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Genetic Counseling | Genetics 101 | Genotype to Phenotype Relationship | GERD | Gifts

 

Genetic Counseling

http://www.angelman.org/resources-education/medical-info/genetic-counseling-in-angelman-syndrome/

The following aspects must be considered in understanding AS genetic risk:

1. Common chromosome deletion:
More that 98% of the chromosome deletion instances occur by a spontaneous event and thus they are not inherited; the recurrence risk is <<1% for these families. However, 1-2% of deletions occur because of an inherited abnormality in the maternal chromosome 15, such as a balanced chromosome translocation. Another very small group (e.g., only a few cases reported in the literature), can have AS due to a very small, maternally inherited chromosome deletion that involves a small area around and including the UBE3A gene. For these cases, the maternal recurrence risk is increased depending on the type of abnormality present. Chromosome study of the mother, including FISH, helps rule out inherited chromosome 15 abnormalities.

2. Paternal uniparental disomy (UPD):
More than 99% of patUPD cases occur as an apparent spontaneous, non-inherited, event. If an individual has AS due to patUPD and has a normal karyotype, a chromosomal analysis of the mother should nevertheless be offered in order to exclude the rare possibility that a Robertsonian translocation or marker chromosome was a predisposing factor (e.g., via generation of maternal gamete that was nullisomic for chromosome 15, with subsequent post-zygotic “correction” to paternal disomy).

3. Imprinting Center (IC) Defect:
There are two types of IC defects: deletions and non-deletions. Non-deletion events do not appear to be inherited and have a <1% recurrence risk. Most deletions are not inherited but a significant proportion of them are (i.e., maternally inherited), and these confer a 50% risk for recurrence.

4. UBE3A mutations:
UBE3A mutation can either occur spontaneously (e.g., not inherited and with no increased recurrence risk) or be maternally inherited and have a 50% risk of recurrence (see below for imprinting inheritance).

5. Individuals with no known mechanism (all 4 above mechanisms have been eliminated):
For parents of AS individuals who have apparent normal genetic tests (no evidence for deletion, imprinting defect, UPD or UBE3A mutation), and thus their children are only clinically diagnosed, it is not known what the recurrence risk is. An increased risk seems likely but probably does not exceed 10%.

6. Germ cell mosaicism:
This term refers to a phenomenon in which a genetic defect is present in the cells of the gonad (ovary in the mother’s case) but not in other cells of the body. This occurrence can lead to errors in risk assessment because a genetic test, for example on a mother’s blood cells, will be normal when in fact a genetic defect is present in the germline cells of her ovary. Fortunately, germ cell mosaicism occurs very infrequently. Nevertheless, it has been observed in AS caused by the mechanisms of large chromosome deletion, Imprinting Center deletion and UBE3A mutation.

7. Imprinting inheritance:
UBE3A mutations and Imprinting Center deletions can exhibit imprinting inheritance wherein a carrier father can pass on the genetic defect to his children without it causing any problems, but whenever a female passes this same genetic defect on to her children, regardless of the sex of her child, that child will have AS. The pedigree diagram below illustrates imprinting inheritance. Here, AS has only occurred after a carrier mother passed on the gene defect (for example as in the two siblings with AS pictured on the left lower part of the pedigree). In addition, a distant cousin in this family also has AS due to the imprinting inheritance. In the diagram, individuals with the light blue circles or squares have AS but everyone else in the family is clinically normal. The white dots represent asymptomatic, normal carriers of the AS mutation. When an AS genetic mechanism is determined to be inherited, genetic testing of family members can usually identify carriers of the gene defect. As you might imagine, professional genetic counseling is advised in these situations.

