Abstract:
This paper covers a neurological disorder called Angelman’s Syndrome (AS). This disorder is characterized by a problem in the activation of the ube3a gene. The lack of activation of this gene causes a variety of symptoms that include seizures, behavioral issues, balance and movement problems, mental retardation, and abnormal facial expressions to name a couple. Preventive measures for this syndrome are in the form of the prevention of the symptoms that are associated with it. Other than relying on the physical symptoms to diagnose AS, there is blood testing that can determine its specific cause. Angelman’s syndrome does not have a cure and the gene abnormality is caused sporadically, therefore there are no preventative measures that are known in order to decrease the odds of an individual initially becoming affected with it. Although the number of people affected is relatively small, there is current research being done to determine a cure for this syndrome.
Cause and Effect Section:
Angelman’s syndrome is most commonly caused by the deletion of the gene E3 ubiquitin protein ligase (UBE3A), located in chromosome region 15. The gene UBE3A is important in giving instructions to make the protein called ubiquitin protein ligase E3A. The role of UBE3A is currently unclear although the product, protein ubiquitin-ligase is involved in labeling proteins for selective destruction. (Howlin, 2011) Other hypothesis say that this protein helps to regulate y-aminobutyric acid GABA4 receptors at the synaptic level. The genetic changes that cause AS occur randomly in early embryonic development. Even though it is caused by genetic factors it occurs sporadically and the majority of the time it is not inherited. Although according to the article titled “Angelman’s Syndrome,” on rarediseases.org, 3-5% of people can inherit this syndrome. A person receives one copy of this gene from each parent. However, the maternal gene is only active in certain parts of the brain. Therefore, when genes are going under replication, if the copy of the maternal gene is lost due to gene mutation or chromosomal change, the person will have no active gene in some parts of the brain. The lack of the segment of chromosome 15 containing this gene is what causes the symptoms of Angelman’s syndrome. Although the lack of the gene is the most common cause of this syndrome there are other causes. One of these causes is called uniparental disomy, which means that a person inherits two copies of a gene from their mother or father instead of one from each. The percentage of people with Angelman’s syndrome due to uniparental disomy is small.
Protein ligase UBE3A is responsible for normal development and nervous system functioning. When this protein is not able to be made it causes the symptoms in Angelman’s syndrome. AS effected individuals have abnormalities in dendritic spines which results from the lack of E6-AP, the by-product of protein ligase. Abnormal dendritic spines causes problems in synaptic plasticity that is thought to cause symptoms of AS. A study performed with drosophila showed that a lack of ube3a activity reduced dendritic branching in the peripheral nervous system of the sensory neurons. (Lu et al. 2009)
In a normal person one copy of the gene E3 ubiquitin protein ligase (UBE3A) is inherited from both mother and father. This gene is then activated or “turned on” in different areas of the brain specifically in neurons. (Dindot, et al., 2007) Protein ligase (UBE3A) recycles proteins and sends amino acids to other proteins in the cell that are marked for degradation, activation, or relocation. The protein can be found in pre and post synaptic locations as well as in cytoplasmic and nuclear locations. According to an Epigenomics article, our knowledge of ubiquitination and protein recycling at the synapse is expanding rapidly. (Lasalle, et al. 2015)
Symptoms and Diagnostic Tests:
There are many symptoms associated with Angelman’s syndrome that impair the daily functions of those who are affected by it. This syndrome delays development, causes mental disabilities, impedes speech, and causes problems with movement and balance. The symptoms of delayed development appear during early childhood, usually between the ages of 6 to 12 months. This syndrome is also characterized with happy and excitable expressions, frequent laughing, arm gestures, and other movements. People affected tend to be hyperactive, have short attention spans, and have a fascination with water. On top of these they generally have a physically smaller head and are affected by seizures. In addition, those affected tend to have coarse facial feature, lighter hair and skin, and scoliosis of the spine that causes a noticeable curvature. Although development impairments will be different from person to person, most of these symptoms are manifested in people with this syndrome.
There are two known ways to test and diagnose Angelman’s syndrome. The first and most effective way of testing, which diagnoses about 80-85% of people with this syndrome according to (Angelman’s syndrome foundation), is a blood test. This blood test is called the methylation test and it screens for 3 of the 4 genetic factors that cause AS. If the test comes back abnormal then further studies are done to determine which genetic factor is causing the problem. The next test to be performed would be the FISH (Florescent in situ hybridization) 15 test or the CGH (comparative genomic hybridization test). If these tests come back positive it would mean that the cause of the AS was chromosome deletion. It has been shown that patients with chromosome 15 deletions are in general the most severely affected. (Clayton-Smith & Laan 2003) If the tests come back negative that would mean the cause is not chromosome deletion and the next test to perform would be a DNA marker analysis. The DNA marker analysis tests for gene mutations that cause AS. These tests are the current way of diagnosing AS, although according to (Genetics home ref.) the cause of AS in 10-15% of people is unknown.
Treatments and Preventions:
Angelman’s syndrome has no cure, but there are therapies and medications that can help to manage the symptoms associated with it. Antiseizure medication can keep seizures from happening as frequently while physical therapy can aid in walking and movement problems caused by the syndrome. Other therapies such as behavioral and communication therapies help the person to have better relationships with others by enabling them to communicate better and help to manage the effects of hyperactivity and shortened attention span. While these have all been management techniques, there are doctors who have been working on possible treatments for AS. One of the drugs being studied to possibly treat AS is a drug that is currently used to treat cancer. The mechanism behind their research is to find a drug that works to “unsilence” or awaken the ube3a gene. Since the drug they found that awakens this gene is the one used in chemotherapy treatment it is possible that the side effects would be similar. The next step in this possible treatment is conducting clinical trials to test its effectiveness in people affected by the syndrome. Since AS is caused by the sporadic mutation or deletion of a gene there is no known way to prevent this condition.
Statistics:
Angelman’s syndrome is not an extremely prevalent syndrome. It only affects 1 in 12,000 – 20,000 people in the world and is reported to affect men and woman equally. More statistics that look at the cause of AS show that in 70% of cases the cause is deletion, 2-3% from UPD, 3-5% from imprinting defect, 5-10% from ube3 mutation or deletion, 1-2% from other chromosome arrangements, and 10-15% of causes are unknown. 10-15% of people who have the signs and symptoms of AS show normal gene results when tested. Also, over 90% of people with this syndrome are affected with seizures. It appears that there is not a significant prevalence of AS in a certain racial ethnicities, geographical areas, or age groups.