Every day there are big announcements about the latest advancement in medicine. Generally the bigger announcements are reserved for the more well know conditions such as autism, down syndrome, cerebral palsy and Alzheimers. What you may not realize is that there is some amazing work being done to cure and treat Angelman Syndrome.
The research for a treatment of Angelman Syndrome is being led by Dr. Edwin Weeber, a professor of molecular pharmacology and physiology at the School of Biomedical Sciences, University of South Florida. He graciously agreed to an interview about Angelman Syndrome and his ongoing research
1. What is Angelman Syndrome, and what is its cause?
Angelman syndrome (AS) is a genetic disorder that occurs in approximately one in every 15,000 births, although it is often misdiagnosed so the actual numbers may be higher. AS was first characterized by Dr. Harry Angelman in 1965 after he noticed similar phenotypes in several pediatric patients.
Dr. Angelman was a general pediatrician who had three children under his care with similar characteristics, such as similar facial structures, frequent laughter, and gestures such as hand-flapping.
He originally called them “puppet children” not only their unique marionette-like movements, but also for a painting, titled “Boy with a Puppet”, which he felt had similar facial features to his patients.
Although he suspected a similar underlying cause in the children, he could not identify it at the time. As more children were subsequently diagnosed, the name was changed to Angelman syndrome. Thirty years would go by before researchers identified the gene responsible for AS (the UBE3A gene).
2. What are typical symptoms of AS?
It typically presents with movement problems that may or may not be associated with tremor, lack of speech, frequent laughter, electroencephalographic (EEG) abnormalities, sleep disturbances, seizures that can be difficult to control, and significant cognitive deficits.
However, symptoms in AS often vary greatly, which is one of the reasons it is often misdiagnosed. Other characteristics frequently seen in AS patients include fascination with water, a wide mouth with wide spaced teeth, and sometimes it is associated with obesity.
Another interesting feature is hypopigmentation, which is a fancy way of saying that some Angelman Patients have light complexion, blond hair and blue eyes despite the skin, hair or eye color of the parents.
3. If a parent is a carrier will there be a chance that their child will also have Angelman Syndrome?
A parent that is a carrier is very rare, but it can happen. There are known cases of multiple siblings with AS. This can happen through inheritance of a mutation in UBE3A from father (Grandfather) to daughter (Mother), then the daughter may pass this on to her children who then are diagnosed with AS. The grandfather and mother show no signs of AS because the paternal UBE3A gene is silenced in both of them. Only when it is inherited from the mother is there a maternal disruption of the gene.
4. If a child is diagnosed with AS is there a chance that future siblings will also have Angelman Syndrome?
Again, this can happen in rare circumstances. Genetic testing can be performed to determine the genetic cause for the maternal UBE3A disruption. If this is the case, then the mother has a 50-50 chance of passing the defective gene on to her kids, but ONLY if she is shown to carry the mutation. Most cases of AS are due to deletions of varying sizes in the UBE3A gene.
5. How did you get interested in AS Research?
That is a long story, but in a nutshell: After receiving my Ph.D. in Neuroscience from the University of New Mexico, I traveled to Houston, Texas and joined the lab of Dr. David Sweatt at Baylor College of Medicine.
Dr. Sweatt is a brilliant neuroscientist and I was lucky to land in his lab. His laboratory was one of the first to use a multidisciplinary approach to studying learning and memory. For example, he would systematically knockout genes in the mouse believed to be involved in memory formation, and then examine the brain morphology, behavior, synaptic function and biochemistry all at one time. Most labs at the time were only capable of performing one or two of those types of techniques.
Down the hall from Dr. Sweatt was Dr. Arthur Beaudet’s laboratory. He co-discovered the gene and developed the mouse model for AS almost 15 years ago. This was revolutionary!
Instead of just disrupting genes thought to be involved in a memory disorder, this lab had identified THE gene involved in AS. The labe then located the same gene in the mouse, then disrupted that gene to make a true human cognitive disorder mouse model.
