Ollie & Yoni's Path
When Michelle was halfway through her pregnancy with Ollie, her doctor noticed that her fluid level was measuring too high. Further testing revealed questions about a space in Ollie’s brain, and later, a poorly formed trachea, however at the time, the doctors ruled these observations at normal variations and when Ollie was born, everything appeared to be normal. We were so relieved. Still, a few months down the road, Michelle started noticing that Ollie was significantly behind other babies his age—he wasn’t sitting up, or looking around at objects the way some of her friends’ babies were.
Soon, Ollie’s pediatrician noticed that one of his eyelids was drooping more than it ought to be, so she sent him for an evaluation by an ophthalmologist. This would be the first in a long line of specialists to come, all of whom noticed various physical anomalies in Ollie, which weren’t related to one another in obvious ways. His optical nerve was smaller than normal. The midline of his brain, the corpus callosum, which divides the right from the left hemisphere, was diminished. He had developed a heart murmur, and they discovered that his aorta was misshapen. The doctors checked his endocrine system, they monitored his circulation, they checked for seizures, they checked his other organs and by 18 months old,
Ollie was seeing twelve different specialists at once. Each one of these doctors was able to note something tangibly different about Ollie’s body, some characteristic that would almost certainly affect his development, but no one was able to put all of these things together and figure out what they meant.
In an attempt to get more answers, we decided to have his DNA sequenced. That we could do this at all is truly remarkable, as the first successful sequence of human DNA was only completed in 2000, at a cost of three billion dollars (!). Ollie’s was done in a couple of months for roughly $20,000, which thankfully our health insurance covered. The sequencing found a candidate gene or the likely cause of Ollie’s issues: a mutation in the PSMC5 gene. Ollie was still the only child in the world that researchers has been able to identify with this exact mutation until Yoni and the Silverman family found us. This gene is important in the creation of a vital cellular mechanism called the proteasome, which functions as a garbage disposal within each cell in our body. Without the garbage disposal or a malfunctioning garbage disposal, damaged junk/proteins may
build up in the cells and in Ollie’s (and Yoni’s) case, the doctors and researcher are particularly concerns about the impact of this possible build-up in his brain.
It is interesting to pause at this point, to recognize how astounding this is. First of all, there are 3 billion base pairs within a DNA. Typed out, this would fill one million pages, or 200 telephone directories (see this TED talk for good comparison). The constant replication of such a large number inevitably leads to errors, and it turns out all of us have 50-100 mutations at any given time in our DNA. Usually these are just simple switches of an A to T, or a C to a G, creating the wrong amino acid. But amongst 3 billion, these few mutations don’t really matter. In Ollie’s case it appears that the mutation is quite unlucky. A specific line within this DNA code wanted the CAG codon and instead got a GAG codon. This created the amino acid arginine instead of proline. This is where I get officially out of my depth but of the 20 amino acids, those two are essentially polar opposites and can’t substitute for each other at all. So, very bad luck for Ollie.
It turns out the proteasome was discovered in 1987 by a gentleman at Harvard Medical School named Alfred Goldberg. We met with Dr. Goldberg about a year ago, and told him our story and showed him the sequencing. He found it very intellectually curious and agreed that the working hypothesis (garbage disposal) made sense and that with a continuous build-up within the cells, time is an enemy. He hypothesized that Ollie’s condition may be neurogenerative like other proteasome and protein related conditions of the brain such as Parkinson’s or Alzheimer’s disease, however, without additional research there was no way to know for sure.
Given his expertise and his lab, we asked if anybody on his team would be able to devote some time to Ollie’s issue and help guide us on a direction. He responded that he would love to focus on this problem, as it was unlike anything he had ever seen (frankly, nothing a parent really wants to hear). Dr. Goldberg said that the way new research like this usually gets done is through the sponsorship of a fellow. Large donations get all the headlines, but it was small sponsorships and donations that really pushed new research forward. He said if we were willing and able to sponsor a fellow in his lab for a year, then that fellow could focus on Ollie’s particular issue.
That is what we have decided to do, for a few reasons. One, it is hard to be given an option – regardless of how low the probability of success – to help your son and not take it. Two, the furthering of good science seems a noble goal. Three, it is very intellectually interesting to ride shotgun with these world-renowned experts.
So Michelle and I, along with Idit and Joe, are currently sponsoring this research. We’ve come to realize that we’ve only just begun what will be a very long journey to understand and possibly find an answer to help Ollie, Yoni, and others like him. Although we are committed to doing this ourselves, we recognize that others might be able to help us accelerate the effort and who may want to share the benefits of furthering science. Our current efforts are focused on sponsoring this research fund. Unlike with a lot of donations, in this case we know exactly where dollars are going, who is doing the work and what the mission is. If you want to contribute or simply stay up to date on the scientific progress, please let me know.
Michelle & Clint
Challenges, good-spirited laughs, and lots of love.
Since birth, Yoni was dubbed with many challenges and false labels. First came a trigger finger where several specialists had to ensure his middle finger could be straightened. Fatigue, lack of balance, low tone, and being nonverbal until age 4 led Yoni to being frustrated when not being able to get his point across. Two lazy eyes due to muscle weakness required muscle tightening surgery on both eyes.
Although some neurologists try to lump Yoni in the cookie-cutter autism category, we knew better. Yoni has always been an affable, sweet boy who loves others. He’s always looking to put a smile on others’ faces as well as having a good time himself. Yoni is a bright boy, putting every Marvel character and situation to memory. He also loves dogs, babies, reading, movies, and hanging with his family and connecting with friends.
We knew there had to be another answer instead of just dosing Yoni with ADHD meds. So, we performed genetic testing in 2012. At first, there were no matches of others who had the PSMC5 mutation. Then, in 2018, we did more genetic testing. But, it wasn’t until 2020, when we followed up to the genetic lab techs who led us to Dr. Sebastien Kury, the head of his genetics lab in France. Dr. Kury surprised us by showing us pictures of 19 other kids who had the similar 26S proteasome disorder, but they all had different genetic disorders than Yoni.
Luckily, there was one boy who had the same exact PSMC5 genetic mutation as Yoni: Ollie Myers. We were thrilled! Reaching out to the Myers’ family has been so comforting, reassuring and truly miraculous. We learned that the Myers family was already wrapping up the first year of their research with the pioneer in all things proteasome, Dr. Alfred Goldberg. We couldn’t believe it. If there was a dream researcher and doctor to have on this project, Dr. Goldberg is the one! Unfortunately, COVID-19 ceased the Myers’ research. But, now with both families, we are very excited to start this renewed research together to find therapies and methods to ensure Yoni and Ollie are properly treated, leading to more comfortable, enjoyable lives.
In good health,
Idit & Joe Silverman