Example of Imprinting

Diagnostic testing for Angelman Syndrome

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Genetics 101

Dr. Charles Williams

See Dr. Charles Williams’ presentation at the 2014 CASS conference:  Infancy to Adulthood: Understanding Angelman Syndrome After Five Decades

THIS IS A “MUST READ” PRESENTATION!!
Alice Evans   San Diego, CA  angel Whitney, age 33

 

The following report was authored by Rebecca D Burdine PhD and Erin Sheldon
Reviewed for accuracy by Wen-Hann Tan, BMBS Children’s Hospital Boston, Boston MA

Angelman Syndrome (or AS) is caused by the lack of function of one specific gene, called UBE3A. To understand this, we first need to understand how chromosomes and genes work together to allow our brains to function.

A typical person has 46 chromosomes inside every cell in their body. We inherit 23 chromosomes from one parent and 23 from the other. Chromosomes are like the instruction manuals containing all the detailed information our cells need in order for our brains and bodies to grow and function. Chromosomes are numbered like volumes in a set of encyclopedias. We inherit one copy of each chromosome from each parent, giving us two copies of each chromosome. We all have two copies of the chromosomes numbered from 1 to 22, plus a sex chromosome inherited from each parent.

Our genes are like the individual topics in the set of encyclopedias. Different genes are located in each chromosome the way that information might be organized in an encyclopedia. Scientists only understand a fraction of how our genes help cause good health or disease and exactly how each gene functions.

It is likely that we all have a number of genetic errors in our chromosomes. This is one reason why it is good that we have two of each chromosome to draw from: if one chromosome has an error, our cells can easily get the information they need from the second chromosome. Nature has provided us with a great back-up system to ensure our cells always have the instructions they need for our brains and bodies to function even when there are inevitable errors in our chromosomes.

The important chromosome for Angelman Syndrome is number 15. This chromosome has a region that is “imprinted.” Imprinting means that some genes on the chromosome are “turned on” or “turned off” depending on which parent contributed the chromosome. Going back to the set of encyclopedias, imagine that we have two versions of the 15th volume, but a chapter in the volume inherited from the father has been washed out and the “pages” are now blank. Similarly, a different chapter in the volume from the mother is washed out and the pages appear blank. Imprinting occurs at the time of conception as part of the normal development of the fetus and each of us have regions on some of our chromosomes that are imprinted, meaning that only one parent’s genetic information is available to our cells as instructions on how to grow and develop. In imprinted regions of our chromosomes, only one parent’s information is accessible to cells in the brain and body, so there is no back-up system if there is an error in the remaining chromosome.

There are many mechanisms that cause what is known as Angelman Syndrome. The most common is a “deletion.” If the 15th chromosome is like a volume in an encyclopedia, with a special chapter that is only in the volume inherited from the mother, then imagine that chapter has been torn out. This is a bit similar to how most people with Angelman Syndrome have a deletion in their chromosome 15. There is a missing chapter in their volume so the brain is missing some of the instructions it needs to grow and develop. The father’s chapter is present but was “washed out” due to the natural process of imprinting so the pages appear blank and the cells in the brain can’t access the information.

Other individuals with Angelman Syndrome have a mutation in the UBE3A gene. This is similar to having a mis-spelling in the important chapter that is only present on the chromosome inherited from the mother. This mis-spelling is so severe that it makes much of the chapter illegible to cells in the brain. Again, the end result is that the brain lacks important information to learn and develop.

Some people with Angelman have uniparental disomy or UPD. In these cases, the individual inherited two copies of this “volume 15” from the father and no copy from the mother. Again, the information that is only in the volume inherited from the mother is missing and both copies from the father are blank or “washed out”.

A small number of individuals with Angelman have an imprinting centre (IC) defect on the maternal chromosome. There is a region on the 15th chromosome that helps the chromosome decide whether the chapters of information are accessible or “washed out”. When there is a defect in the maternal IC, the chapters that are normally accessible become inaccessible. Even though the “volume 15” is complete and normal, the cells in the brain can’t access the information that they need.

Lastly, a few individuals have all or most of the symptoms of Angelman Syndrome, but every test of their genes turns out normal. In many of these cases, it is likely that we just don’t yet have the technology and expertise to understand what is wrong, but additional research is likely to reveal new causes of AS, which will help these families understand what is causing Angelman Syndrome in their loved one(s).

