Angelman Syndrome: Symptoms, Treatment + Podcast

Everything to know about AS, from the experts.

Podcast

Author and Contributing Experts to this Guide include:

Jessica Bucher Genetic Counselor, MSGC LinkedIn
Lynne Bird Clinical Geneticist
Regina Uribe Parent advocate of Angelman Syndrome
Paula Evans Parent advocate and Chairperson of FAST LinkedIn

What is Angelman Syndrome?

In 1965, English physician Dr. Harry Angelman first described three children with signs that would later become known as Angelman syndrome (AS). 1

His first published reports led other doctors to doubt its existence because the condition was so rare. It was until the 1980s that the first cases of AS started to be reported in North America.

Today, it’s estimated that AS affects as many as one in 12,000 births worldwide. 2

It is a genetic disorder, but most cases of Angelman syndrome are not inherited from a parent.

“Angelman Syndrome is an intellectual disability syndrome with seizures, sleep disturbance, absence of speech and easily provoked laughter. Lack of achieving developmental milestones is usually evident in the first year of life and diagnosis is usually made before about three years of age now,” said Dr. Lynne Bird, a clinical geneticist and pediatric specialist who has been treating children with birth defects a wide variety of genetic conditions for 25 years.

As stated by Genetics Home Reference, Children with Angelman syndrome typically have a happy, excitable demeanor and frequent hand-flapping movements. Hyperactivity, a short attention span, and a fascination with water are common. Most affected children also have a small head size (microcephaly) and an abnormal side-to-side curvature of the spine (scoliosis). 3

As children get older, they become less excitable and sleeping problems tend to improve. But intellectual disabilities, seizures and severe speech impairments remain throughout their entire lives. 4

Despite these challenges, the life expectancy of people with this condition appears to be nearly normal. 5

What Causes Angelman Syndrome?

Angelman Syndrome is a genetic disorder caused by a loss of function of the UBE3A gene.

In every cell of the body, we have genetic information. Genes are chapters of genetic information, housed on chromosomes. Chromosomes, and genes as a result, come in pairs; one from an individual’s mother, and the other from the individual’s father.

Sometimes, it is important for the body to turn “on” and “off” certain copies of genes. This process is known as “imprinting”, and can silence a gene.

The UBE3A gene is located on the 15th chromosome. Dr. Bird explains the typical UBE3A gene imprinting pattern, followed by the abnormal way UBE3A is expressed in individuals with Angelman syndrome.

“The UBE3A gene is imprinted, which means that it's silenced depending on which parent you inherit it from. In this case, UBE3A is paternally imprinted which means the father's copy of the gene is silenced and only the mother's copy is active in brain cells. There are four ways we know of that can result in the mother's copy of the gene being missing, silenced or defective,” explained Dr. Bird.

In people with AS, this maternal gene is not doing its job, and that impacts their Messenger RNA (mRNA).

The body’s DNA uses mRNA as to deliver “blueprints” to the protein-assembly factories in human cells. People with AS have a UBE3A gene disruption on the maternal copy of the gene that interrupts this delivery service.

When this happens, their neurons do not produce functional UBE3A protein in the brain, triggering AS symptoms.

The four ways that the UBE3A gene does not do its job are: 6

  • Deletion of the AS/PWS region on the maternally inherited chromosome 15
  • Uniparental disomy (UPD) of the paternal chromosome 15. UPD occurs when a person receives two copies of a chromosome, or of part of a chromosome, from one parent and no copy from the other parent
  • An imprinting defect (ID)
  • A pathogenic variant in UBE3A
  • Other unidentified causes

In most cases, genetic changes occur as random events during the formation of reproductive cells or in early embryonic development. AS is typically not inherited, but there are rarely inherited causes.

For the vast majority of AS cases, scientists understand the cause which is why the bulk of AS research is focused on studying the UBE3A gene and trying to find ways to turn on, or unsilence the copy from the father. 7

The causes of Angelman syndrome are unknown in up to 15% of affected individuals. 8

Signs and Symptoms of Angelman Syndrome

There are several signs and symptoms that may indicate the presence of Angelman syndrome. Clinical characteristics will lead to tests to confirm or differentiate the diagnosis.

The age at which someone is diagnosed with AS will vary, but those diagnoses are happening faster than ever because testing for the condition has improved.

“Most of the classical cases are now usually recognized prior to a year or a year and a half or so. But the milder or less classical, less typical, cases don't get diagnosed sometimes until several years of age. The older patients in the community who didn't have access to testing 20 or so years ago may still be undiagnosed. So, there are potentially a lot of undiagnosed adults out there, because they grew up in an age where we didn't really have a way to test,” said Dr. Bird.

In general, suggestive and clinical signs and symptoms can include:

  • A severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs. Microcephaly and seizures are also common.
  • There is also a unique inappropriate happy demeanor that includes frequent laughing, smiling, and excitability.
  • Developmental delays can first appear at around six months old, but the unique clinical signs and symptoms of AS do not appear until after age one. These may be subtle at first, and that can result in a correct diagnosis taking years to achieve.
  • There may be a normal prenatal and birth history, no major birth defects and a normal head circumference at birth. Metabolic, hematologic, and chemical laboratory profiles are normal as well.
  • For the most part, brains are structurally normal when viewed through an MRI or CT, although some mild cortical atrophy or dysmyelination may be present.
  • There is evidence of developmental delay by age 6 to 12 months. This will worsen and eventually be classified as severe.
  • Speech will be impaired with minimal to no use of words. Receptive language skills and nonverbal communication skills will be higher than expressive language skills. Appropriate use of even one or two words in a consistent manner is rare. Most older children and adults can communicate by pointing, using gestures and through communication boards. Infants display a lack of cooing or babbling.
  • Movement or balance will be impacted, usually in the form of ataxia of gait and/or tremulous movement of the limbs.
  • Frequent laughing and a happy demeanor are often accompanied by hand-flapping movements and hypermotoric behavior.

In the vast majority of cases (80% or more), the following are usually present:

  • Delayed or disproportionately slow growth in head circumference, usually resulting in absolute or relative microcephaly by age two. 50% of children develop microcephaly by age 12 months.
  • Seizures, usually starting before age three. Seizure types can be quite varied and include both major motor and minor motor types.
  • Abnormal EEG, with a characteristic pattern of large-amplitude slow-spike waves.

Signs and symptoms that are less frequent include:

  • Flat occiput
  • Occipital groove
  • Protruding tongue
  • Tongue thrusting or sucking and swallowing disorders. This can result in difficulties is breast feeding or bottle feeding. It can also lead to gastroesophageal reflux due to muscle hypotonia during infancy.
  • Prognathia
  • Wide mouth, widely spaced teeth
  • Frequent drooling
  • Excessive chewing/mouthing behaviors
  • Strabismus
  • Hypopigmented skin, light hair and eye color (compared to family); seen only in those with a deletion.
  • Hyperactive lower-extremity deep-tendon reflexes
  • Uplifted, flexed arm position especially during ambulation
  • Wide-based gait with pronated or valgus-positioned ankles
  • Increased sensitivity to heat
  • Attraction to/fascination with water
  • Fascination with crinkly items such as certain papers and plastics
  • Abnormal food-related behaviors
  • Obesity
  • Scoliosis
  • Constipation
  • Hyperactivity

The average child with AS walks between ages two and six years old. At that time, they may have a jerky, robot-like, stiff gait, with uplifted, flexed, and pronated forearms, hypermotoric activity, excessive laughter, protruding tongue, drooling, absent speech, and social-seeking behavior.

About 10% of children with AS are non-ambulatory.

Sleep problems are common with AS. Frequently awakening at night is common. Dyssomnias (difficulties in initiating or maintaining sleep), irregular sleep-wake cycles, disruptive night behaviors such as periods of laughter, and sleep-related seizures have been documented.

People with AS cannot live independently. Living at home or in home-like placements is necessary.

Depending on how AS is acquired, there are some clinical differences that correlate with the genotype. These can vary widely but may include:

  • The deletion class is the most severely involved regarding microcephaly, seizures, relative hypopigmentation, motor difficulties (e.g., ataxia, muscular hypotonia, feeding difficulties), and cognition and language impairment.
  • UPD and ID individuals have better physical growth (e.g., less likely to have microcephaly) and have less movement and ataxia abnormalities and have a lower prevalence (but not absence) of seizures.
  • The ID group tends to have the highest cognitive, receptive language, fine motor, and gross motor abilities compared to other subtypes.
  • The UBE3A mutation group generally is intermediate between the deletion and the ID classes in terms of microcephaly, seizures, motor difficulties, and language ability. Some with UBE3A may have relatively high cognitive abilities, fine motor, and gross motor skills as presumably the effect of their mutation (e.g., location and type of DNA change within the gene) causes less severe clinical problems.

Diagnosis of Angelman Syndrome

When a clinician, or maybe a neurologist or geneticist who is familiar with the condition suspects AS, they may order a blood test for DNA methylation

“That single test can pick up three of the four varieties of Angelman syndrome, approximately 85% of cases. If that test is negative then, one can go on to do an additional blood test, which would look at the spelling of the UBE3A gene to pick up the remaining cases that we know of,” explained Dr. Bird.

