Thursday, November 23, 2017

What we learned at the San Diego family conference

On November 2, Patrick, Aubrey, Emelyn and I boarded a plane to San Diego where we spent four days with nearly 30 other DDX3X families. There are two reasons we make the trip to these family weekends. First, we have the chance to spend time with families who get what it’s like to have a daughter with DDX3X. They understand the struggles and the joys. We learn from them and they learn from us. We share a powerful connection and it’s important to nurture that bond. Secondly, we get to hear from medical professionals who are actively researching the DDX3X mutations. At the bottom of this post, I’m including bios for the medical professionals who were in attendance at our San Diego family day.

Sisters enjoying the world at 25,000 feet.
The first three days were filled with fun family activities…Sea World, music therapy, swimming, and more. 




The final day was the family conference. (Check out this article from the San Diego Tribune about our DDX3X family day.) It was packed with so much great information from the medical team that it’s taken me nearly two weeks to distill it all down into the following key points:

DDX3X Foundation dollars are already advancing our understanding of the DDX3X gene…

Pediatric Neurologist Elliott Sherr, MD, PhD at the University of California, San Francisco is heading up research to better understand the function of the DDX3X gene—what does it do in its normal, non-mutated form and what happens to its function when it mutates? The funds raised are paying for the scientists who are exclusively studying DDX3X at Dr. Sherr’s lab. Additionally, the funds have enabled the creation of a mouse model. (And if you’re a science geek, then you’ll be excited to know that CRISPR technology was used to create the mouse model.)

Dr. Sherr and his research team have already made a number of significant advances in the short time they have been working on DDX3X. Nearly 70 children, including Emelyn, have enrolled in a study where we shared MRI scans, genetic information, saliva samples, and developmental data. From that information, Dr. Sherr and his team have tabulated the data and made several observations so far:

MRI scans show a small/thin corpus callosum (this is the band of nerve fibers joining the two sides of the brain), a smaller cingulum bundle (this is the nerve cell highway), and, in about a quarter of the girls, abnormally folded brain tissue known as polymicrogyria or PMG.

Emelyn does not have PMG but does have a “diffusely thin corpus callosum,” as well as a “small and deficient dorsal cingulum bundle” (dorsal means back) and “missing ventral cingulum bundle” (ventral means front). She also has a small, underdeveloped hippocampus.

The type and location of the mutation on the DDX3X gene appear to correlate to the individual’s level of function. There are four types of mutations that can happen: missense, nonsense, frameshift, and splicing. These mutation types can happen at various places on the DDX3X gene. It appears that about 90% of mutations happen inside the helicase, which is on the last two-thirds of the gene.

Emelyn’s mutation is a frameshift mutation occurring at Isoleucine 214, changing what should have been an amino acid to a threonine residue, creating a premature stop codon at position 7 of the new reading frame, i.e. p. Ile214ThrfsX7. What does all that mean? It means this “spelling error” causes a loss of normal protein function. From what I can tell (keep in mind my last biology class was in tenth grade), Emelyn’s mutation, at Isoleucine 214, happens about a third of the way into the sequence causing the protein to be more altered than someone with a mutation further down the sequence.

Why, oh why, didn't I pay better attention in high school biology.
Additionally, Dr. Sherr and his team are studying both normal DDX3X genes and mutated DDX3X genes in a test tube model in order to better understand how a normal DDX3X protein functions. So far they have learned that a normal DDX3X gene unwinds quickly, whereas a mutated DDX3X gene unwinds at a slower pace. In other words, the mutated DDX3X gene does not function at 100% like a normal DDX3X gene. When the time comes, the model used to study function can be adapted to use drug screening technology to test hundreds or even thousands of candidate drugs in a single day.

Dr. Sherr is confident that his team can dramatically accelerate their efforts, continue to make significant advances, and move closer to a viable treatment for girls with DDX3X. However, in order to keep him and his team going, we have to keep funding coming.

The next step is to create stem cell lines to better understand how normal DDX3X functions to maintain cell health. Then, develop an understanding of how specific mutations in DDX3X affect how that cell functions. Emelyn and I had blood drawn in California for this process, as did a few other mother/daughter pairs. Stem cell lines will be made from our blood to advance understanding of both normal DDX3X and mutated DDX3X.