Scientists are still trying to understand what exactly the UBE3A gene does. All we know for sure is that UBE3A is vital to how the brain develops and controls speech, movement and learning. When the UBE3A gene is blocked from functioning normally, the individual has Angelman Syndrome. UBE3A is a gene that is also being investigated for a role in autism and genetic disorders like Isodicentric 15. Research into future treatments and cures for Angelman relies on finding a way to make the UBE3A present in the paternal “volume” available to the brain. Essentially, if we think of the genetic information on the father’s chromosome as being “washed out” and invisible, scientists are searching for ways to make the data reappear so that the brain can access the information and individuals with AS can develop to their fullest potential.

Chromosome 15Mutation examples

 

The illustration on the left of Chromosome 15 highlights in red the section that contains the UBE3a gene and is often deleted from the maternal chromosome in Angelman Syndrome.

This illustration on the right shows the different mechanisms that cause Angelman Syndrome. The red chromosomes represent the chromosome inherited from the mother while blue represents the father. The first example shows a normal pair of “volume” 15s with the father’s chromosome chapter with UBE3A “washed out” or silent, while the mother’s chapter is active and UBE3A is expressed, making the genetic instructions in that area available to the cells in the brain. The remaining examples illustrate the known mechanisms that cause Angelman Syndrome by making the mother’s genetic information inaccessible to the cells in the brain. For example, in deletions, the UBE3A gene is completely missing as that “chapter” has been “torn out”. In UBE3A mutations, the UBE3A gene is “mispelled” which makes this copy of UBE3A non-functional.

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Genotype to Phenotype Relationship

Does the type of genetic cause of Angelman Syndrome make a difference in development?

(Genotype to Phenotype Relationship)
Dr. Charles Williams used this illustration (see below) in his genetic presentation at the 2014 CASS (Canadian Angelman Syndrome Organization) conference.
http://www.peds.ufl.edu/divisions/genetics/programs/angelman_syndrome/AS_five_decades.swf

Genotypes

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GERD

Gastroesophageal reflux disease, or GERD, is a digestive disorder that affects the lower esophageal sphincter (LES), the ring of muscle between the esophagus and stomach. Many people, including pregnant women, suffer from heartburn or acid indigestion caused by GERD. Doctors believe that some people suffer from GERD due to a condition called hiatal hernia. In most cases, heartburn can be relieved through diet and lifestyle changes; however, some people may require medication or surgery.

What Is Gastroesophageal Reflux?
Gastroesophageal refers to the stomach and esophagus. Reflux means to flow back or return. Therefore, gastroesophageal reflux is the return of the stomach’s contents back up into the esophagus.

In normal digestion, the lower esophageal sphincter (LES) opens to allow food to pass into the stomach and closes to prevent food and acidic stomach juices from flowing back into the esophagus. Gastroesophageal reflux occurs when the LES is weak or relaxes inappropriately, allowing the stomach’s contents to flow up into the esophagus.

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Gifts

When shopping for gifts (holiday, birthday, etc.) your child’s therapists can offer suggestions. Check alternative sites like amazon.com before purchasing from therapy catalogs. Many times, the same items will be on Amazon for a fraction of the cost.
Rachel Brewer  N. Little Rock, AK  angel Ava,  age 4

I think the greatest gift I have given my angel is hippotherapy or horseback riding lessons.  She has done this for almost four years and her progress is astounding.  Her core body strength has significantly improved.  She doesn’t like to “exercise” but riding makes it fun and she doesn’t realize that she is working so hard.  Her posture, walking, and strength have gotten so much better.  Be sure to find someone that is a certified (PATH is one) instructor.
Robbin Clark

My niece loves anything soft. Fleece is a favorite and she loves the feel. She also has an obsession with scarves.

My angels love puzzles, iPods and playdoh.
Melissa Jones  Cortland, Ohio  angels:  Andre, age 15, Christina age 14, Ryan age 13 and Ashley age 12.

Melissa, you are our inspiration!

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