Angelman syndrome be detected before birth through prenatal testing and preimplantation genetic testing (PGT). High-risk pregnancies require prior identification of the disease-causing mechanism in the family.

High risks are defined as the prenatal detection of all the known molecular genetic alterations that give rise to AS is possible through DNA and/or chromosome/FISH analysis of fetal cells obtained by chorionic villus sampling or amniocentesis.

Prenatal testing should take place only after a genetic high risk has been established and the couple has been counseled regarding the risk to their unborn child,

Parents with normal chromosomes who have had one child with AS caused by either deletion or UPD, have a low recurrence risk but may be offered prenatal testing for reassurance.

Parents who have had one child with AS caused by a UBE3A pathogenic variant should be offered prenatal testing even if the mother does not have a UBE3A pathogenic variant because of the possibility of germline mosaicism.

Molecular genetic testing to establish the diagnosis can be based on either the clinical findings or the laboratory findings that suggested the diagnosis of AS.

With a symptomatic individual who has not had any prior molecular genetic testing DNA methylation analysis is typically the first test ordered. DNA methylation analysis identifies approximately 80% of individuals with AS.

Further testing is usually required to identify the specific underlying molecular mechanism

If DNA methylation analysis is normal, then testing of UBE3A may be considered as part of a multi-gene analysis.

In some cases, more comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if testing of UBE3A or use of a multigene panel fails to confirm a diagnosis of someone with features of AS.

Treatment & Care Options for Angelman Syndrome

“My evaluation typically starts with recording the family history. Asking about the pregnancy and the birth, which are most often unremarkable and then discussing the developmental and medical history of the patient and then I examine the child.

“Typically, the physical examination is essentially normal in Angelman syndrome but the behavior, the quality of movement and the personality may show some signs typical of Angelman syndrome,” said Dr. Bird.

“I usually begin the discussion by explaining the genetics behind Angelman Syndrome. Explaining the four different molecular varieties and which variety their particular child has and then I move on to explaining what the symptoms are like and what it will mean for their child to have Angelman syndrome,” she added.

One of the most important aspects of treatment is making sure that a child with AS gets to the appropriate specialist. For example, due to seizures being a common symptom, one of the first things a general practitioner will do is arrange for a patient to see a neurologist.

As summarized by Dagli et al. in GeneReviews on “Angelman syndrome”, treatment will also often include services through a physical therapist, occupational therapist or speech communication therapist as well. Augmentative communication aids such as picture cards or communication boards are often introduced at the earliest appropriate time. Introducing sign language as early as possible is also helpful.

Dietary evaluations are helpful to make sure individuals have an adequate diet. Reflux is common and may be helpful to address to help feeding issues and weight gain.

Evaluations for possible scoliosis (curvature of the spine) and foot or ankle support may also be helpful.

An MRI and EEG are also typically recommended following an initial diagnosis. It is important to see a neurologist familiar with Angelman syndrome considering some medications may worsen seizures while others are known to work better for individuals with Angelman syndrome.

Those patients who develop strabismus will need to arrange services through an ophthalmologist.

Sleep disruption can be a concern and melatonin is sometimes used as directed by a doctor, in some people with Angelman syndrome. Discussing a safe, but confining bedroom space with the doctor can be helpful.

Constipation may require the use of laxatives such as high fiber or lubricating agents on a recurring basis.

“The treatments we have are entirely supportive. We try to manage the medical problems as well as we can and we try to promote healthy development through therapies and behavioral interventions. Seizures can be treated with medications or sometimes special diets,” said Dr. Bird.

In addition to all of the above treatments, a consultation with a clinical geneticist and/or genetic counselor usually takes place as well.

Clinical trials may hold the best chance for improving treatments in the future.

“I've been involved in clinical trials for Angelman Syndrome since 2001. One of the most important research studies has been the natural history study, which helps us understand the typical trajectory of the disorder, so that we have a firm understanding of the baseline in order to measure the effectiveness of any potential treatment. Enrollment is ongoing for that study, as well as for an industry sponsored study that Roche is conducting to determine the best outcome measures that should be used in future clinical trials,” said Dr. Bird.

There is still a long path to a cure, however. Both of those trials are observational and don’t include any treatment.

Added Dr. Bird, “There is an ongoing study of a drug named Gaboxadol that may have benefit. A safety trial showed it to be quite safe and possibly effective. So, a definitive trial to assess the effectiveness is currently ongoing.

“There are a couple of studies just getting started that will assess compounds called ASOs, antisense oligonucleotides, which are short pieces of DNA, designed to unsilence the sleeping paternal copy of the UBE3A gene. Since the gene silencing occurs only in the brain, these medications need to be delivered directly into the spinal fluid, which takes special expertise.”

Potential Complications from Angelman syndrome

The potential complications for someone with Angelman syndrome are well documented. Although some symptoms will abate with time, others become lifelong challenges.

Children with AS are actually at risk for medication overtreatment. This is because their movement abnormalities can be mistaken for seizures, and because EEG abnormalities can continue even when seizures are controlled. 9

In some cases, when risperidone (Risperdal®) or other atypical antipsychotic drugs are administered, care must be taken to avoid over-sedation and other side effects. 10

One of the questions that frequently comes up is whether or not someone with Angelman syndrome can reproduce. This is a somewhat complicated issue.

Theoretically, people males and females with Angelman syndrome would likely have typical fertility. Puberty may be delayed. However, there are other concerns with reproduction. This includes difficulty with sexual education,

During adolescence, puberty may be delayed by up to three years but sexual maturation occurs with normal development of secondary sexual characteristics. After puberty, females with AS are fertile and pregnancy has been reported.

To date. there is no report of a male with AS reported to have conceived a child, but it appears that that is theoretically possible.

Problems occur in other areas of sexuality. Due to developmental issues, why physiologic development is relatively normal, there can be concerns related to potential sexual abuse, normal masturbation behaviors, approach to contraception, and access to gynecological care, among others.

Because communication is difficult, sexual education is problematic. AS children with developmental handicaps still need to learn about address emphasis on body parts and on private and public components, differences between boys and girls, issues of how babies are made, understandings regarding acceptable social behaviors, and continued reinforcements and instruction about relationship boundaries.

All people with developmental handicaps are at increased risk for sexual assault and abuse, so parents should focus on awareness and prevention with AS children. This can be especially challenging because people with AS often have an outgoing personality and fondness of hugging or otherwise wanting to be close to others.

Prognosis of Angelman Syndrome

Life expectancy data for people with AS is limited, but the data that is available tends to support the notion of a nearly normal lifespan.

While AS is not fatal, people with the condition continue to experience quality of life challenges.

“I find the communication challenges to be the greatest barrier for the person with Angelman syndrome,” said Dr. Bird.

“For the researchers who are trying to understand what the real capabilities are of someone who has Angelman syndrome, it's generally felt that we underestimate the intellectual ability because we don't have instruments that adequately capture a person’s abilities. This is because they can't communicate verbally, and sometimes, they can't show us non-verbally what their abilities are, due to impairments in motor function. Other people might consider behaviors, a great barrier and certainly the sleep challenges are significant,” added Dr. Bird.

In older children, an excessive appetite and decreased physical activity could lead to obesity. This needs to be monitored to reduce the extent of scoliosis and obesity. 11

Behavioral issues are common and neuroleptic medication may be prescribed to treat these problems. 12

“If we could find a treatment that truly alters the trajectory of this condition and raises the ceiling for what people who have Angelman syndrome can accomplish, then we could start to make the case that universal newborn screening is appropriate.

That would let us identify all individuals with Angelman syndrome as soon after birth as we can, so that they can be treated promptly to maximize their developmental potential,” said Dr. Bird.

The ability diagnose AS earlier will allow the medical community to do a better job of lessening symptoms, thereby normalizing a child’s development to a greater degree.

“If we can help a patient and their families sleep better, improve their communication and self-help abilities, that would be a huge win. The difference between having a child who's permanently in diapers and one who achieves continence is enormous for quality of life,” she added.

What to do Next: Living with Angelman Syndrome

Getting an accurate diagnosis is critical, because it means that the best course of treatment can begin immediately.

At the same time, a new diagnosis of Angelman syndrome can feel overwhelming. But a supportive family will rally and learn how to cope as a unit.

“It'll always have a sting, you just learn to cope with it,” said patient advocate Regina Uribe.

“If you can build a support system, it really helps. As parents, it can be easy to forget to take care of ourselves, but I think it's really important. If we are healthy mentally, and physically, we're able to do a better job for our children. Take advantage of possible respites or your extended family members and friends to be able to come and help you and create a bigger tribe of support. People want to help and it's okay to ask for help,” she added.

Part of the issue with care is that people with AS will experience symptoms in different ways. Because the standard is different for each patient, that also creates challenges as well.

