Tag Archive for: Angelman syndrome

colorful strands of DNA

Paving the way to activate a single gene in Angelman syndrome

colorful strands of DNA

Angelman syndrome (AS) is a rare disorder that causes neurodevelopmental issues such as intellectual disability, impaired speech and motor skills, epilepsy and sleep disruptions. This single gene disorder is caused by mutations or deletions in the maternal copy of the UBE3A gene.

Angelman syndrome (AS) is a rare disorder that causes neurodevelopmental issues such as intellectual disability, impaired speech and motor skills, epilepsy and sleep disruptions. This single gene disorder is caused by mutations or deletions in the maternal copy of the UBE3A gene. To date, there is no treatment for AS.

It is easier to treat this syndrome when the disrupted gene is present but repressed. If experts can figure out how to activate it in clinical trials, they believe patients could receive a treatment that tackles the root of the problem. Children’s National Hospital experts support this vision and the AS community by helping establish appropriate biomarkers for current and future clinical trials.

While the field is trying to figure out the best scientific method to quantify progress in clinical trials for AS, the Sidorov Laboratory found that overnight sleep testing is not necessary for detecting Angelman syndrome electroencephalography (EEG) biomarkers, according to the study published in Autism Research. The data further suggests that while sleep EEGs do not provide additional benefit for detecting delta EEG rhythms, sleep itself represents a valuable AS biomarker.

What this means

“It is encouraging to see that wake EEGs are sufficient, and perhaps ideal, for detecting delta waves in a clinical trial setting,” said Michael S. Sidorov, Ph.D., principal investigator with the Center for Neuroscience Research at Children’s National. “With this biomarker, researchers can measure how AS severity changes in children over the course of a clinical trial. This enables trials to test the efficacy of exciting new treatments.”

The hold-up in the field

In the past decade, the research community has focused on activating the dormant paternal copy of the UBE3A gene in pre-clinical models. Presently, there are three ongoing phase I clinical trials for AS in the U.S. These trials use antisense oligonucleotides (ASOs), which can modify gene expression to treat genetic disorders, and have been FDA approved for other disorders. These new compounds specifically target the gene activation to unleash the existing copy of UBE3A. However, there is a need for better and more accurate ways to know if the drug is working or not. The field has not reached a consensus yet on the appropriate biomarkers that can correctly measure success.

There are also challenges associated with performing overnight EEG studies in children with AS due to the severe sleeping problems, difficulty in tolerating the process and sample recruitment.

The patient benefit

Elizabeth R. Jalazo, M.D., assistant professor of pediatrics at the University of North Carolina in Chapel Hill, chief medical officer at the Angelman Syndrome Foundation, is also the parent of a child with Angelman syndrome. Dr. Jalazo, who was not part of the study, mentioned that her experience with a daughter with a rare disorder had brought challenges to their family over the last seven years. But, alas, she said the joy Evelyn has brought to their lives far outweighs the day-to-day challenges of special needs parenting.

“As a parent I’m thrilled that we can potentially capture as much meaningful EEG data in a short daytime EEG rather than subjecting our children to overnight EEG studies,” said Dr. Jalazo. “As a clinician this is equally exciting from a clinical trial feasibility standpoint.”

One of the greatest challenges facing Angelman syndrome and other neurodevelopmental disorder therapeutic development is the lack of appropriate endpoints to assess the efficacy of our interventions.

“I worry very much that without objective measures specific to Angelman syndrome, potentially beneficial therapeutics may fail to meet the mark and ultimately not reach the community,” she added.

The scientific community has transitioned from the hope of clinical trials to lessen those day-to-day challenges to witnessing first-in-human trials of potentially transformative therapeutics in just the last few years.

“It is a biomarker work like this that is critical as we delve into the exciting landscape of clinical trial design and advance therapeutics for Angelman syndrome,” said Dr. Jalazo.

You can read the full study “Evaluation of electroencephalography biomarkers for Angelman syndrome during overnight sleep” in Autism Research.

 

DNA Molecule

Using genomics to solve a 20-year case study

DNA Molecule

“The advent of different technologies and techniques over the years allowed pieces of her diagnosis to be made – and then brought all together,” says Andrew Dauber, M.D., MMSc.

After 20 years, a patient’s family received an answer to a decades-long genetic mystery. Their daughter had two rare disorders, Angelman syndrome and P450scc deficiency, which was detected after researchers found out she had uniparental disomy, two copies of chromosome 15 from one parent and none from another.

The research paper, entitled “Adrenal Insufficiency, Sex Reversal and Angelman Syndrome due to Uniparental Disomy Unmasking a Mutation in CYP11A1,” was published on March 22, 2018, and recognized as the best novel insight paper published by Hormone Research in Paediatrics in 2018, announced at the Pediatric Endocrine Society’s Annual Meeting in Baltimore on Saturday, April 27, 2019.

By using a variety of genetic tools, including whole-exome sequencing, microarray analyses and in-vitro modeling for gene splicing, the researchers were able to confirm this patient had uniparental disomy, a recessive genetic condition. They learned that after she received two impaired copies of chromosome 15 from her father, this woman developed a hormonal problem that led to adrenal insufficiency and sex reversal. This explained why she physically presented as a female, despite having testes and a Y-chromosome. It also explained other symptoms, including developmental delays and seizures.

“It’s a unique conglomeration of symptoms, manifested by the combination of these two very rare disorders,” says Andrew Dauber, M.D., MMSc., the division chief of endocrinology at Children’s National Health System and a guiding research author of this study. “The advent of different technologies and techniques over the years allowed pieces of her diagnosis to be made – and then brought together, commencing a 20-year diagnostic odyssey.”

For example, each of the conditions this patient has is known and rare: Angelman syndrome affects about one in 10 to 20,000 people in the U.S. Typical symptoms include those observed in this patient: delayed development, intellectual disability, speech impairment and seizures. Side-chain cleavage disorder, which leads to adrenal disorders and sex reversal, is also very rare. In 2005 the chances of survival with a P450scc defect were slim, but since then more than 28 infants have been diagnosed with this gene deficiency, which is required to convert cholesterol to pregnenolone, a hormone in the adrenal gland.

Dr. Dauber notes the chances of this occurring again are highly unlikely. The odds here are one in a gazillion. In this case, one disorder unmasked another, leaving researchers with new insights into the methodology for unraveling ultra-rare genetic disorders or for more common rare conditions.

“Knowing about the gene that caused the adrenal insufficiency and understanding this etiology won’t change medical care for this patient, but it will change the way researchers think about genetic detective work and about combining different technologies,” says Dr. Dauber. “We know that genetic disorders can be complex presentations of different disorders combined. This patient didn’t have one disorder, but three.”

When asked about the significance of the award, Dr. Dauber notes that, “It’s not that other people haven’t recognized this concept before, but this case is a striking example of it. Different technologies will unveil different types of genetic changes, which is why you have to use the right technology or the right technologies in the right combination to piece together the whole picture.”

Ahlee Kim, M.D., the lead study author and a clinical research fellow at Cincinnati Children’s Hospital Medical Center, will receive the award and the honorarium.

Additional study authors include Masanobu Fujimoto, Ph.D., Vivian Hwa, Ph.D., and Philippe Backeljauw, M.D., from Cincinnati Children’s Hospital.

The research was supported by grant K23HD07335, awarded to Dr. Dauber, from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Additional funding included grant 1UL1TR001425 from the NIH’s National Center for Advancing Translational Sciences.