The miracle of life is a never-ending interest of study and very difficult to grasp. The complexity of how our DNA is inherited, duplicated, mutated, and expressed varies in uncountable ways. Leon and Diane Rosenberg (2012) state that gene expression can be modified by changes in DNA structure or chemical modification of DNA, which in turn alters the fundamental function of a gene (p. 97). Although humans are almost 100% alike we are so different from one another. Genes depict our looks, eye color, height, temperament, and even blood pressure inherited from our parents.
During reproduction 23 pairs of chromosomes are inherited by our parents, which make up our DNA. Some of these unpredictable changes are called mutations. Mutations can occur during cell division or can be caused by mutagens that disrupt the normal function of our chromosomes. Disruption of our genes normal functions causes deviations in the formation of gametes, which are the cause of most genetic disorders in humans, such as the genetic disorder Angelman syndrome (AS). Characteristics of Angelman syndrome An English physician Dr. Harry Angelman first described the genetic condition Angelman syndrome in 1965.
Dr. Angelman coined AS characteristics as “Happy Puppet Syndrome” from a painting he saw while visiting Italy that reminded him of his patients with AS. Due to the complexity of Angelman syndrome (AS) and its genetic components, geneticists have found similarities and slight variations on how AS is expressed on each affected individual. AS characteristics are first most commonly seen at around 6mo to 12mo because many developmental milestones are not met. For example, a baby that is 12mo of age should be able to hold their head up and crawl. Another concern is a child’s sleeping pattern.
Children with AS have difficulty sleeping and need less sleep than normal. Lack of meeting these milestones, sleep disturbances, in addition to excessive smiling and excitement can be a base for clinical findings that match those with Angelman syndrome. The Genetics Home Reference (2016) interprets AS distinct features of this condition include mental disability, severe developmental delay, jerky movements, lack of muscle control and balance, spaced out teeth, microcephaly, epilepsy, speech impairment, seizures, and frequent laughter and smiling.
Most children with AS have an unusual happy attitude and flap their hands with excitement (p. 2). You can also find that children with AS have a fascination with water. Most children with AS are mobile by the age 2. 5 to 6yrs of age but some depend on a wheelchair for ambulation. Adam, Horsler, Mount and Oliver (2015) say that 10,000-12,000 children are born with AS and that they rely on medical attention to assist them with daily living activities such as eating, bathing and toileting needs for the rest of their lives because unfortunately their is no known treatment for this condition (pp. 624-2625).
Although some children with AS are impaired cognitively, some are able to communicate by pointing at objects, using charts or verbalizing two to three words. Puberty onset seems to present normally for adolescent AS patients. Also, AS patients appear healthy but often suffer from seizures, gastrointestinal reflux and constipation. All of these clinical findings severely impair the quality of life of a person with Angelman syndrome.
Eight percent of Angelman syndrome is not inherited but it is caused by a deletion or imprinting defect, but in very small cases it can be inherited because of a mutation in the maternal UBE3A and the likelihood of passing the affected gene on increases. Recognizing key characteristics that resemble Angelman syndrome helps physicians and parents seek help and care early on. Proper diagnosis of AS syndrome can significantly have an impact on the correct treatment and therapeutic care for improving the quality of life for a child with Angelman syndrome.
Diagnosis of Angelman syndrome Successful genetic diagnostic tools are available today due to the many contributions to research for Angelman syndrome. According the Angelman Project (2003) Dr. Charles Williams, an English, pediatrician, directed the University of Florida discovered a genetic “marker” for Angelman disorder in 1987. Dr. Williams and his team found a missing genetic code on a tiny portion of chromosome #15. In 1997, Dr. Joseph Wagstaff (Children’s Hospital, Boston) and Dr. Arthur Beaudet (Baylor College of Medicine) contributed to the research of Angelman syndrome by discovering a mutation on the UBE3A gene that was caused by a deletion (pp. 1-3).
Angelman syndrome is a genetic heterogeneous condition, meaning the maternal UBE3A gene deficit causes AS but it can also cause many other varying disorders similar to Angelman syndrome. To date, Angelman syndrome has four genetic causes that can be confirmed through genetic testing which are deletions, uniparental disomy, imprinting and mutation of the UBE3A gene. All four genetic diagnoses affect gene UBE3A on chromosome #15.
In order to provide proper treatment and therapeutic care for individual with AS, proper diagnosis must be confirmed by using some the genetic diagnostic tools that are offered. A child expressing core clinical findings that suggest the diagnosis of Angelman syndrome can be confirmed with testing that involves analysis of DNA. These tests can provide laboratory results that indicate whether Angelman syndrome is caused by a deletion, uniparental disomy, imprinting deficit or UBE3A mutation. An important and accurate test such as methylation analysis can confirm 70-80% of all cases of AS.