“Angelman syndrome is a spectrum and there are kids with a variety of needs. For example, my daughter doesn't have seizures, but over 70 percent of kids with Angelman Syndrome suffer with seizures. Finding that right medication balance is difficult and I just see so many of my friends that struggle with seizures. It's heartbreaking and not everyone experiences the medicines the same way. So, there is no one size fits all answers,” said Uribe.

Aside from the medical issues, there are also financial issues that are also a burden with Angelman syndrome as well.

“In Arizona, we're extremely lucky that we are able to have all of our therapies paid for and all of our medical bills paid for. But not every state offers the same benefits and opportunity.

“That's really difficult, when you're trying to take care of your child, it's almost like luck of where you are and what kind of services you have available including access to therapies and even the quality of your school. So, there's so much variance in the types of resources that are available to you, both free and not free and the quality of them,” said Uribe.

Paula Evans, a parent advocate and founder and chairperson of the Foundation for Angelman Syndrome Therapeutics, amplified other challenges that AS families must confront as well.

“One is communication and the other is epilepsy. You could take communication and then all of the things that stem from there. Children with Angelman syndrome can have a very unique behaviors. A lot of those behaviors stem from the fact that they can't verbally communicate. Then seizures, I mean, it feels like the onset of seizures is so devastating,” said Evans.

“First, you're given the diagnosis of Angelman syndrome…and then you're just getting your arms around that, you're feeling like you know what, we're doing good as a family. I see my child is making progress. I have the diagnosis and I have my child in the right programs and they're getting the right therapies and now…they're just moving in the right direction and you're feeling all this pride as a parent...and then boom, you're hit with the first bout of seizures and you're just back to square one emotionally,” she added.

“Epilepsy in children with Angelman syndrome is so complicated and it's ever evolving and you could go years with phenomenal seizure control and then out of the blue, your child just has a seizure and you lose control. So it's trying different meds and it's brutal, especially if your child was so well controlled for years and then develops kind of like a different type of seizure and they go backward and there's a regression in skill,” said Evans.

“The epilepsy can really negatively impact the child's quality of life. You could have a child that's completely mobile and walking and enjoying school and their friends and then boom, they could be hit with a seizure crisis and actually regress and not be able to walk anymore.”

For More Information on Angelman Syndrome

“We have two incredible foundations, the Angelman Syndrome Foundation, and the Foundation for Angelman Syndrome Therapeutics or FAST, that are doing just incredible work in not only supporting families but advancing fundamental research and therapeutic research,” says Uribe.

Both organizations offer a lot of resources and information. The Angelman Syndrome Foundation offers clinics around the country, where you can go and reach out to doctors who understand what Angelman Syndrome.

“They work in a team environment to really help you come up with plans of care that are going to fit your individual needs. This is incredibly important, because of the vast differences of our kids. There's similarities, but no two kids are alike, so having doctors that we understand and can help you is incredible,” she said.

Organizations and resources where you can find more information on Angelman syndrome include:

Angelman Syndrome Foundation, Inc. (ASF) 4255 Westbrook Drive Suite 219 Aurora IL 60504 Phone: 800-432-6435 (toll-free); 630-978-4245 Fax: 630-978-7408 Email: info@angelman.org www.angelman.org

Go here on the website for an A-Z resource list.

Foundation for Angelman Syndrome Therapeutics (FAST) PO Box 608 Downers Grove IL 60515 Phone: 630-852-FAST; 866-783-0078 Fax: 630-852-3270 Email: info@CureAngelman.org www.cureangelman.org

My46 Trait Profile Angelman syndrome

National Library of Medicine Genetics Home Reference Angelman syndrome

NCBI Genes and Disease Angelman syndrome

American Epilepsy Society (AES) www.aesnet.org

Epilepsy Foundation 8301 Professional Place East Suite 200 Landover MD 20785-7223 Phone: 800-332-1000 (toll-free) Email: ContactUs@efa.org www.epilepsy.com

Case Studies: Two Families Directly Impacted by Angelman Syndrome

In addition to being leading advocates for Angelman syndrome awareness, research, and the push for a cure, Regina Uribe and Paula Evans have both been directly impacted by Angelman syndrome.

Here are their stories:

Paula Evans

Paula is a parent advocate, founder and chairperson of the Foundation for Angelman Syndrome Therapeutics (FAST). She is also the co-founder and CEO of Genetics Biotherapeutics, a biotechnology company singularly focused on developing a therapeutic for Angelman Syndrome.

My daughter Ainsley was born in 2004 and we received her diagnosis when she was 10 months old.

In 2005, I think I came to the diagnosis differently than many parents because I wasn't devastated when I received the news and the reason I wasn't devastated was because it was not fatal.

Unlike many parents who come to this because their child is missing their milestones, I came to Ainsley's diagnosis because she was hospitalized multiple times before nine months of age. There was so many conflicting reports from the doctors.

They ranged from she's just constipated to there's something significantly wrong with her.

When I started hearing the term neurological, I was terrified that I was going to lose her. So, I felt like any diagnosis that meant that Ainsley wouldn't die was good news for me. When we got the diagnosis of Angelman Syndrome honestly, I was relieved that it wasn't fatal.

That was my first reaction and of course, there was devastation that followed, particularly around the fact that she wouldn't be able to speak.

After about a year of having our diagnosis and kind of just learning the landscape of early intervention, therapies and specialized doctors and neurology and genetics and all of that, I gravitated towards a group of parents who were interested in the research.

They were focused on what causes the syndrome and if there was anything that could be developed to alleviate those symptoms and this was a very different time.

This is 15 years ago. None of that research existed at that time, so it was a really exciting time and like I said, I was really fortunate to meet really just a handful of parents that have the same interests that I did.

And then, probably at the time when my daughter was about two and a half years old, a groundbreaking paper came out on Angelman Syndrome from a researcher named Dr. Edwin Weaver. It was the first time they were able to ameliorate the symptoms of the disorder in an animal model.

That really shifted the landscape for Angelman and along with a small group of parents that I had met online, we gathered at a conference in St. Louis and we met this researcher.

A little over a year after that, I started the nonprofit organization because I felt that at that point in time, there should be significant funding being invested in translational research that would lead to human therapeutics for the disorder.

That was the premise as to why the FAST Foundation was started and kind of my journey into life with Angelman Syndrome.

Regina Uribe

Regina is a parent advocate for Angelman Syndrome

My daughter Natalia was born in 2015 and she was our first child. Like every few parent, we don't know what we're really doing and soon after, about six months, we started noticing that she was falling behind her milestones.

My husband and I would argue and I would say, "Let it be. She'll be fine," versus my husband who took the stance of, "Something is wrong. We need to find what's wrong."

That lasted until she turned three, when she was diagnosed with Angelman Syndrome. It was a long three years of not knowing what was wrong but knowing that something was wrong.

You want to hope that everything will be all right but with understanding that it might not be all right.

It was a long journey with a lot of things I learned that I'm excited to share with parents.

My husband and I had two very different approaches regarding the medical community. I approached it very much trusting them.

While there are some wonderful doctors, I also learned that as parents, we need to be the advocates for our kids, because although doctors are very knowledgeable, they see your child at these discrete points of times.

They're not with your child 100% of the time and don't do the best with the information that they have. And sometimes, if you see three different doctors, you might get three different answers.

As parents, we really have to advocate for ourselves and trust your gut.

It's this balance of listening to medical professionals but also understanding that they're humans too and they might be wrong. You have to almost do that balance of like pushing forward and if something doesn't seem right or you're not sure if that answer is correct, get a second opinion.

You never know if there might be something different or someone else may have a different perspective. We would go to the pediatrician when they're so young, it's hard…if they don't have any other major issues, just delays…it's really hard for the doctors to tell you because the range of normality is so wide.

We knew she was delayed but it was like…wait and see, wait and see…she shouldn't have any other issues. There were no seizures, no other physical traits that would link to the syndrome and so that's also really hard when you're bordering, like it could, it could not be.

You're just dealing with a lot of unknowns. So, it was just a lot of trial and error, go see different doctors, try and rule out things and keep moving forward.

We went to see a geneticist early on and we did get the microarray but that came back negative. I know one of the things I wished the doctor would have told me is the options that were beyond that one test.

It took another year until we finally went back to get the whole exome sequence, to be able to test for Angelman syndrome because she had the mutation type.

It was a long journey of a lot of just back and forth, trial and error and kind of trusting your gut that something was wrong and really pushing for a diagnosis.

