Get to Know ASXL Rare Research Endowment (ARRE) Foundation

About ASXL-related disorders

ASXL-related disorders are ultra-rare neurodevelopmental disorders typically caused by a de novo change to one of the three ASXL genes. The ASXL genes are part of the epigenetic system, and they control the opening and closing of chromatin (tightly wound structures of DNA) so DNA can be “read” at the proper time in human development.

Bohring-Opitz Syndrome, caused by truncating variants in the ASXL1 gene, has been clinically described since 1999. The gene was identified in 2011. Shashi-Pena Syndrome was identified as a unique syndrome linked to truncating variants in ASXL2 in 2016. Bainbridge-Ropers Syndrome was identified as a unique syndrome linked to variants in ASXL3 in 2013. Whole exome or genome sequencing is the most common way for these disorders to be diagnosed, though they are being added to more specific testing panels as the disorders are better described in the medical literature. We estimate that there are about 500 people who are currently diagnosed worldwide with ASXL-related disorders with many more living undiagnosed due to lack of access to genetic testing. Shashi-Pena Syndrome is the least prevalent of the ASXL disorders with only about 50 people with a known diagnosis. We estimate there are approximately 200-250 individuals diagnosed with Bohring-Opitz Syndrome, and approximately 300 people diagnosed with Bainbridge-Ropers Syndrome.

ASXL Clinical Features

The three ASXL syndromes have overlapping characteristics on a wide spectrum of severity that commonly includes developmental delay, intellectual disability, feeding

difficulties/failure to thrive, severe constipation, orthopedic complications, seizures, sleep disturbances, and challenging behaviors, including self-injury. While research interest in ASXL-related

disorders is growing rapidly with support from the ARRE Foundation there remains little understanding of the natural history or mechanisms of disease. Additionally, most clinical providers only see one or two patients due to the rarity of these disorders and there are no known treatments or standards of care. The variability and range of the spectrum of symptoms is not well documented and poses additional challenges for research into these conditions. With poorly documented natural history and a known patient population that is primarily still in childhood, doctors and families have limited knowledge of what is coming next for their children other than what parents learn from each other through online support groups. The only treatments are to manage symptoms as they arise and there is no known therapeutic pathway.

Get to Know ARRE Foundation

The ASXL Rare Research Endowment (ARRE) Foundation, is a patient advocacy organization that was founded by parents of children with ASXL-related disorders in 2018 to support research that focuses on improving the quality of life for individuals with ASXL-related disorders. Led by a Board of Directors that includes five parents and with hands-on support from a core team of additional parent/family volunteers, the ARRE Foundation is focused on two-part mission: i) to build a research community that can advance the limited understanding of the ASXL genes, their associated disorders, and develop standards of care and ii) to support families with educational resources that help them manage their loved one’s complex care. The ARRE Foundation has one full-time staff person. The ARRE Foundation has funded five research grants, provided funding for a registry and biobank for ASXL-related disorders at UCLA, hosts the annual ASXL Research Symposium and biennial ASXL Family Conference, and developed resource library for families. We are building a network of researchers and healthcare professionals who are interested in studying and treating ASXL-related disorders and have helped grow that group from 10 researchers in 2018 to over 70 in 2023. We also support families with educational programs and resources that provide best practices for care management of their loved one.

I am Especially Proud of...

When the organization first started there were not many researchers interested in the ASXL genes and even fewer that were looking into the germ cell mutations that cause our syndromes. Over the years we have increased interest by funding grants, organizing scientific conferences, inviting new researchers, introducing the academics to the patients that their work affects, reaching out to scientists and doctors with adjacent interests, creating videos to help them understand patient urgency, and organizing virtual clinical and basic science research roundtables. Through these efforts, we have increased our pool of interested researchers from 10 to 70. These actions combined with innumerable smaller efforts have had the overall effect of having an increasing number of people thinking more deeply about our syndromes. They are running more trials (some of which have been funded outside our group), looking closer at possible clinical features we do not yet fully understand, and working together to create the missing research tools to help drive research forward.

We are optimistic that in the coming days we can build the network both broader and deeper, creating the constructive collaboration needed to find answers that will directly impact the lives of the patients living with these syndromes every day.

Excited to REN Because...

We are strong believers in collaboration and mentoring. We hope to learn from others, share our strengths and move along this path together. Advances in the treatment of epilepsy- finding safer options, more effective options, and creating a better understanding of what we have- is something we look forward to being a part of.

My Journey and Motivation...

When Isabelle was born, being thrown into a world of monitors, oxygen, feeding difficulties and missed milestones was hard. Then, right when we thought we were getting the hang of

things, she began to experience serious grand mal seizures. The seizures have created heartache, anxiety, medical PTSD, regression of some of the very hard-earned skills she had developed, and even broken bones that have permanently reshaped her femurs. Just when we think we have them under control, something happens, and they come back with a vengeance. Working together with other patients and families that are facing similar difficulties has led to some progress and a reduction in seizures. In addition, through being a part of the foundation, we have created relationships with people that understand our situation and developed a sense of belonging that comes from having support even through tough times.

By: Amanda Johnson, Executive director

Julie Lopez, Parent to ASXL1 daughter- board member