1:14-15
Larsen, William J “Human Embroyology 3rd Ed.” Churchill Livingstone 2001, 2:48-49
Weeber E, Levenson J, Sweatt J (2002). "Molecular genetics of human cognition". Mol Interv 2 (6): 376–91, 339
Buntinx IM, Hennekam RC, Brouwer OF et al. (March 1995). "Clinical profile of Angelman syndrome at different ages". American Journal of Medical Genetics 56 (2): 176–83.
Laan LA, den Boer AT, Hennekam RC, Renier WO, Brouwer OF (1996). "Angelman syndrome in adulthood". Am. J. Med. Genet. 66 (3): 356–60
Williams C (2005) “Neurological aspects of the Angelman syndrome” Brain & Development 27: 88–94
www.angelman.org
Angelman Syndrome
SYMPTOMS
Angelman Syndrome is a neuro-genetic disorder involving the chromosomal region 15q, between positions 11-13. The symptoms primarily include intellectual development retardation, epilepsy, speech impairment, ataxia, and persistent laughing or smiling.
CAUSATIVE MUTATIONS
A healthy individual receives 2 copies of the 15 chromosome, one maternal and one paternal.
The chromosomal region 15q11-13 (base pairs 23,133,488-23,235,220), contains the gene UBE3A. However in brain, UBE3A is expressed differently due to epigenetic imprinting, the mechanism for which is DNA methylation. The maternal allele is expressed and the paternal imprinted. Therefore any defect in the maternal allele, caused …show more content…
by micro-deletion, paternal disomy, translocation, or single gene mutation, can cause AS. The most common cause is a 4Mb maternal deletion on the chromosome, inhibiting UBE3A expression.
CONSEQUENCES OF MUTATIONS
UBE3A codes for E6-AP, ubiquitin protein ligase.
Mutations in UBE3A result in truncated and denatured E6-AP production in the brain. This causes the failure to tag proteins for degradation with ubiquitin, and therefore the failure of proteasomes to recognize and digest them. This particularly affects the hippocampus and cerebellum, where the maternal allele is almost completely exclusive. This in turn causes the characteristic physiological symptoms of the disease, including difficulty converting short to long term memory (hippocampus), motor, language, and attention span difficulties (cerebellum). Gene mutations correlate to the least affected patients, and chromosomal deletion to the most …show more content…
affected.
TREATMENT/PROGNOSIS
There is currently no cure, and severity varies greatly. Melatonin and anticonvulsants can control sleep and epilepsy respectively. However hyperactivity and seizures tend to decrease with age. Physical, occupational and communication therapies improve prognosis. Patients tend to develop strong non-verbal methods of communication, and their ability to understand is much greater than their ability to express. Although EEG’s remain abnormal, AS is not degenerative, and they tend to be less acute over time. Life expectancy is near average.
WORD COUNT: 294
REFERENCES
Charles A.
Williams, M.D, Sarika U. Peters, Ph.D. Stephen N. Calculator, Ph.D. “Facts about Angelman syndrome 7th Edition January 1, 2009”. Angelman syndrome Foundation inc.
Magenis, RE; Brown MG, Lacy DA, Budden S, LaFranchi S. (1987). "Is Angelman syndrome an alternate result of del(15)(q11q13)?". Am J Med Genet. 28 (4): 829–38.
Sadler, T.W. “Langman’s Medical Embroyology 8th Ed.” Lippincott Williams 2000, 1:14-15
Larsen, William J “Human Embroyology 3rd Ed.” Churchill Livingstone 2001, 2:48-49
Weeber E, Levenson J, Sweatt J (2002). "Molecular genetics of human cognition". Mol Interv 2 (6): 376–91, 339
Buntinx IM, Hennekam RC, Brouwer OF et al. (March 1995). "Clinical profile of Angelman syndrome at different ages". American Journal of Medical Genetics 56 (2): 176–83.
Laan LA, den Boer AT, Hennekam RC, Renier WO, Brouwer OF (1996). "Angelman syndrome in adulthood". Am. J. Med. Genet. 66 (3): 356–60
Williams C (2005) “Neurological aspects of the Angelman syndrome” Brain & Development 27: 88–94
www.angelman.org