Referenced Sources

  1. Angelman, H. (1965). ‘Puppet’ Children A Report on Three Cases. Developmental Medicine & Child Neurology, 7(6), 681-688.
  2. Angelman syndrome: MedlinePlus Genetics. (n.d.). Retrieved October 8, 2020.
  3. Angelman syndrome: MedlinePlus Genetics. (n.d.). Retrieved October 8, 2020.
  4. Angelman syndrome: MedlinePlus Genetics. (n.d.). Retrieved October 8, 2020.
  5. Angelman syndrome: MedlinePlus Genetics. (n.d.). Retrieved October 8, 2020.
  6. Dagli, A. I., Mueller, J., & Williams, C. A. (1993). Angelman Syndrome. In M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews®. University of Washington, Seattle.
  7. Symptoms and Causes – Angelman Syndrome Foundation. (n.d.). Retrieved October 8, 2020.
  8. Angelman syndrome: MedlinePlus Genetics. (n.d.). Retrieved October 8, 2020.
  9. Dagli, A. I., Mueller, J., & Williams, C. A. (1993). Angelman Syndrome. In M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews®. University of Washington, Seattle.
  10. Dagli, A. I., Mueller, J., & Williams, C. A. (1993). Angelman Syndrome. In M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews®. University of Washington, Seattle.
  11. Dagli, A. I., Mueller, J., & Williams, C. A. (1993). Angelman Syndrome. In M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews®. University of Washington, Seattle.
  12. Dagli, A. I., Mueller, J., & Williams, C. A. (1993). Angelman Syndrome. In M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews®. University of Washington, Seattle.