Additionally, a mouse model is already in the initial stages as mentioned above. The model will be genetically engineered to address two key biological questions:
  • Can the mouse model (with the same mutations as our girls) show similar physiological and cognitive challenges as girls with a DDX3X mutation?
  • If a mouse is born with a DDX3X mutation, can the team genetically engineer the mouse after birth to a mouse without a DDX3X mutation? This will help the team understand whether fixing the biology of DDX3X after birth can lead to a better or even normal developmental outcome.
Not only are our DDX3X girls rare, so are DDX3X parents…

The DDX3X Foundation was created in 2016 by two DDX3X moms, Beth and Liz. They are working moms who have taken on the role of co-presidents of the DDX3X Foundation as a volunteer gig. Beth’s daughter was the first person diagnosed with DDX3X. She is our connection to Karlla (see below). Liz’s daughter was also diagnosed shortly after the discovery of DDX3X. She is our connection to Dr. Sherr. These two moms, plus a team of other moms and dads (including our family), are fully vested in raising awareness for DDX3X and continuing to fund the research being led by Dr. Sherr’s team.

DDX3X moms and dads united with researchers to help
our gives live the richest lives possible.
Over the past year, our DDX3X family group has fundraised to provide Dr. Sherr and his team approximately $115,000. We need an additional $60,000 before December 31, 2017, to keep devoted scientists working on DDX3X. In 2018, we’ll need another $120,000. Dr. Sherr and his team are working to publish a peer-reviewed paper detailing what he and his team have learned about DDX3X so far. The hope is that the paper, which is about a year from publication, will garner attention from the National Institute of Health (NIH) to help accelerate our funding stream because advancing this to the level of a viable treatment will require $1 to $2 million dollars a year in the very near future. Until then, it’s up to the DDX3X parents to reach out to our networks to raise the funds.

You can help us get there…

Will you consider a donation to the DDX3X Foundation to advance research? You won’t just be helping Emelyn, you’ll be helping the approximately 160 diagnosed girls, plus the nearly 15,000 estimated undiagnosed girls who likely have DDX3X. And cracking the code on DDX3X will open doors to treating other rare diseases as well. The impact of this research is far-reaching. Contributions are coordinated through the Delaware Community Foundation and are tax-deductible. You can make a donation online at delcf.org/donations/ddx3x or you can mail a check, made payable to the Delaware Community Foundation, to PO Box 1636, Wilmington, DE 19899 (don't forget to put DDX3X Fund in the memo line).

Dr. Sherr was humble in his gratitude for our support,
both financially and through our participation in the ongoing
DDX3X study.
Thank you for your support along our journey…

I’m grateful you just spent the last 15 minutes reading this mammoth post that likely taxed your brain. But more than that, I’m grateful you love and care for our sweet Emelyn. It means more than you will ever know to have you on our journey.

I can't explain it, but every time I fly I crave Chinese food.
Immediately after the conference we headed to the airport
and had Chinese, of course. When I opened Emelyn's
fortune cookie it was empty. I'm still philosophizing about
the meaning of her empty cookie, but it gave me tingles
about her future.


Dr. Sherr and his team:
Elliott Sherr, MD, PhD is a professor in neurology and pediatrics at the Institute of Human Genetics and the Weill Institute of Neurosciences at the University of California, San Francisco (UCSF). He co-directs the Comprehensive Center for Brain Development at UCSF. In this capacity, he cares for children with neurodevelopmental disorders, including autism, intellectual disability, and epilepsy. In addition, he directs the Brain Development Research Program, a group that studies the genetics and biology of autism, and other disorders of neurodevelopment. The lab uses gene discovery to understand how disruption in brain development may lead to cognitive and behavioral impairments and they leverage these models as a basis for developing novel therapeutics. Dr. Sherr’s specific areas of interest include the development of proteomic biomarkers to enable early detection and treatment for autism, and the study of a newly recognized common cause of developmental delay in girls, the gene DDX3X. His lab has directed a large multisite brain imaging study that is helping to connect changes in brain structure and function to the clinical deficits observed in autism (Simons VIP). Dr. Sherr is also a member of a large epilepsy genetics consortium (Epi4k), for which he led a team that advanced our understanding of the genetic causes of severe childhood epilepsies. For his research, Dr. Sherr was the 2006 recipient of the Philip R. Dodge Young Investigator Award from the Child Neurology Society.

Dr. Sherr is a native of California and completed his undergraduate degree in philosophy and biology at Stanford University. He obtained his M.D. and Ph.D. at Columbia University in New York and completed his clinical training in pediatrics and neurology at UCSF. He lives in San Francisco with his wife, a biotechnology finance executive, and their three children.

