This is a story about fixing an impossible problem in an unexpected way.
Kasha Morris is a retired teacher that co-founded the TANGO2 Research Foundation with her husband Mike in 2018 after a fifteen-year diagnostic journey for their son Ryan. Faced with the reality of a life-limiting ultra rare genetic condition they got to work to help their son. Although TANGO2 was newly discovered, their search would take them back twenty years to uncover some answers in an unexpected place.
Transcript
On Halloween night 20 years ago, my husband, Mike, and our five‑year‑old daughter, Caitlin, were out trick‑or‑treating and having fun in the neighborhood, while I was home with our two‑year‑old son, Ryan, and feeling sorry for myself.
Ryan was dressed as Bob the Builder whose motto is, "Can we fix it? Yes, we can." But his costume was really only for a photo‑op, because, once again, Ryan was not feeling well and I didn't know how to help him.
His first year, everything was great. He was a happy, healthy little boy, sitting, saying a few words, getting ready to take his first steps. But on the day of his first birthday, he had this strange episode where he was crawling crooked like a crab. I remember saying to myself, "That's strange."
But after a nap, I didn't see it again. Until about six weeks later when he couldn't sit without falling and his neck was tilted to the side and he didn't have the strength to lift it. This time I was really worried, so I called his pediatrician. But when you tell a pediatrician that your one‑year‑old is tippy and off balance, they're not too concerned. Most one‑year‑olds are tippy and off balance.
In January 2003, Ryan had an episode where his muscles were so weak he could not sit, he could not hold his head up, he couldn't even open his fingers to hold a toy. I knew something was really wrong. Personal cell phones were not a thing yet, but I did have a digital camera that I had just gotten for Christmas, so I recorded Ryan having those symptoms and then I insisted that the pediatrician see him that day.
When he saw that video, he sent us to the emergency room. That was one of many emergency room visits that year. We went to multiple hospitals, saw dozens of doctors. Ryan had hundreds of tests and everything kept coming back normal, even though it was clear things were far from normal. Ryan's health was declining and he was losing the skills he once had.
When I'm under stress and want to have some control over a situation, I get organized. I'm the kind of person who loves sticky notes and making lists in a fresh new notebook and a pen that writes really well, or a binder where the metal rings line up perfectly.
At this time, medical records were not digital. So, in order to send test results and visit summaries to a new doctor, you had to send paper copies in advance. This system does not work well when you're seeing multiple doctors in a short period of time.
So, I got myself a big, blue binder and a package of clear plastic sleeves and I started to collect every test result and every visit summary. That year, I watched as that binder got fatter and fatter and I also watched as Ryan's health and quality of life declined.
Since his symptoms were episodic, sometimes they would be gone by the time we entered a doctor's office. So, I also started keeping track of his days on a calendar that I kept in this binder. I would mark each day as being a red, yellow, or green day.
Green days were great. No episodes. He was laughing, smiling, playing. A yellow day was a mix of episodes but some good moments too. And a red day was much like that day of Halloween 2003 when there was nothing I could do but hold my little ‘Bob the Builder’ in my arms and wonder, “Can we fix this? I don't know if we can.” We had already tried multiple therapies and specialists and medications.
And on this Halloween night, just for the sake of having something new to try, I gave Ryan a Flintstone vitamin for the first time. The next day is a green day. The day after that was a green day. And the day after that was a green day. Was it the Flintstone vitamins? Can we fix this?
Ryan started to gain back some of the skills he had lost. At two‑and‑a‑half, he started walking. At five, he could talk in simple sentences. He never did gain back or bridge the gap that had developed between him and his peers, but his green days were plentiful. He was able to play basketball on the driveway with his dad and learned to ride a bike and was able to go trick‑or‑treating in the neighborhood in the years to come.
Now, don't get me wrong. Ryan wasn't cured. He still had episodes that would pop up from time to time with no rhyme or reason. He would have trouble balancing and extreme fatigue or garbled speech. They would affect his quality of life and we would go back to the doctors to see if there was anything new we could try.
And every time we went to a doctor, Mike would mention the Flintstone vitamins and how it seemed to help Ryan the very next day. And each time, it was dismissed as being insignificant. He mentioned it so many times that it got to the point that I would roll my eyes and be embarrassed when he brought it up.
In middle school, when Ryan hit puberty, he had an uptick in both the frequency and the severity of these symptoms. So his neurologist suggested genetic testing with whole exome sequencing. And it took more than a year for us to get an appointment, get blood drawn, have the tests done and get an appointment for a follow‑up visit.