Transcript

Jessica: You're listening to the Rare Disease Connection, a production of Aspect Health and raredisease.com. There are roughly 7,000 rare diseases and estimates are that a rare disease affects nearly one in 10 Americans and hundreds of millions of people worldwide. When you hear numbers like that, it's clear that rare diseases aren't so rare and it's impossible to know how many rare diseases go undiagnosed. If you or someone you loved is affected by a rare disease, you likely have more questions than answers and that's why we're here. Rare disease connection and our additional resources on raredisease.com and yourdna.com, bring together the people whose expertise can explain what you're facing. Jessica: From diagnosis, to prognosis, to treatment options. All the way to questions like who do I talk to and where are the people who have been through this before. You'll find those answers here from doctors, geneticists, academics, genetic counselors, patient organizations and other patient and their families who are all within your reach. We're here to connect you. This is Rare Disease Connection. Hi, everyone, this is Jessica, co-host of Rare Disease Connection and genetic counselor. Once again, I'm excited to bring you some recent conversations I've had with experts from around the world about a very specific rare genetic disease, Angelman Syndrome. Before you listen, we know that hearing from these experts is only the beginning for you. Jessica: That's why we've taken the information here in this episode and we've added additional resources, other explanations, links for you and references, all in a downloadable guide on Angelman Syndrome. You can get over to raredisease.com/angelman and you'll get a free copy of that guide. Once again, go to raredisease.com/angelman after you listen and get all those additional resources from us. Please do so, because there's so much that we've pulled together to help you on your journey in understanding this disease. It will certainly help support you and your ongoing plan of action. The experts are here so let's talk about Angelman Syndrome. Our first conversation is with Dr. Lynne Bird. Okay, would you mind just introducing yourself? Dr. Lynne Bird: I'm Lynne Bird, I'm a clinical geneticist, trained first in pediatrics and then clinical genetics and I see children who have birth defects and a wide variety of genetic conditions and I've been in practice for about 25 years. Jessica: Wonderful, and how did you originally become involved with Angelman Syndrome? Dr. Lynne Bird: Well, a very special family drafted me for the project. They wanted their newly diagnosed son to be able to participate in Angelman Syndrome research and they elected me to be the local site investigators on those studies which were just getting started at the time. Jessica: Great, and what is Angelman Syndrome? Dr. Lynne Bird: Angelman Syndrome is an intellectual disability syndrome with seizures, sleep disturbance, absence of speech and easily provoked laughter, lack of achieving developmental milestones is usually evident in the first year of life and diagnosis is usually made before about three years of age now. Jessica: How common is Angelman Syndrome? Dr. Lynne Bird: Estimates is varied but I think one in 20,000 would be a reasonable ball park. Jessica: What is the underlying cause of Angelman Syndrome? Dr. Lynne Bird: Angelman Syndrome is a genetic disorder. It's due to a defect in the gene UBE3A and this is a gene which is imprinted, which means that it's silenced depending on which parent you inherit it from. In this case, UBE3A is paternally imprinted which means the father's copy of the gene is silenced and only the mother's copy is active in brain cells. There are four ways we know of that can result in the mother's copy of the gene being missing, silenced or defective. Jessica: How is Angelman Syndrome typically diagnosed? Dr. Lynne Bird: Most often a clinician, maybe a neurologist or geneticist who is familiar with the condition will suspect it and send a blood test for DNA methylation and that single test can pick up three of the four varieties of Angelman Syndrome, approximately 85% of cases. If that test is negative then, one can go on to do an additional blood test, which would look at the spelling of the UBE3A gene to pick up the remaining cases that we know of. Jessica: What is the typical age of diagnosis for people with Angelman Syndrome? Dr. Lynne Bird: That number is always changing as our ability to recognize the condition gets better and our testing improves, but most of the classical cases are now usually recognized prior to a year of age or a year and a half or so but the milder or less classical, less typical cases don't get diagnosed sometimes until several years of age. The older patients in the community who didn't have access to testing 20 or so years ago, may still be undiagnosed, so there are potentially a lot of undiagnosed adults out there, because they grew up in an age where we didn't really have a way to test. Jessica: What does an appointment for someone who is newly diagnosed look like in your clinic? Dr. Lynne Bird: Well, my evaluation typically starts with recording the family history. Asking about the pregnancy and the birth, which are most often unremarkable and then discussing the developmental and medical history of the patient and then I examine the child. Typically, the physical examination is essentially normal in Angelman Syndrome but the behavior, the quality of movement and the personality may show some signs typical of Angelman Syndrome. I usually begin the discussion by explaining the genetics behind Angelman Syndrome. Explaining the four different molecular varieties and which variety their particular child has and then I move on to explaining what the symptoms are like and what it will mean for their child to have Angelman Syndrome. Dr. Lynne Bird: I usually provide advice regarding management of symptoms, arranging rehabilitative therapies and I assist with coordinating the care needs. Usually someone with Angelman Syndrome will need to see a neurologist because seizures are very common. So, if they haven't already been to see a neurologist, I'll usually suggest an appointment even in advance of the first seizure so that parents can be prepared. Many children will have some gastrointestinal problems such as reflux or constipation. Some will need to see a gastroenterologist. Some will have strabismus where the eyes don't line up properly. Dr. Lynne Bird: Some patients will need an ophthalmologist to address that and the major focus is on getting services such as physical therapy, occupational therapy and speech or communication therapy setup in order to help the individual achieve his or her maximum potential. Jessica: What are the current treatments available to patients with Angelman Syndrome? Dr. Lynne Bird: Currently, the treatments we have are entirely supportive. We try to manage the medical problems as well as we can and we try to promote healthy development through therapies and behavioral interventions. Seizures can be treated with medications or sometimes special diets. The sleep problems, we try to manage with a combination of behavioral techniques and medications, and their medications that help us manage reflux and constipation when needed. However, presently, there's really no treatment that is proven to alter the natural history of the condition but there are some drugs being trialed and more studies about to begin shortly using a variety of different strategies. Jessica: Are you currently involved in any clinical trials and if so, can you tell us a little bit about those? Dr. Lynne Bird: Yes, I've been involved in clinical trials for Angelman Syndrome since 2001. One of the most important research studies has been the natural history study, which helps us understand the typical trajectory of the disorder, so that we have a firm understanding of the baseline in order to measure the effectiveness of any potential treatment. Enrollment is ongoing for that study, as well as for an industry sponsored study that Roche is conducting to determine the best outcome measures that should be used in future clinical trials. So, neither of those studies include any treatment, they're observational. Dr. Lynne Bird: There have been several treatment trials, which have been done and have not shown any benefit. There is an ongoing study of a drug named Gaboxadol that may have benefit a safety trial, showed it to be quite safe and possibly effective. So, a definitive trial to assess the effectiveness is currently ongoing. There are a couple of studies just getting started that will assess compounds called ASOs antisense oligonucleotides, which are short pieces of DNA, designed to unsilence the sleeping paternal copy of the UBE3A gene. Since the gene silencing occurs only in the brain, these medications need to be delivered directly into the spinal fluid, which takes special expertise. Dr. Lynne Bird: The advances in genetic technologies that have occurred over the last 10 or 20 years have really made it an exciting time in rare disease research in general, and in Angelman Syndrome research in particular. Jessica: That is really exciting, and how can patients get in touch with your clinic to see if they would be a good candidate? Dr. Lynne Bird: So families who want to hear about the research options can certainly contact me directly. My email is lbird@rchsd.org. One of the best ways though, to find about any currently available research studies for any condition is the website, clinicaltrials.gov which allows you to search on a particular condition or a particular treatment and find the studies that have been completed or ongoing or currently recruiting and where are those studies are being conducted and more information. Jessica: What are the greatest barriers you see with patients with Angelman Syndrome? Dr. Lynne Bird: I find the communication challenges to be the greatest barrier for the person with Angelman Syndrome but also for the researchers who are trying to understand what the real capabilities are of someone who has Angelman Syndrome. It's generally felt that we underestimate the intellectual ability in Angelman Syndrome because we don't have instruments that adequately capture their abilities because they can't communicate verbally and sometimes they can't show us non-verbally what their abilities are because of impairments in motor function. Other people might consider behaviors, a great barrier and certainly the sleep challenges are significant. Dr. Lynne Bird: I'm not implying that, my opinion about what the most significant challenge or greatest barrier is held by all but I think that's one thing that if we could change, would really impact the quality of life for families. Jessica: On that note, what are your hopes for the future of Angelman Syndrome? Dr. Lynne Bird: Well, my hope would be that we could actually normalize the development of children with Angelman Syndrome so that they could have a more typical childhood experience but this is of course is a huge aspirational goal and it's likely that we will only get there in increments and baby steps, but even if all we can do is ameliorate some of the symptoms, for example, help them and their families sleep better, improve their communication and self help abilities, that would be a huge win. The difference between having a child who's permanently in diapers and one who achieves continence is enormous for quality of life. Dr. Lynne Bird: If we could find a treatment that truly alters the trajectory of this condition, and kind of raises the ceiling for what people who have Angelman Syndrome can accomplish, then we could start to make the case that universal newborn screening is appropriate so that we identify all individuals with Angelman Syndrome as soon after birth as we can, so that they can be treated promptly to maximize their developmental potential. Jessica: What has been the best thing about working in the field of Angelman Syndrome? Dr. Lynne Bird: Well, without a doubt ... I mean, it's been extremely interesting, of course but without a doubt the best thing is the families. The families are absolutely incredible and I really feel that it's a privilege that I've gotten to know them. They are absolutely devoted to their children and many of them have funded their own travel to participate in natural history studies. They've raised money for research and incredibly they remain cheerful in the face of constant sleep deprivation and they never lose hope. They're really my heroes. Jessica: Thanks to Dr. Bird. Regina Uribe is a parent advocate of Angelman Syndrome. Let's hear from Regina. All right, Regina, thanks so much for joining us today on the Rare Disease Connection. I wanted to just start by asking you if you mind sharing a little bit about yourself? Regina Uribe: Sure. My name is Regina Uribe. I am a mom of two beautiful kids, a five year old daughter, Natalia who is my angel and my son, Alexander, who's one and a half, a wonderful husband. I live in Phoenix, Arizona. Born in Mexico City but have been in Arizona for a long time and I work as a consultant for an Ed Tech company. Jessica: Great, and would you mind telling us how you started your journey with Angelman Syndrome in your life? Regina Uribe: Yeah so, my daughter Natalia was born in 2015 and she was our first, like every few parent, we don't know what we're really doing and soon after, about six months, we started noticing that she was falling behind her milestones and my husband and I would argue and say like, "Let it be. She'll be fine," versus my husband is like, "Something is wrong. We need to find what's wrong," and so that lasted for until she turned three, when we finally got the diagnosis, that she was diagnosed with Angelman Syndrome. So, it was a long three years of not knowing what was wrong, but knowing that something was wrong and you're bordering that, you want to hope that everything will be all right but with understanding that it might not be all right. Regina Uribe: It was a long journey with a lot of learnings that I'm excited to share with parents. Jessica: What was the journey like with the medical community or doctors, how did you approach that to begin with? Regina Uribe: Sure, so I think my husband and I had two very different approaches. I approached it very much trusting with the medical community and while there are some wonderful doctors, I also learned that as parents, we need to be the advocates for our kids, because doctors while they are very knowledgeable, they see your child at these discrete points of