According to Robertson (2015), “DNA methylation is vital to a number of cellular processes such as embryonic development, X-chromosome inactivation, genomic imprinting, gene suppression, carcinogenesis and chromosome stability” (p. 2). Methylation analysis evaluates the status of a gene, and it tests whether a gene is expressed or not expressed. A positive laboratory result of a methylation test could mean a gene is inactivated which is dictated by epigenetics. Epigenetics controls gene function and it is responsible for the deficient expression of a gene or in other words, turning a gene to the “on” or “off” position.
In the case of Angelman syndrome, a positive methylation test can suggest deficient expression of the maternal UBE3A gene caused by a deletion, uniparental disomy (UPD) or imprinting defect on chromosome #15. Causes of Angelman Syndrome Our intricate DNA system has the ability to repair, rejuvenate, or destroy impaired genetic material. In most cases our body can detect that there is a deviation from the normal processes of cell formation and embryonic development and sends a signal to our body that the embryo wont survive resulting in a spontaneous miscarriage.
In some cases, the embryo miraculously survives, but lives with a genetic condition. Luk (2016) suggests that most people affected with AS do not have a history of Angelman syndrome in their family. Angelman syndrome most of the time is caused by an imprinting defect that inactivates the maternal UBE3A gene, detected on chromosome #15 (pp. 1-5) Normally we inherit one copy of the UBE3A from each parent and they are usually both active, but in certain parts of the brain only the inherited maternal UBE3A gene is active.
When a parent specific gene is activated it is called genomic imprinting. If the maternal UBE3A fails to activate caused by mutations or deletions of chromosome #15, a person will not have active copies of the UBE3A gene in certain parts of the brain causing Angelman syndrome characteristics. Deletions of maternal UBE3A causes this gene to lack crucial genetic information for instruction to function properly. The United States of Health & Human Services explains that “the UBE3A gene function plays an important role on how our brain receives and conducts and develops.
This gene is responsible for providing instructions for making a protein called ubiquitin ligase E3A. E3A’s are enzymes that target other proteins to be broken down” (p. 1). The maternal UBE3A gene carries instruction to degrade the protein ubiquitin ligase, which is maternally expressed in the brain if imprinted correctly. Mutations, UPD, and deletions of the UBE3A gene causes Angelman syndrome. If a deletion of the maternal UBE3A is found, it means that this spontaneous mutation has a missing piece of information on chromosome #15 which is not passed on from generation to generation.
In the case that AS is caused by uniparental disomy (UPD), both chromosome #15 come from the paternal side and the maternal chromosome #15 is non existent. Lacking chromosome #15 from the maternal side is crucial and severely impairs a child from developing. This happens when chromosome #15 is missing in the egg, thus the paternal chromosome #15 duplicates itself to complete the correct number of chromosomes. Imprinting deficit results when the maternal #15 chromosome is blank, the paternal chromosome #15 is then duplicated, and crucial maternal genetic information is lost.
Rarely, malfunction of the maternal UBE3A gene is the cause of Angelman syndrome but when it is, it is usually inherited. This mistake on the genetic code can happen on two locations of a chromosome #15. These regions are called exons. Exon 9 and exon 16 seem to carry mutations that affect the way UBE3A functions. This type of mutation increases the likelihood of seeing multiple Angelman syndrome cases in one family. The diagnostic tools that detect any of the four genetic mishaps that causes Angelman syndrome, aids researchers with therapeutic care, treatment, and hopefully soon, a cure for AS.
Treatment of Angelman syndrome A cure for Angelman syndrome is still under research, but some clinical trials have shown some success in aiding with treatment and reducing the characteristics caused by AS in hopes to improve the quality of life for a person with AS. The Department of Molecular and Human Genetics (DMHG 2015) has “developed a potential therapeutic intervention for Angelman syndrome by reducing Ube3a-ATS with antisense oligonucleotides (ASOs)”(DMHG 2015. ) This therapy is geared toward un-silencing the paternal UBE3A gene and in hopes to activate the expression of the paternal UBE3A gene.
Due to the affected UBE3A gene causes most of the phenotypic characteristics of AS, the DMGH is hoping that activating more of the paternal UBE3A gene would benefit the patient with restored UBE3A gene. In trial therapy for AS, Meng, Ward, Chun, Bennett, Beaudet, and Rigo (2015) found that targeting the paternal UBE3A therapy tested on mice suggested positive findings in attempts to un-silence the paternal UBE3A gene (pp. 401,411). Trials for humans have not begun yet, but hopefully soon.
Angelman syndrome started of with just characteristics coined by an English physician that coined Angelman syndrome as “Happy Puppets Syndrome” but with years of research and dedication it is now called Angelman syndrome and geneticists know that its caused by a single gene mutation in chromosome #15 and more specifically the maternal UBE3A gene. Diagnostic testing is available for families to confirm the diagnosis of Angelman syndrome. The future holds more genetic research and testing with the hopes that one day Angelman syndrome will have a successful therapy that could potentially cure and prevent this condition.