But, finally, in July of 2017, we sat in the geneticist's exam room. I had my big binder and a fresh sheet of paper and a pencil ready to take notes. Mike and I, when we had met this geneticist a few months earlier, we had kind of nicknamed her the Tasmanian Devil, because of the way she rushed into the room, talked a mile a minute, answered your questions quickly and zoomed out of the room before you even knew what happened.
But when she walked in this day, I knew something was different. She walked in slowly and set a box of tissues down on the table. Ryan had a diagnosis. She told us five letters and a number. TANGO2. It's an acronym for Transport and Golgi Organization.
She had one sheet of paper with one paragraph on it explaining it. Ryan had Tango2‑related metabolic encephalopathy and arrhythmia. What?
She went on to explain that Ryan was at risk for metabolic crisis, muscle weakness called rhabdomyolysis and life‑threatening arrhythmias. It's also neurodegenerative, getting worse over time. It had only been discovered in 2016, so it was a new genetic condition with very little known about it.
She did say that it was predicted that about one in a million people were affected, but she had seen one other patient with it and that child did not survive. There were no treatments, no cure and the prognosis was poor.
My pencil was still. I did not take any notes. I don't even think I asked any questions.
After what seemed like just a few minutes, we left with that one sheet of paper with one paragraph and with doctor's appointment scheduled with two cardiologists, a neurologist, an orthopedist, a nutritionist.
For 15 years we had searched for a diagnosis and, now, we only had more questions and no answers. Can we fix this? We didn't know if we could.
We did what most people do when you want to find out more information about something. We Googled it. And there were two other articles about TANGO2 from 2016 when it was first discovered. With words like ‘encephalopathy’ and ‘rhabdomyolysis’, we didn't know what we were reading. We knew, though, that for 15 years we had worried about Ryan, but now we were afraid for Ryan. We wanted to know more.
A couple months later, we found a Facebook group called TANGO2 Disease, and there we found nine other families with 12 other kids that had TANGO2. It is indescribable what it's like to find other families that know exactly what you've been through and what you're still going through.
I read and reread every post. I wanted to know everything we knew. What experiences had they had? What were their symptoms? What had worked? What had not worked? What did they try? What medications had they used? Where did they live? How old were they?
I started taking notes and keeping them in a spreadsheet. Parents were literally the world experts on this disease. No one knew more about it. I wanted to gather and collect everything we knew.
We found out that the oldest living with this disease was 18, and Ryan was 16. A clock was ticking for him, but we just didn't know how fast.
So, when Mike and I wondered, "Can we fix this?", we didn't know if we could, but we knew we had to try.
We decided to start the TANGO2 Research Foundation in 2018. We gathered a few other families from the Facebook group and we got to work. I remember saying to him, "We don't know how to run a research foundation."
And he said, "We'll figure it out as we go." And we did.
Like a spoke of a wheel, we started making connections to other families, doctors, scientists, researchers, anyone who was connected to or interested in TANGO2. And my spreadsheet of notes grew. It would eventually become the basis for a natural history study of the disease.
Those 12 families joined the natural history study and answered over a hundred questions about their experience with TANGO2. We were looking for patterns. Why did some kids have metabolic crisis and others like Ryan didn't? Why did some kids survive and others didn't?
As this researcher asked us all questions, once again, Mike mentioned the Flintstone vitamins and how Ryan seemed to improve the very next day. This time, someone listened.
The researcher asked the other families about vitamins. Did their child take any? If so, which ones? When?
A year later, at our first TANGO2 family conference, we started to hear of some early indications coming from that natural history study. Kids who were not having a metabolic crisis were on vitamins. She said that it was the mention of Flintstone vitamins that led her to investigate this. No eye rolling now.
Fast forward to 2023. We now have about a hundred patients enrolled in the natural history study, and the evidence is only stronger. In two recent studies coming from the natural history study, not only are they finding that vitamins, particularly B vitamins, prevent metabolic crisis, but they also improve neurological outcomes.
In a study of two unrelated sibling pairs, while the older had multiple crises and were very disabled, the younger siblings had little to no symptoms at all, even at the ages of 8 and 13. Unlike their older siblings, the younger ones had started taking vitamins in infancy.
In an independent basic science research project, B5 rescued the symptoms in TANGO2 fruit flies. And in TANGO2 heart cells, B9 corrected the arrhythmias.
Ryan is now 22 years old. He's out of puberty, taking his vitamins regularly, and he has had the best three years of his life. Zero episodes and more energy than ever. Every day is a green day.
We still have more work that needs to be done. We don't yet know the function of TANGO2. We don't know why the B vitamins help. That will come. For now, we celebrate that lives are being saved and the quality of life is improving for kids like Ryan around the world.
And now when I ask myself, "Can we fix it?" I say, "Yes, we can," and, “Yabba‑Dabba‑Doo!”