times. They're not with your child 100% of the time and don't do the best with the information that they have but sometimes you're going to get ... if you see three different doctors, you might get three different answers. As parents, we really have to advocate for ourselves and trust your gut. Regina Uribe: It's this balance of listening to medical professionals but also understanding that they're humans too and they might be wrong. You have to almost do that balance of like pushing forward and if something doesn't seem right or you're not sure if that answer is correct, get a second opinion because you never know if there might be something different or someone else may have a different perspective. I think, we would go to the pediatrician and the pediatrician when they're so young, it's hard ... if they don't have any other major issues, just delays, it's really hard for the doctors to tell you because the range of normality is so wide. Regina Uribe: So, it's ... we knew it was delayed but it was like a wait and see, wait and see, it shouldn't have any other issues. No seizures, no other physical traits that would link to the syndrome and so that's also really hard when you're kind of bordering, like it could, it could not be. You're just dealing with a lot of unknowns. So, it was just a lot of trial and error, go see different doctors, try and rule out things and keep moving forward. I think we went to see a geneticist early on and we did get the microarray but that came back negative. I know one of the things I wished the doctor would have told me is the options that were beyond that one test. Regina Uribe: So, it took another year until we finally went back to get the whole exome sequence, to be able to test for Angelman Syndrome because she had a different ... she had the mutation type. So, it was a long journey of a lot of just back and forth, trial and error and kind of trusting your gut that something was wrong and really pushing for a diagnosis. Jessica: That's so helpful for other parents to know. It sounds like you've worn so many hats. Being a new mom, you're advocating, you're working, you're trying to figure all these things out and being an expert in something that you've never heard of before. I'm wondering what your advice is to parents who are struggling in that period of time with the wait and see or even if they now have a new diagnosis? Regina Uribe: Yeah. I think for parents that don't have a diagnosis yet, one of the best advices that I got from actually my sister in law, who is a pediatrician, she said, regardless of the diagnosis, the approach is going to be the same. Therapy, therapy, therapy. We started therapy really early at nine months and that's what I would say, yes, definitely fight for a diagnosis because unfortunately, diagnoses are important to get state support. Medical issues are expensive and therapies are expensive, so yes, fight for the diagnosis but focus on the ... the treatments can be the same a lot of the times not always but therapy plays a huge role. Regina Uribe: So, getting therapies in early and really becoming ... like you said, you're wearing so many hats and advocate, you'd have to learn all these medical terms and push and do your own research for what the symptoms can mean and then you also have to become a therapist yourself and therapy has made a huge difference in doing it early on, so that's what I would advocate for the non-diagnosed parents. For the newly diagnosed parents, what I would say is, it's okay to mourn for your child that you had an expectation of and there's one poem, I don't know what it's called them, Welcome to Holland and that helped my husband and I to understand that the world that you were not expecting is just different, but it's so wonderful. Regina Uribe: Our kids are so wonderful. So, once you let go of your expectations of what you thought it should be and just focus on what it is and the beauty that is your child, we found it a lot easier to cope because you are just ... open up to a whole new community that you wouldn't have otherwise thought and we are so lucky that Angelman community is amazing. The therapy, the team, people just like love your child and it's such a blessing. So, with all the hardships, we get it, it's so hard and mourn, but know that there's so much opportunity and beautiful community that you will now have access to, that you wouldn't have otherwise. Jessica: That's a really good point and something that we commonly hear with rare disease is that parents see themselves making this new reality that they once never imagined that they could handle and changing their expectations to something that is beautiful and they do have a great quality of life with their new expectations, but that mourning, it is okay and that is ... it's such a great way to put all that, so it sounds like that will be really good advice for somebody who has a new diagnosis as well because it can feel overwhelming of course. Regina Uribe: Yes, absolutely and even like you heard me, kind of getting teary and emotional, it'll always have a sting, you just learn to cope with it. Jessica: When you were talking about how important those therapies were, what are some of the services or therapies, treatments that have been the most helpful from your experience? Regina Uribe: Sure. So, for my daughter, I mean, they've all been helpful in different stages and so, she has been in physical therapy and occupational therapy since she was nine months and speech, I would say early on was harder, just because with Angelman Syndrome, speech therapy, given that they're nonverbal, I think developmentally, they're just not there yet. What you do with the therapists doesn't seem ... it's a lot harder to see the results, so it's, I would say, the most frustrating part and then a lot of speech therapists don't ... there's kind of like a split, I almost feel like within the community of therapists of like, when you introduce like the augmentative communication device, and this is where the community just provides a lot of value, where you can share your worries. Regina Uribe: They will advise to start early and introduce different options and they have so many techniques that you don't always get from your therapist. So, I think it's like the community plus and therapists and kind of this collaborative relationship to really provide the care, the best care for your child, I think is the most fruitful but yeah speech, occupational, speech therapy all have played an incredible role and I would add, we went ahead and did horse therapy for ... before she was walking, that was amazing. She loved horses and I think it really helped accelerate her strength, core strength and really prepare her to be walking independently. Jessica: Great and what makes a family or a patient and the family facing a diagnosis of Angelman Syndrome most successful do you think? I know you talked about the community that you surround yourself with, are there things that have made you more successful in times? Regina Uribe: It's support. It's hard for it to fall into one person, so as much as possible, if you can build a support system, it really helps. As parents, it can be easy to forget to take care of ourselves, but I think it's really important. If we are healthy mentally, physically, we're able to do a better job for our children but it can be overwhelming wearing all of those different hats, so taking advantage of possible respite or your extended family members and friends to be able to come and help you, and kind of creating this bigger tribe of support, I think is important and people want to help and it's okay to ask for help. Regina Uribe: We can't all be superheroes and we are amazing but we also just need to take care of ourselves individually. So, I would say that that was something that for us has been incredibly important is just building a circle of support around us. Jessica: I love that you mentioned that. That is so important to take time to care for yourself as well. What is the greatest struggle or the unmet needs for people with Angelman Syndrome right now, do you think? Regina Uribe: I saw that question and I struggle to answer it in because ... I'll kind of give you an answer and a non-answer at the same time. Angelman Syndrome is a spectrum and there are kids with a variety of needs. For example, my daughter doesn't have seizures, but about 70 ... over 70% of kids with Angelman Syndrome suffer with seizures and that's really hard. Finding that right medication balance and I just see so many of my friends that struggle with seizures and it's heartbreaking but not everyone experience it in the same way, the medicines the same way. So, there is no one size fit all answers but I would say many of us struggle with sleep. I think there is just a wide range even of support services that the State offers, right? Regina Uribe: Here in Arizona, we're extremely lucky that we are able to have all of our therapies paid for and all of our medical bills paid for, for her under the state but not every State offers the same benefits and opportunity. So, that's really difficult, when you're trying to take care of your child, it's almost like luck of where you are and what kind of services you have available, and that's the same for access to therapies and even the quality of your school. So, there's so much variance in the types of resources that are available to you, both free and not free and the quality of them. Regina Uribe: I know many parents also just struggle thinking about when our children grow old, who's going to take care of them? That's just also a hard pill to swallow. Jessica: Is there anything that you are hoping to see for the future of Angelman Syndrome say, in the next five years or even more? Regina Uribe: I feel blessed that we have two incredible foundations, the Angelman Syndrome Foundation, and the Foundation for Angelman Syndrome Therapeutics or FAST, that are doing just incredible work in not only supporting families but advancing fundamental research and therapeutic research. My husband and I got a scholarship to go to Chicago in December, to listen to what pharmaceutical companies were doing in relation to Angelman Syndrome and it is just humbling and exciting to see that there are, I think, five or more human clinical trials for Angelman Syndrome. That's huge. There's a lot of research and there's a lot of hope for a cure for better therapeutics that could help curb some of the symptoms. Regina Uribe: So, I would say for newly diagnosed families that listen and hear, there's so much exciting science behind finding a cure for Angelman Syndrome and I know that it is within our child's lifetime to see some incredible things happen. Jessica: That's really exciting. Is there anything that you want to share about the support organizations, anything that has been helpful to you that you would recommend for others? Regina Uribe: Yeah, so I think going to the conferences, both FAST and ASF, Angelman Syndrome Foundation offer family conference, research conference. Get involved with the community. There is something magical about meeting another parent who has a child with the same diagnosis where you automatically feel bonded, because you know they understand. Yet, it's great to be connected virtually but when possible, connecting personally also is an incredible experience. I'm always a big support of volunteering, so I have co-coordinated the Phoenix walk here to raise awareness about Angelman Syndrome with Angelman Syndrome Foundation and fundraise for that organization. Regina Uribe: I think both organizations offer a lot of resources, both information and then Angelman Syndrome Foundation offers ... they have clinics around the country, where you can go and reach out to doctors who understand what Angelman Syndrome is and they work in a team environment to really help you come up with plans of care that are going to fit your individual needs. This is incredibly important, like I mentioned earlier, because of the vast differences of our kids. There's similarities, but no two kids are alike, so having doctors that we understand and can help you is incredible. Jessica: Great. Is there anything else that you want to share with us before we end our time talking together? Regina Uribe: I think they're ... our kids are incredible and my daughter continues to surprise me every single day with what she is able to do and I always just try to remember and focus on how is her progress like and always assume competence and never compare her to anyone else because my daughter just like any one of our child is so unique and have so many strengths and just focusing on that just really helps me, so hopefully it can help another parent. Jessica: Thanks to Regina. Paula Evans is a parent advocate and chairperson of the foundation for Angelman Syndrome Therapeutics. Let's hear from Paula. Okay, Paula, would you mind introducing yourself? Paula Evans: Sure. My name is Paula Evans. I am the founder and the chairperson of the Foundation for Angelman Syndrome Therapeutics, also known as FAST. I am the co-founder and CEO of Genetics Biotherapeutics, a biotechnology company singularly focused on developing a therapeutic for Angelman Syndrome and I'm also mom to a 15 year old ordinary girl with Angelman Syndrome. Jessica: Would you mind ... On that note, would you mind telling us how you started your journey with Angelman Syndrome? Paula Evans: Sure. So my daughter Ainsley was born in 2004 and we received her diagnosis when she was 10 months old, so in 2005 and I think I came to the diagnosis differently than many parents because I wasn't devastated when I received the news and the reason I wasn't devastated was because it was not fatal and I was ... unlike many parents to come to this because their child is missing their milestones, I came to Ainsley's diagnosis because she was hospitalized multiple times before nine months of age. There was so many conflicting reports from the doctors from, she's just constipated to there's something significantly wrong with her. Paula Evans: When I started hearing the term neurological, I was terrified that I was going to lose her. So, I felt like any diagnosis that meant that Ainsley wouldn't die was good news for me. When we got the diagnosis of Angelman Syndrome honestly, I was relieved that it wasn't fatal. That was my first reaction and of course, there was devastation that followed, particularly around the fact that she wouldn't be able to speak. That's how I came into Angelman Syndrome. After about a year of having our diagnosis and kind of just learning the landscape of early