I was hooked immediately. To Dr. Beaudet’s and Dr. Sweatt’s credit, and to let everyone know how generous they were, when I left Baylor to start my own lab, they freely gave me the mice to continue my work. These mice are all over the world now, being used by many AS researchers to this day.
6. You are heavily involved in working for a cure for Angelman Syndrome please share your progress.
Scientific progress is often marked in decades and by seminal findings. An entire career for a scientist may be focused on answering one or two important questions. With that in mind, I believe the AS field has progressed as much as any field studying a specific disorder.
When you think about the years, resources and brain power put toward a cure for cancer, schizophrenia or Alzheimer’s disease, the progress made in AS is phenomenal. We have identified biologicals (proteins and such), drugs and gene therapies that have relieved many of the symptoms in the AS mouse model.
Some of these drugs, like Minocycline, can be taken to clinical trial very quickly, while others may take years to develop into a true therapeutic. Our lab is conducting research on both of these approaches and progress IS being made in my lab and in others. I know that is a cagey answer to the question, but simply having an identified FDA approved drug in clinical trial is a good indication of tremendous progress.
7. Will this be a preventive cure or would it be beneficial to children already diagnosed with AS?
We only look at potential therapeutics with the mindset that it will be used for patients already diagnosed with AS. Once those therapeutics are found and show positive results, only then can we make an educated guess on how they might work in very young children with AS.
This brings up another interesting caveat; early post natal screening for AS would be needed for a preventative therapy to work!
8. In layman’s terms how does Minocycline potentially help treat AS?
It is impossible to say just yet how it may be working. Minocycline is a member of the family of tetracyclines. It is the most lipid soluble tetracycline, which means that it can deeply penetrate into the brain.
The beneficial effects of minocycline are just now being realized, and perhaps all anti-bacterials have therapeutic properties no one knows about.
One possible way that it works is by stimulating the growth of small spines on the processes of nerve cells. These spines allow synapses to form. An overarching prediction is that AS is a basic problem with how neurons communicate with each other.
Minocyline may work by increasing connections between neurons and overcoming those deficits in communication. My lab is currently working on the mouse model to understand how minocycline may work. It is important to note that Minocycline is attractive as a potential therapeutic because we know much about it and how well it is tolerated in humans. Side effects are very slight and not common, despite long-term use of the drug.
Our ongoing clinical trial will tell us if it can be useful as an AS treatment, while other therapeutics are discovered and designed.
9. Does this drug help with other conditions?
It is currently being used in clinical trials for the treatment of ALS, Fragile X Syndrome, Alzheimer’s disease and Huntington’s Disease. It is unclear how Minocycline may be working with those disorders; however, positive results or negative results from the ongoing clinical trials will help identify other potential areas of research and other likely other helpful drugs.
10. In addition to children, could Minocycline potentially help adults who have AS?
There is no reason to believe that if minocycline is found to have a positive effect on any outcome (seizure, attention, verbalization, sleep, etc.) that it would not be equally beneficial in older AS patients.
One of the major reasons the clinical trial for Minocycline, and likely future clinical trials, focuses on younger patients (4-12 years of age), is because we know more about that age group then any other. Also, by narrowing to a specific age range, we reduce variability in the results and therefore may not need as many patients to see a statistically significant result. Clinical trials are extremely expensive and making them as efficient as possible is a huge consideration.
11. Where can one learn more about Angelman Syndrome and the ongoing research to find a treatment for AS?
I have worked very closely with the Foundation For Angelman Syndrome Therapeutics (FAST). Their very acronym exemplifies their mission; to find a treatment or cure for Angelman syndrome as quickly, and importantly as efficiently as possible. Their web site is www.cureangelman.org. They often post the latest ongoing research and they are responsible for funding the basic research that identified Minocycline and the subsequent ongoing clinical trial.
I will also post the results of the Minocycline trial and our other ongoing research projects on my own web site, www.weeberlab.com.