On this particular trip our family had the opportunity to sit down with Dr. Sherr as well. He met with nearly every family there on Saturday one at a time. We were his first appointment at 9 am and ten hours later he was still meeting with families. Beyond the MD and the PhD, I have to tell you, he is an incredibly kind and personable man. He clearly cares deeply about each and every one of our girls. We were thrilled to meet with him and ask him some of our specific “Emelyn” questions

Thanks to our funding, Dr. Sherr has the following wicked smart individuals working with him on the DDX3X mutation:

Bethany Johnson-Kerner, MD, PhD is an Alpha Omega Alpha honors graduate from the College of Physicians and Surgeons of Columbia University, where she also completed her Ph.D. in neuroscience. She is currently completing her clinical training in pediatrics and neurology at UCSF. For her Ph.D. thesis project at Columbia, she generated induced pluripotent stem cells (IPS cells) from patients who had a disorder of peripheral nerves that control muscle function, called giant axonal neuropathy. She used advanced laboratory techniques to make those stem cells into nerve cells, studying both healthy cells and cells from patients. She also showed that she could restore normal function to patient-derived nerve cells by putting back the normal gene.
Dr. Johnson-Kerner will be creating stem cell lines to better understand how normal DDX3X functions to maintain cell health, then she will study how specific mutations in DDX3X affect how that cell functions.

Ruiji Jiang, MD, PhD is a dual doctoral student (physician-scientist) completing his thesis work in Dr. Sherr’s lab. Dr. Jiang will be working with Dr. Li to develop a method to screen for drugs that could repair the function of DDX3X in cultured cells.

Lindsey Suit, a Berkeley undergraduate, will be completing her honors thesis on the spectrum of clinical challenges faced by girls with mutations in DDX3X.

Brieana Fregeau is the research coordinator for the Department of Neurology at UCSF and Brain Development Research Program. I don’t have a full bio on Brieana, but I get the feeling she’s the grease that keeps this super smart team running smoothly.

There is an extra special, and also wicked smart, member of our DDX3X tribe who is vested in each and every one of our girls:

Karlla W. Brigatti, MS LCGC joined the Clinic for Special Children as its first genetic counselor in 2014, bringing extensive experience in clinical genetics and research from across the lifespan. She earned her Bachelor of Science in Cell and Molecular Biology from the University of Pittsburgh in 1994 magna cum laude and her Master of Science in Human Genetics from Sarah Lawrence College in 1998. Prior to joining the Clinic for Special Children, she was the senior coordinator of the FASTER Trial at Columbia University, the largest NIH-funded trial in Obstetrics and Gynecology to date, and later the founding coordinator for the Center for Prenatal Pediatrics at Columbia University, introducing multidisciplinary and state-of-the-art innovation to the care of highly complex pregnancies before and after delivery. After moving to the Lancaster area in 2006, she served as senior genetic counselor in clinical genetics, pediatric oncology, and neurology at the Children’s Hospital of Philadelphia (CHOP), working with families from across the globe for over five years in the Friedreich Ataxia Center of Excellence at CHOP on various natural history and clinical drug trials for the condition. She has authored over 20 lay and scientific publications, mentored undergraduate, graduate, and medical students, and served on the Human Genetics Faculty at Sarah Lawrence College. She is currently completing a one-year program in Rare Disease Clinical Research Training through the National Institutes of Health. In addition, she currently serves on the Board of the CROWN Foundation, promoting research in women’s and newborn health. Her research interests include gene discovery, implementation of personalized medicine, and rare disease advocacy. She is certified by the American Board of Medical Genetics and is a member of the National Society of Genetic Counselors. Karlla feels this experience has enriched and prepared her for her work at the Clinic for Special Children. She promotes the partnership between clinical care and innovative research to improve the lives of those with genetic conditions. That trust and mutual investment with the community is a key element to the Clinic’s longtime success in advancing Genomic Medicine. (I might add, this also makes Karlla an incredibly valuable member of our DDX3X tribe!)

In order to be, as Karlla put it, “clinical trial ready” Nicholas Bascou and Deanna Steele from the Program for the Study of Neurodevelopment in Rare Disorders (NDRD) at Children’s Hospital of Pittsburgh of UPMC were also in attendance on behalf of Dr. Escolar:

Maria Escolar, MD, MS is a graduate of the Escuela Colombiana de Medicina. She has a Master of Science in Human Nutrition from Columbia University and completed a residency in general pediatrics and fellowship in child development and behavior at Cornell University Medical Center in 1995. Dr. Escolar is board-certified in neurodevelopmental disabilities. She has 15 years of experience as a practicing clinician and researcher. Dr. Escolar has authored multiple original manuscripts, including two New England Journal of Medicine articles. She is nationally and internationally known for her work in neurodevelopment of children with leukodystrophies and mucopolysaccharidosis. Her research focuses on behavioral and neuroimaging outcome measurements.

NDRD was established in 2002 because of the need of help children and their families understand the overall impact of rare neurological diseases on child development. Our family is considering traveling to Children’s Hospital of Pittsburgh of UPMC to take part in a natural history study, but that’s a whole other blog post, so stay tuned.

There are other important members of the DDX3X medical team as well, but these are the folks we had the opportunity to hear from in San Diego.  

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