intervention, therapies and specialized doctors and neurology and genetics and all of that, I gravitated towards a group of parents who were interested in the research. Paula Evans: What causes the syndrome and if there was anything that could be developed to alleviate those symptoms and this was a very different time. This is 15 years ago. None of that research existed at that time, so it was a really exciting time and like I said, I was really fortunate to meet really just a handful of parents that have the same interests that I did and then, probably at the time when my daughter was about two and a half years old, a groundbreaking paper came out on Angelman Syndrome from a particular researcher named Dr. Edwin Weaver. It was the first time they were able to ameliorate the symptoms of the disorder in an animal model. Paula Evans: That kind of really shifted the landscape for Angelman and I, myself and this small group of parents that I had met online, gathered at a conference in St. Louis and we met this researcher and to make a long story short, it was probably about a little over a year after that, that I started the nonprofit organization because I felt that at that point in time, there should be significant funding being invested in translational research, research that would lead to human therapeutics for the disorder. That was the whole ... really the premise as to why the FAST Foundation was started and kind of my journey into life with Angelman Syndrome. Jessica: Can you tell us a bit more about the organization? Paula Evans: Sure. We started it, it'll be 12 years ago this August because I started it on my daughter's fourth birthday, so it was August 2008. Just a reminder, that was the beginning of the last economic crisis, so great time to start a nonprofit looking for donations. It was exciting times back then I had this great group of parents, very talented, very smart, very savvy. At that time, I certainly didn't have a full grasp on the science but I was blessed to have a fantastic board member who did, a microbiologist named Becky Burdine. It was really exciting times and it was really about just building, we came ... the foundation was started on a message that was so novel to the community that it was really just ... those early days was just building the relationship with the community. Paula Evans: Spreading the message that we should be able to treat this as a treatable disorder and at that time, that was just such a foreign concept. I mean, parents, when they were given this diagnosis, were told that, there was no hope. There would never be a treatment. Just take your child home and love them and that was it. Those were the parents that weren't being told to institutionalize their child. It was a very different landscape back then. We have this radical new message and really our first objective was to just inform the community and educate them on ... because back in that day, most parents didn't even know what caused it. Paula Evans: We were just given this disorder, this diagnosis and basically just told that all the things that your child would not do and there was no hope. I mean, that was the takeaway that most parents got. So, it was really just ... We set out to educate the community, on what causes this and how we could think about going about developing treatments for it and really just unveiling this radical new message that maybe we could all hope for better for our children. So, those were the early days of the organization and then, in 2011, the foundation funded a clinical trial in the community. It was on a symptomatic ... potential symptomatic treatment called Minocycline, a well studied antibiotic. Paula Evans: The foundation was able to fund that on our own and I think that was really a game changer for the Angelman community for many, many reasons. We learned so much from that clinical trial that helped propel us forward and prepare for better trials and better therapeutics. We sent a very clear and loud message to industry that this was a community and a disorder that wanted therapeutics and was willing to participate in the hard work it takes to evaluate therapeutics. So, I really think that was a remarkable turning point. Like I said, we learned many things from that. One of the most valuable things I think we learned was that, at that point in time, the available tools to assess therapeutic benefit in individuals with Angelman Syndrome were non-existent. Paula Evans: I think that the two most important takeaways to me from that trial was that we needed better tools to assess our children for therapeutics and that we sent a very clear message to industry that this is a disorder that you can invest in because this is a community that is willing to participate in these trials and that's a big thing for industry, recruiting enough patients for a rare disease clinical trial is always ... there's always some angst around that in the pharma world and I think the message was loud and clear that this is a community that would sign up for trials and would do that heavy lifting to evaluate therapeutics. We were very proud of that and then after that, it just seems like ... gosh, it was just an explosion. Paula Evans: I don't know how else to describe it. We were doing a lot of work. The organization was funding a lot of work to position ourselves for when ... we knew that some of these technologies that were on the future horizon, like we were able to see they were there. They were on the horizon, but we knew that Angelman Syndrome as a disorder would not be in a position to capitalize on those emerging technologies once they were ready for primetime. We did a lot of work, we funded a lot of research that would position ourselves to be able to take advantage of those emerging technologies and I'm really proud of that because here we are in the age of gene activation therapies and gene replacement therapies. Paula Evans: Angelman Syndrome is one of just a handful of these rare diseases that are ready, willing and able to evaluate those in this patient population. I'm enormously proud of the work the foundation has done to ready us for this point in time. Jessica: If I might ask, I think I was reading your story and you did not previously have a background in medicine or science. Tell me a little bit about how you prepared yourself for this huge task at hand. Paula Evans: Honestly, this has been a labor of love for me. I worked with an all volunteer ward all these years. I mean, we just recently have brought paid staff on, after building this organization for 12 years. My whole team worked voluntarily, which is really a testament to my team because all of them were parents of children with Angelman Syndrome. There are so many parents in the community that are so quick to thank me and I always say, "No, like, I couldn't have done anything without you guys. You guys are the ones that have raised the money to get us to where we are." Secondly, this wasn't selfless. I don't deserve any accolades. Paula Evans: I had a child, I was given this devastating diagnosis and when I received Ainsley's diagnosis, when she was 10 months old, it came with a laundry list of all the things that she would never do. She may never walk. She'll never talk. She might never go to school. She's never going to have a job. She's never going to get married. She's not going to have any friends. I mean, they literally took every one of my dreams for my baby and just stomped on it like a cockroach running across the floor. It was breathtaking, really and I just kept looking at this baby of mine that to me had nothing but potential and possibilities. Paula Evans: By the time Ainsley was five, she already accomplished 90% of the things the doctors told me she would never do. She's been my most motivation all of these years, but I have a horse in this race. I've worked really hard because at the end of the day, I had much hope that this would benefit my own child and her future and that when I leave this planet, I'm leaving her in a better position to advocate for herself. That has been my motivation always and I'm probably at a different point in time now, because my daughter is 15 and I've kind of went through all of those milestone phases that parents really is heartbreaking that they don't get to experience when their child has a diagnosis like Angelman Syndrome, so kind of those are kind of behind me. Paula Evans: I can look at my daughter and be enormously proud of ... what a beautiful young lady she's grown into and like I said, she's defied all the odds multiple times but I am at a point now where, if there's anything that can be done scientifically, therapeutically to give Ainsley the tools that she needs to advocate for herself, and make her own choices in life and to be able to do that, when I'm no longer here to help her do that, then I will consider that the ultimate success. Jessica: That's incredibly inspiring and what are the current trials and treatments that researchers are working on today as a result of the Foundation for Angelman Syndrome Therapeutics? Paula Evans: This is really breathtaking. I try not to do the pat on the back. I think it's really important to have your actions, speak for themselves but this I'm enormously proud of. This happens on a larger scale, like for various cancers, where they receive significant funding from the National Institutes of Health to work in these consortiums to tackle a big problem. We created one free Angelman Syndrome which was kind of unheard of in rare disease because researchers basically live to publish, so that they get more funding to work on their hypotheses and get them published, so they get more funding. That's kind of the role of a scientist. Paula Evans: We brought together a group of scientists and we asked them if they would share their knowledge and their research in real time with each other, so that we're able to accelerate the rate of research significantly and to get a bunch of scientists that are kind of clawing for the same rare disease money, this isn't cancer. It's not Alzheimer's, where there's a significant pool of money to draw from, to have them share their data in real time with potential competitors was a huge ask. We were able to assemble this amazing team, because Angelman Syndrome kind of affects the child holistically. It's not just motor, it's not just epilepsy. It's not just cognition. Paula Evans: It's not just sensory, it affects the individual holistically and we really needed that holistic approach, so we needed an expert in genetics. We needed an expert in epilepsy. We needed an expert in drug delivery. We needed a varied skill set and we needed them to be speaking to each other in real time, so that we weren't wasting time that we were accelerating from one piece of it to the next piece of it, without waiting two years for that paper to be submitted, published and then available. We're really looking to accelerate research significantly and to be able to find a team of scientists that had that level of expertise specifically in Angelman Syndrome or a related field that was going to contribute significantly to the understanding of Angelman Syndrome. Paula Evans: Moving any particular area of research forward was ... it was quite a feat and we were able to do that we brought together ... it grew into five different laboratories with upwards of 30 scientists working collaboratively. We called it the FIRE initiative and it stood for the FAST integrative research environment because it wasn't a bricks and mortar center of excellence but it was this virtual center of excellence and we were able to accomplish amazing things from that program. We developed two completely novel animal models of the disease. A rat model of Angelman Syndrome and a pig model of Angelman Syndrome. Paula Evans: We were able to significantly contribute to several gene therapy approaches and one of them was ... I'm sure, you know at this point with Angelman Syndrome, there's this silent copy of the paternal UBE3A gene on the allele from the Father, from the paternal allele is normally silenced in all of us, right? Children with Angelman Syndrome are missing that maternal copy and because the paternal copy is normally silent in the brain, they don't have any copy. One of the areas of research and therapeutics is can we activate that normally silent paternal copy of UBE3A and compensate for the loss of maternal contribution? Paula Evans: That was within our FIRE grant, that was one of the approaches that we were funding. That started back in 2012 and I think in the summer of 2017, we realized that ... I don't want to get too technical here, but there's a mechanism that silences that paternal gene in all of us and it's called the antisense transcript. That transcript is responsible for other processes in the body, not just silencing that paternal copy of UBE3A. We knew looking at that transcript, you can't shut the whole thing down in order to allow the paternal to come on. You have to very precisely hit that transcript in a place where you're not going to disrupt some of the other genes that could be causative of product release syndrome. Paula Evans: It was really ... Understanding that transcript, we invested a lot of time and money into understanding what that transcript does, where it does it, how it does it, why it does it. In probably mid 2017, the researcher that we funded for that did identify what I call the sweet spot. I use air quotes for that. Jessica: Mm-hmm (affirmative). Paula Evans: Really that sweet spot where you should be hitting that transcript and we did some quick proof of concept studies with an antisense oligonucleotide, which that class of drugs is perfectly suited for that kind of precise targeting and we were able to activate the paternal in animal studies and myself and our Chief Science Officer, Allyson Berent approached our board of directors and said, "What do you guys think of us just starting our own biotech company," because in order to develop that in the next stages, it was going to take a significant investment, right? We don't want to rely on donor dollars for that nor did we want to put all of our donor dollars in that basket. Paula Evans: You don't know until you know if something's going to work and we owe it to our children, we have a moral obligation to pursue every promising strategy that there is. We didn't want to, you know what I mean, kind of put too much into the one basket, but it was very evident that we needed to pursue that. We did something that no other NPO to date has done and the FAST organization launched a for profit and set about the task of developing this antisense oligonucleotide strategy for human application. We launched the biotech company in early December of 2017 and it was approximately two years later that we were in human clinical trials. Paula Evans: We were able to raise enough money to develop that through IND, investigational new drug studies, which is what the FDA wants to see before you go into humans and I'm enormously proud of that. I mean, we're sitting with fingers crossed that this type of approach is effective, and it significantly alters the course of the disorder for individuals with Angelman Syndrome, but the course of action we took was novel. It was brave and aggressive and if it's actually effective and successful, I think it'll be a story for all stories. Jessica: Absolutely proud, sounds like an understatement with that story, my goodness. How can patients learn more or enroll in these trials? Paula Evans: This particular trial is the first ever trial in Angelman Syndrome that is testing the potential to treat the disorder at the root cause. That's important. There'll be many more to follow, I'm sure but this is the first one and it's the only one in the clinic thus far and I think the easiest place to go is clinicaltrials.gov, where you'll find basically all clinical trials, but if you go to clinicaltrials.gov and just type in Angelman Syndrome in the search bar, you'll find the study on GTX-102 but Genetics, the biotech company also tries really hard to keep the community updated by disseminating information to both the FAST NPO and the Angelman Syndrome Foundation NPO. Paula Evans: As well as, there's two organizations up in Canada and Canada is a proposed site for the GTX-102 trial, which is also known as the KIK-AS study. We try and disseminate the information in a broad way through the patient organizations. The study itself has its own website, which is kik-as.com but if you're looking to enroll, if you want to get more information, you can easily start at clinicaltrials.gov. Jessica: Great. What do you think is the greatest struggle or unmet need for people with Angelman Syndrome now? Paula Evans: I honestly think there are two areas where individuals with Angelman Syndrome struggle the most and I think ... and they're so interchangeable and it depends on the day and if you ask any parent on any given day, the answers will fluctuate between these two and one is communication and the other is epilepsy. You could take communication and then all of the things that stem from there, right? So, children with Angelman Syndrome can have a very unique behaviors. A lot of those behaviors stem from the fact that they can't verbally communicate. Then seizures, I mean, it feels like the onset of seizures is so devastating. Paula Evans: It's almost as devastating as the news of the disorder itself, right? You're given the diagnosis of Angelman Syndrome and it's just devastating, and then you're just getting your arms around that, you're feeling like you know what, we're doing good as a family. I see my child is making progress. Now, that I have the diagnosis and I have my child in the right programs and they're getting the right therapies and now, he or she is sitting up or they're starting a four point crawl and you see all these ... they're just moving in the right direction and you're feeling all this pride as a parent that ... and then boom, you're hit with the first bout of seizures and you're just back to square one emotionally. Paula Evans: It's just devastating to watch, but that kind of never goes away because the epilepsy in children with Angelman Syndrome is so complicated and it's ever evolving and you could go years with phenomenal seizure control and then out of the blue, your child just has a seizure and you lose control and it's trying different meds and the epilepsy is, it's hard, it's brutal. It's brutal, especially if your child was so well controlled for years and then develops kind of like a different type of seizure and they go backward and there's a regression in skill or it's just very difficult. Paula Evans: The epilepsy part of it is very difficult only because it can really negatively impact the child's quality of life. You could have a child that's completely mobile and walking and enjoying school and their friends and then boom, they could come ... they could be hit with a seizure crisis and actually regress and not be able to walk anymore. So, the epilepsy part of it is awful but if you're in a place as a parent where, I have epilepsy under control, my kid is on a medication, that's great and the benefits far outweigh any potential side effects we're seeing. They're in a really good place. Paula Evans: They're developing, they're moving forward. They're hitting milestones in a great place then it's the communication. I think it fluctuates depending on where you are with your particular child but those are definitely the two most difficult things to manage. Jessica: Is there anything specific that you want to highlight for a parent who has a child with Angelman Syndrome, anything that has related helped you along the way? Paula Evans: Yes. So, I speak to a lot of newly diagnosed parents and I always say the same thing. I had mentioned when I received my daughter's diagnosis, I had ... A doctor literally just walk into her room, as my husband and I stood over her crib, our precious little girl and literally took every one of our dreams for her and squashed it like an ugly bug in the room. I decided to ignore all of that and just look at my child as my child and I was going to teach her and I knew she was fully capable of learning. I didn't know how her brain might learn, so I didn't want to shut her off from any opportunity and when I speak to newly diagnosed parents, my advice to them is always set the bar really high. Paula Evans: Your child is going to amaze you and they're going to accomplish things that every doctor has told you they're not going to accomplish. If you set that bar really low, if you listen to those doctors and set that bar as low as they tell you to set it, that's where your child is going to go. If you set that bar really high, give them the opportunity to rise to the occasion, our kids are smart. They're clever. They have nothing but potential. When you get that diagnosis, it's the same child that you had before you got that diagnosis. Don't let that diagnosis ... Of course, it's going to change your life and it's going to change your child's life. Paula Evans: I don't mean to imply that it doesn't but our kids are incredible. They're completely capable of achieving great things. It may take a little longer, it may take a little more hard work but don't give up. Set that bar high. Let them rise to the occasion. You can always lower the bar if you need to but set it high and know that your child is smart and they're capable, and it's just going to take a little extra work than it would with a typical child. They're capable of amazing things. Jessica: I love that message. What are your hopes for the future of Angelman Syndrome? Paula Evans: My hope every single day is that we develop therapeutics that help every single individual regardless of age, regardless of genotype and what that therapeutic means to that particular individual because everyone is in a different place, right? So, if you talk to a parent of a child who's one, two years old, it's really funny, they're going to say to you, "I just want my child to walk. I want them to be able to walk." They just want them to walk, right, because that's kind of a first big milestone for little kids. Once our kids kind of master that milestone, then it's communication, right, because in a typical child development, the next phase would be first words and babbling. Paula Evans: So, no matter where you are on this journey, my goal, my definition of success is that we're going to improve the life of every individual with Angelman Syndrome, regardless of their age, regardless of their genotype. I happen to speak to a dad today of a 39 year old with Angelman. We were just chatting back and forth about how clever our kids are and how smart they are and their memories and how they remember everything, and things that you don't want them to remember, they remember. You just want them to be able to make their own choices when you're no longer here, to make those choices for them and to know that when ... as a parent, when you leave this planet and you leave your child that they're able to advocate for themselves to make their own choices in life. Paula Evans: I want my daughter to decide where she wants to live and who she wants to live with and what she wants to do once she's done with school and what are her interests and how does she want to explore those and just that autonomy and just to be able to advocate for themselves and I think a lot of that revolves around improved communication. My goals are kind of pie in the sky, I want it all. I want all of these children to live a less challenged life and whatever that means or where that child is in their own particular journey, it's just reducing the challenges they face to achieve their highest potential and their highest level of happiness and contentment with life. Paula Evans: I mean, what do you want for ... every parent wants their child right, to just be happy and follow their dreams and if we can, therapeutically help individuals with Angelman, achieve those same goals then in my opinion, will have been successful. Jessica: Paula, thank you so much for your time. This is incredibly inspiring and we'll of course link the FAST foundation on our website as well, so that we can help with donations or whatever you would need in that way also, but it's incredibly inspiring. Paula Evans: I want to say one more thing. If you have an audience of parents that have received a diagnosis for their own child of a rare disease and they feel helpless, and they don't know what to do, you can change things. You have the power to change things and whether it's something small for your child or something big, you have that power, we're often left so powerless as parents in the face of a rare disease diagnosis. I started small, I made changes at my daughter's school for more inclusiveness and then I just went bigger and bigger and bigger. I couldn't have done this without a group of other parents. Paula Evans: Don't feel that you can't change your child's world because you can. You really can. You can change the future. You can change the present, you can do it and sometimes it's just jumping in and saying I have no experience in rare disease, I have no experience in science or genetics or biology but I'm going to hook up with people and I'm just going to do what I can to change the outlook that I was given. I'm just going to do what I can and that's very empowering because when I started this organization, like you noted, I didn't have a background in science and genetics and all of that. Paula Evans: I said, "You know what, I know I can raise money and I can help fund research that will move all of this forward. That's what I can do," and that's what I did. The biggest joke in my foundation, as I always say, I'm just a housewife from Darien, Illinois. If I could do this, anyone can. I speak to a lot of parents in the rare disease community because of my work with genetics and trying to mentor them on how to get to the next step and it could seem really daunting, but I'm telling you, you can do it. You can make a huge difference. Once you kind of wrap your hands around the diagnosis, and you feel like you're in a good place, and you want to do more, just do it. That's my advice. Just do it. Paula Evans: Just take that leap of faith that you're going to make a difference and go out and make that difference. Jessica: That's such a good message because there's so many times where people feel so lost and the doors are closing and knowing that that door can open at any point is really helpful. Paula Evans: Dealing with, they're not qualified, right? I think that's the biggest takeaway. As a parent, you're like, "Well, I don't know anything about science and research and genetics and I'm not qualified to do anything," but you can. Everybody has the ability to do something. You can do something. You can make a difference and it's empowering and you'll find people out there that are very like minded in the same position and you help each other and it's one foot in front of the other and hopefully you get to a place where we are where we're ready to turn on the silent gene and replace the missing gene and we're ready for that. It didn't happen overnight but it happened and it was parents that drove this. Paula Evans: It was parents that made a difference and no one is going to work harder at this than a parent whose child's future is on the line. My advice to parents all day long is believe in your child, set the bar high, don't always listen to the doctors. They may not know what they're talking about, when they tell you all the things your child isn't going to do, and then, when you feel like you're in a good place and you want to jump in and say, "I want to make a bigger difference," just do it. Just do it. You can't do it incorrectly. There's always a way that you can make a difference. Jessica: Thank you, Paula. We would like to thank our guests one more for their time and commitment to Angelman Syndrome. We all find ourselves with a small bit of information that only leaves us wondering, "Okay, what now? So, what now?" We know that hearing from these experts is only the beginning for you. That's why we've taken the information here and added additional resources, explanations, links and references for you in a downloadable guide on Angelman Syndrome. You can get your free copy of that guide by going to raredisease.com/angelman. There, you can download a recap of this episode that links the key points as well as several links and resources for you to further explore. Jessica: Finally, if you need to speak with someone directly about Angelman Syndrome or your personal situation, we're here to help. Visit raredisease.com/help to get in touch. We're standing by. This is Rare Disease Connection, a production of Aspect Health and raredisease.com.

Clinical Trials

Study on the Brain Network of Angelman Syndrome

Fudan University

Learn More on ClinicalTrails.gov

Angelman Syndrome Natural History Study

Boston Children's Hospital

Learn More on ClinicalTrails.gov

Minocycline in the Treatment of Angelman Syndrome

University of South Florida

Learn More on ClinicalTrails.gov

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